Bradley and Daroff's Neurology in Clinical Practice, 8th, V2P2

95
Alzheimer Disease and Other Dementias

Ronald C. Peterson, Jonathan Graff-Radford
OUTLINE
Normal Aging and Mild Cognitive Impairment, 1452 Neuroimaging, 1483
Normal Aging, 1452 Genetics, 1485
Preclinical Stage of Dementia, 1453 Pathology, 1486
Mild Cognitive Impairment, 1453 Frontotemporal Dementia Treatment, 1488
Subjective Cognitive Impairment, 1455 Vascular Dementia (Vascular Cognitive Impairment), 1488
Dementia, 1455 History, 1488
Dementia Epidemiology, 1455 Diagnostic Criteria, 1489
Diagnostic Approach, 1455 Epidemiology, 1490
Alzheimer Disease, 1458 Vascular Risk Factors, 1490
Background, 1458 Subtypes, 1490
Definition of Alzheimer Disease Over Time, 1458 Clinical Presentation, 1490
Alzheimer Epidemiology, 1458 Large-Vessel Stroke, 1490
Atypical Alzheimer Disease, 1461 Cerebral Small-Vessel Disease, 1490
Neuropsychiatric Features of Alzheimer Disease Neuropsychological Testing, 1491
Dementia, 1461 Treatment, 1491
Diagnostic Criteria, 1462 Normal Pressure Hydrocephalus, 1492
Neuropsychology in Alzheimer Disease Dementia, 1463 Gait Disturbance, 1492
Biomarkers in Alzheimer Disease, 1464 Cognitive Disorder, 1492
Genetics, 1468 Urinary Incontinence, 1492
Alzheimer Pathophysiology, 1468 Assessing Comorbidities, 1492
Alzheimer Pathology, 1469 Neuroimaging, 1492
Treatment, 1471 Confirmatory Diagnostic Tests, 1493
Patient Safety, 1472 Biomarkers, 1493
Neurodegenerative Dementias Associated With Parkinsonism, 1473 Biopsy Studies, 1493
Synucleinopathies, 1473 Diagnostic Criteria, 1494
Tauopathies, 1478 Chronic Traumatic Encephalopathy/Post-Traumatic
Frontotemporal Dementias, 1480 Dementia, 1494
Nomenclature, 1480 Other Causes, 1494
Diagnostic Criteria, 1480 Autoimmune or Paraneoplastic Dementia, 1494
Frontotemporal Dementia Epidemiology, 1481 Other Non-Degenerative Dementias, 1495
Behavioral Variant Frontotemporal Dementia, 1481 Young-Onset Dementia, 1495
Hippocampal Sclerosis of Aging, 1481 Future Directions, 1496
Argyrophilic Grain Disease, 1481

NORMAL AGING AND MILD COGNITIVE include individuals who subsequently develop cognitive impairment.
IMPAIRMENT Research on normal aging using biomarkers for both Alzheimer disease
(AD) and non-AD related pathologies will hopefully improve these meth-
Normal Aging odological issues. Despite the aforementioned limitations, a brief review of
A cognitive continuum exists from normal aging through mild cognitive cognitive change with age is important.
impairment (MCI) to dementia. This continuum is better understood Before age 60, a consistent pattern of cognitive change with age
when realizing that it occurs on a background of some degree of cognitive occurs. General knowledge and vocabulary are stable or improve while
decline with aging. While the theoretical ideal is to age without cognitive problem solving, speed of processing and reasoning decline (Salthouse,
change, typically cognitive function declines over time. Research has pro- 2012).
vided normative data on cognitively normal individuals at each decade Age-related decline occurs primarily in cognitive speed, working
of life, but this approach has been criticized because these studies likely memory, and encoding (Hedden and Gabrieli, 2004). The pattern on
1452
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CHAPTER 95 Alzheimer Disease and Other Dementias 1453
neuropsychological testing associated with normal aging includes a fluorodeoxyglucose positron emission tomography (FDG-PET) or
decline in learning and acquisition performance with delayed recall magnetic resonance imaging (MRI), but without cerebral amyloid
relatively preserved (Petersen et al., 1992). Recognition performance deposition. This group, termed suspected non-Alzheimer pathophysi-
also is preserved with age. Age-related cognitive decline is heteroge- ology (sNAP) did not have imaging evidence consistent with cerebro-
neous as a substantial minority may show minimal decline (Benton vascular disease or synucleinopathy as the cause of brain injury (Jack
et al., 1981). Cognitive reserve refers to different capacities for the et al., 2012; Knopman et al., 2012b). In general, these sNAP patients
brain to maintain cognitive functioning in setting of brain pathology have a lower risk of becoming symptomatic after 5 years compared
or injury (Stern et al., 2018). to patients with amyloid or amyloid plus neurodegeneration related
Age-related cognitive decline is associated with different neuro- biomarkers (Vos et al., 2013). In synuclein-related neurodegenerative
anatomical changes compared to cognitive decline from AD. Loss of disorders, autonomic symptoms, rapid eye movement (REM) sleep
synaptic density occurs as a function of age independent of Alzheimer behavior disorder, and anosmia can predate cognitive and motor
pathology (Masliah et al., 1993). While AD is characterized by early symptoms by many years. Ioflupane dopamine transporter scanning
damage of the entorhinal cortex and relative preservation of the den- appears to be a promising biomarker in these conditions (Boeve,
tate, age-associated medial temporal lobe changes occur in the dentate 2013). Preclinical stages of frontotemporal dementia (FTD) have not
with preservation of the entorhinal cortex (Small et al., 2011). Brain been studied as much as AD. The available biomarker data will be
volume normally declines with age but at a significantly slower rate reviewed subsequently in this chapter. The 2011 National Institute on
than AD patients. In addition to the hippocampus, which declines in Aging (NIA) (Sperling et al., 2011) preclinical AD criteria are summa-
volume by 1%–2% a year in normal aging (Du et al., 2006), the pre- rized in Table 95.1 (Knopman et al., 2013; Vos et al., 2013).
frontal cortex also undergoes an age-related decrease in volume (Raz
et al., 2005). Mild Cognitive Impairment
MCI refers to an in-between state of normal cognitive aging and demen-
Preclinical Stage of Dementia tia. In MCI, cognitive change is greater than expected for age but inde-
Many studies have shown the pathophysiological processes leading to pendence in the community and activities of daily living are preserved
dementia can begin decades prior to cognitive symptoms. An evolv- (Petersen, 2004; Petersen et al., 2009). On average, MCI patients perform
ing understanding of the preclinical stages of dementia has resulted in 1–1.5 standard deviations below matched normative data. In 2018, the
significantly increased interest in targeting it as a possible therapeutic American Academy of Neurology published evidence-based guidelines
time window. In the preclinical phase of dominantly inherited AD, on the concept of MCI, documenting the prevalence of MCI to be 6.7%
cerebrospinal fluid (CSF) amyloid beta 42 (Aβ42) decreases 25 years at 60–64 years, 8.4% between ages 65 and 69, 10.1% between ages 70 and
before expected symptom onset (Bateman et al., 2012). Recent studies 74, 14.8% between ages 75 and 79, and 25.8% for ages 80–84. The rate of
have revealed that in the general population the sequence of biomark- progression from MCI to dementia was between 9% and 20% per year
ers leading to dementia is more diverse than dominantly inherited depending on the specific nature of the population (Petersen et al., 2018).
AD. In addition to cognitively normal individuals with biomark- In 2004, Petersen published criteria for MCI (Table 95.2; Petersen,
ers compatible with preclinical AD, the Mayo Clinic Study of Aging 2004). These criteria, proposed at the Key Symposium in Stockholm
identified a group of patients with evidence of neurodegeneration on (Winblad et al., 2004), emphasized the concept as a syndrome between
TABLE 95.1 National Institute on Aging Criteria for Preclinical Alzheimer Disease (AD)
Amyloid Beta
(Positron
Emission % of diagnostic
Tomography or category
Cerebrospinal Neuronal Cognitive (Knopman et al., 5-Year Risk of Dementia
Diagnostic Category Fluid) Injury* Change 2013) (Vos et al., 2013)
Normal AD Stage 0 (normal AD − − − 43% 2%
biomarkers biomarkers)
Preclinical AD Stage 1 (asymptomatic + − − 16% 11%
amyloidosis)
Stage 2 (amyloidosis + + − 12% 26%
plus evidence of neural
degeneration)
Stage 3 (amyloidosis, + + + 3% 56%
neurodegeneration,
subtle cognitive change)
sNAP† (neurodegenera- − + − 23% 5%
tion, no amyloidosis)
*Biomarkers of neuronal injury include increased cerebrospinal fluid (CSF) tau, hippocampal atrophy, and abnormal fluorodeoxyglucose positron
emission tomography (FDG-PET) metabolism.
†Suspected non-Alzheimer pathway, not part of 2011 NIA criteria.
Data based on studies by Knopman, D.S., Jack, C.R., Jr., Wiste, H.J., Weigand, S.D., Vemuri, P., Lowe, V.J., et al., 2013. Brain injury biomarkers
are not dependent on beta-amyloid in normal elderly. Ann. Neurol. 3, 472–480; and Vos, S.J., Xiong, C., Visser, P.J., Jasielec, M.S., Hassenstab, J.,
Grant, E.A., et al., 2013. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2, 957–965.
1454 PART III Neurological Diseases and Their Treatment
normal aging and dementia. Diagnosing MCI is the initial step, fol- recently, the Diagnostic and Statistical Manual of Mental Disorders-5
lowed by a determination of etiology of the syndrome. (DSM-5) described an analogous concept of “mild neurocognitive dis-
In 2011, the NIA and the Alzheimer Association published guide- order.” A comparison of the recent MCI criteria is presented in Fig.
lines for the diagnosis of MCI due to AD (Albert et al., 2011). More 95.1 (Albert et al., 2011; Petersen et al., 2014). The American Academy
of Neurology published guidelines recommending clinicians assess
patients for MCI (Petersen et al., 2018).
TABLE 95.2 Mild Cognitive Impairment The concept of MCI is important because it identifies persons who
Criteria are at great risk of developing dementia. While the annual risk of devel-
aMCI naMCI oping dementia in the elderly general population is approximately
1%–2%, MCI patients seen in the clinic setting have a 10%–15% annual
Cognitive decline with intact Cognitive decline with intact ADLs, often
risk. In population-based studies of MCI the annual risk of develop-
ADLs, often corroborated by an corroborated by an informant
ing dementia is slightly lower at 5%–10% (Farias et al., 2009; Petersen
informant
et al., 2010; Roberts et al., 2014). The prevalence of MCI in subjects age
Memory impairment Nonmemory cognitive impairment (lan-
70–89 is approximately 16% (Petersen et al., 2010). Identifying MCI
guage, attention, executive function,
patients allows for monitoring of progression, provides opportunity
visual-spatial)
for appropriate counseling, and offers a possible therapeutic window
Multidomain aMCI if other Multidomain naMCI if more than one
for intervention in the future.
domains involved other nonmemory domain involved
Several biomarkers predict the risk of converting from MCI to
ADL, Activity of daily living; aMCI, mild cognitive impairment—amnestic; dementia. On structural MRI, MCI patients with hippocampal vol-
naMCI, mild cognitive impairment—nonamnestic. umes on the 25th percentile are 2–3 times more likely to convert to
Mild Cognitive Impairment
Cognitive complaint
Not normal for age

Not demented
Cognitive decline
Essentially normal functional activities
MCI
Yes Memory impaired? No
Amnestic MCI Nonamnestic MCI
MCI Criteria
Amnestic MCI Amnestic MCI Nonamnestic MCI Nonamnestic MCI
Key Symposium
Single domain Multiple domain Single domain Multiple domains
JIM, 2014
DSM-5 Mild Neurocognitive Disorder
MCI due to AD
• Uncertain No or conflicting Aβ or MRI or FDG-PET or tau
• Intermediate Plus biomarker for Aβ OR MRI or FDG-PET or tau
• High Plus biomarker for Aβ AND MRI or FDG-PET or tau
Prodromal AD Plus biomaker for Aβ or tau/Aβ
Fig. 95.1 Comparison of Recent Criteria for Mild Cognitive Impairment (MCI). The criteria outlined in blue were
proposed at the Key Symposium. Other criteria include those of the fifth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-5) and MCI due to Alzheimer disease (AD) (Albert et al., 2011). Aβ, Amyloid beta;
FDG-PET, fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging. (Reproduced
from Petersen, R.C., Caracciolo, B., Brayne, C., Gauthier, S., Jelic, V., Fratiglioni, L., 2014. Mild cognitive impair-
ment: a concept in evolution. J. Intern. Med. 275, 214–228 with permission from Journal of Internal Medicine.)
dementia compared to MCI patients with hippocampal volumes on

the 75th percentile (Jack et al., 2010). In CSF, low Aβ 42 and high total HS
tau (t-tau) and phospho tau (p-tau) levels are associated with pro- FTD
gression in MCI patients (Mattsson et al., 2009). Other risk factors for
conversion include APOE ε4 allele (Petersen et al., 1995, 2005), tem- VaD
AD
poral-parietal hypometabolism on FDG-PET (Chetelat et al., 2003),
and amyloid deposition on Aβ PET imaging (Wolk et al., 2009). One
criticism of the MCI concept is that a proportion of patients diagnosed
with MCI revert to normal. Interestingly, recent longitudinal studies LBD
demonstrated that those patients who fluctuate between normal cog-
nition and mild cognitive impairment have a significantly higher risk
of developing dementia over time. Therefore, a diagnosis of MCI even
with reversion to normal has prognostic value (Lopez, 2013; Roberts
et al., 2014). This fluctuation is analogous to labile hypertension and
Fig. 95.2 Frequency of Different Pathologies in State of Florida Brain
glucose intolerance with respect to the ultimate development of hyper- Bank. AD, Alzheimer disease; LBD, Lewy body disease; VaD, vascular
tension or diabetes mellitus. dementia; HS, hippocampal sclerosis; FTD, frontotemporal dementia.
Subtyping MCI into amnestic and nonamnestic categories also (Based on data from Barker, W.W., Luis, C.A., Kashuba, A., Luis, M.,
has predictive value. Amnestic MCI (aMCI), which is more common, Harwood, D.G., Loewenstein, D., et al., 2002. Relative frequencies of
refers to memory impairment often noticed by family and even the Alzheimer disease, Lewy body, vascular and frontotemporal dementia,
patient but with intact cognitive skills in other domains (language, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer
executive function, visual-spatial) and preservation of functional Dis. Assoc. Disord. 16, 203–212.)
capacity. In contrast, nonamnestic MCI (naMCI) patients have
declines in nonmemory cognitive domains such as language, executive
function, and visual-spatial skills. The vast majority of aMCI patients 20 years (Prince et al., 2013). In the United States, the estimated prev-
progress to AD dementia (Petersen et al., 2005). Those with naMCI alence of dementia among those 71 and older using an in-home visit
may progress to dementia with Lewy bodies (DLB) but can also prog- is 13.9%. A sharp increase in dementia prevalence occurs with age
ress to FTD, vascular dementia, and even AD dementia (Ferman et al., (Plassman et al., 2007).
2013b; Molano et al., 2010). However, data from the Rotterdam study indicate the incidence of
dementia may be declining (Schrijvers et al., 2012). This has been rep-
Subjective Cognitive Impairment licated in the UK (Matthews et al., 2013) and Rochester, MN (Rocca
While restricted insight into memory loss has been a distinguish- et al., 2011). One possible explanation is that this decrease is related to
ing feature of individuals with cognitive impairment, recent stud- improved treatment of vascular risk factors.
ies have demonstrated that patients with cognitive complaints, Dementia can result from numerous causes, including brain injury
good insight, and normal cognitive testing called subjective cog- (cerebrovascular disease or trauma) or infectious and metabolic dis-
nitive decline (SCD) are three times more likely than controls to eases, but the most common causes are neurodegenerative diseases.
develop MCI with AD-related biomarkers (Jessen et al., 2010; van Fig. 95.2 represents frequency of the predominant pathologies in a
Harten et al., 2018). SCI has been associated with elevated levels of large dementia brain bank (Barker et al., 2002). However, it is clear
tau regionally in the entorhinal cortex and global elevation of Aβ that while each patient has a predominant pathology, the majority of
(Buckley et al., 2017). patients have multiple pathologies at autopsy. In fact, only 30% had AD
pathology without other pathologies. Similarly, in the Rush Memory
and Aging Project, over 50% of autopsied subjects with dementia had
DEMENTIA
multiple pathological diagnoses (Schneider et al., 2007).
Dementia is an encompassing syndromic term for a decline in cog- In a longitudinal clinicpathological study of aging, AD was the
nitive abilities of sufficient severity to interfere with function during most common underlying pathology (65%) but occurred without
daily activities (i.e., shopping, paying bills, cooking, driving, etc.). other pathologies rarely (9%). On an individual level, AD p athology
The term dementia does not imply an underlying etiology, although accounted for approximately 50% of cognitive decline on average,
neurodegenerative diseases represent the most common causes. The highlighting the importance of pathological heterogeneity in age-
decline from a prior higher level of functioning must be p resent related cognitive decline (Boyle et al., 2018). In fact, even among
in order to distinguish dementia from a developmental cognitive patients diagnosed with AD-dementia, multiple pathologies are the
disorder. The cognitive deficit cannot be due to delirium or altered rule rather than the exception (Schneider et al., 2007, 2009). With age,
sensorium, which can be distinguished by the presence of marked fluc- amyloid accumulation plateaus (Jack et al., 2017), tau, TAR DNA-
tuations and acute-to-subacute temporal pattern, although dementia binding protein 43 (TDP-43), and cerebrovascular pathologies con-
patients are more susceptible to delirium than the general population. tinue to accumulate (Josephs et al., 2014; Schneider et al., 2007, 2009).
The practice guideline on dementia from the American Academy
of Neurology (AAN) recommended use of the DSM-IIIR dementia Diagnostic Approach
criteria (which were subsequently updated to the DSM-5 criteria). The In 2001, the AAN published evidence-based guidelines for the diagno-
DSM-5 criteria use the term major neurocognitive disorder to approx- sis of dementia (Knopman et al., 2001).
imate dementia.
History
Dementia Epidemiology The history is the most important component of the dementia diag-
An estimated 35.6 million worldwide were living with dementia in nosis. Ideally, the history should be taken from not only the patient
2010, with a prediction the number would double approximately every but also an individual who knows the patient well as lack of awareness
TABLE 95.3 Key Parts of the History

Cognitive Symptoms Motor Symptoms Autonomic Symptoms Sleep Behavioral
Impaired recent memory (repetitive Presence of tremor or Bowel/bladder symptoms Presence of REM sleep Change in personality,
questions/statements, forgets appoint- myoclonus behavior disorder socially inappropriate
ments, loses items easily) behavior
Language difficulty (trouble understanding Trouble swallowing/ Presence of orthostasis Excessive daytime Loss of empathy/interest
others, trouble getting words out, trouble slurred speech sleepiness in hobbies, family
finding words, uses incorrect words)
Visual spatial difficulty (getting lost more Change in gait/falls Sexual dysfunction (erectile Evidence of sleep apnea Compulsive behaviors,
easily, trouble reading, difficulty recogniz- dysfunction) (snoring, stopped change in dietary prefer-
ing familiar people) breathing during sleep) ence
Executive/attentional dysfunction (poor Muscle cramps atrophy, Change in sweating Evidence of stridor Disheveled, decreased
judgment, difficulty problem solving, fasciculations interest in hygiene
difficulty maintaining focus, trouble with
calculations)
REM, Rapid eye movement.
of impairment commonly accompanies dementia. This individual can seizures, meningitis, or encephalitis, chemotherapy, brain radiation,
provide invaluable information regarding impairment in activities of sleep apnea, and other sleep disorders, depression and other psychiatric
daily living (ADLs). Other key elements of the history include identi- illness, and medication use may all be informative.
fying the presenting symptom, mode of onset, duration of symptoms, Family history. Knowledge about genetic causes and risk factors
and rate of progression. Neurodegenerative causes of dementia typi- has rapidly increased in the last few decades. Thus a careful family
cally present with an insidious onset and slow rate of progression, while history is essential. Identify not only first degree relatives but other
the sudden onset of symptoms should raise suspicion for stroke, med- relatives with dementia. It is also important to ask about Parkinson
ication effect, infection, autoimmune process, or psychosocial stress- disease, amyotrophic lateral sclerosis (ALS), and psychiatric disease.
ors. Patients may have a subacute onset over weeks or months. The Patients with one phenotype may have relatives with another. For
dementias presenting with this course will be discussed in Chapter 94. example, one patient may have FTD and a relative may have ALS from
Thorough evaluation of patients referred for cognitive symptoms to a the same gene mutation.
memory clinic can identify a potentially reversible or partially revers- Medications. A thorough review of medications is essential as
ible disorder in up to 9% of cases (Clarfield, 2003) and a treatable coex- medication side effects exacerbate an underlying cognitive impairment
isting disorder in up to 23% (Hejl et al., 2002). Several key components or even mimic a dementia. A temporal association or worsening
of the dementia history are reviewed in Table 95.3. Background infor- with starting a medication should be taken seriously and prompt
mation such as age, level of education, occupation, social stressors, and consideration of a medication taper. While numerous medications
cultural background can influence the presentation of dementia and are associated with cognitive side effects, the most common include
should be taken into consideration. As a general framework, when an anticholinergic agents (often present in medications for incontinence
older patient presents with a progressive amnestic disorder with sub- or antihistamines), benzodiazepines, zolpidem and other sedatives,
sequent decline in other cognitive domains, AD dementia is the most opioids, and muscle relaxants. Table 95.4 is a partial list of medications
common diagnosis. Alternatively, if the initial presentation is one of that can be associated with cognitive symptoms.
a change in language, personality, or behavior with relatively spared Neuropsychiatric history. A thorough neuropsychiatric history
memory, FTD is the most likely consideration. The presence of par- provides important information by identifying potentially treatable
kinsonism, hallucinations, fluctuations, and REM sleep behavior dis- symptoms and narrowing the differential diagnosis. According to the
order with dementia are most suggestive of DLB. Vascular cognitive AAN guidelines, depression should be screened for in all dementia
impairment (VCI) (Corriveau et al., 2016) can be temporally related patients because it occurs frequently and is treatable (Knopman
to a stroke or develop gradually with prominent cognitive slowing and et al., 2001). While depression can mimic dementia, depression is
executive dysfunction with cerebral small-vessel white matter disease. also a risk factor for and occurs frequently with AD and DLB (Boot
Often vascular disease occurs together with other causes of demen- et al., 2013; Ownby et al., 2006). Traditional teaching suggested that
tia as a comorbid component of the clinical picture. In the setting of patients with dementia have consistent memory deficits and executive
subacute dementia, consider Creutzfeldt-Jakob disease, autoimmune dysfunction of which they are unaware or minimize, while depressed
dementia, and their differential diagnosis. patients are more likely to complain about cognitive impairment and
Medical history. The past medical history can provide clues to the perform variably on cognitive testing due to attention deficits and
diagnosis or identify contributors to the cognitive decline. A careful poor effort on testing (although in practice, distinguishing the two is
head injury history is important because significant head trauma is difficult due to the significant overlap). However, more recent work
a risk factor for dementia (Guo et al., 2000). Repeated head injuries on the MCI stage of dementia due to AD has demonstrated that early
may suggest chronic traumatic encephalopathy (CTE) such as can neuropsychiatric features such as apathy, agitation, and dysphoria may
occur in contact sports or the military (McKee et al., 2013). Histories be presenting features of a neurodegenerative process (Geda et al.,
of stroke, hypertension, diabetes, high cholesterol, atrial fibrillation, 2014). Important neuropsychiatric symptoms to review include change
smoking, or other vascular risk factors are important clues to vascular in mood (depression, mania), change in personality, and presence
disease contributing to dementia. A history of cancer or autoimmune of delusions, obsessive behaviors, or hallucinations. The presence
disease in the setting of a subacute cognitive decline may point to of certain neuropsychiatric features may narrow the differential
a paraneoplastic disorder or autoimmune dementia. A history of diagnosis. For example, personality changes in behavioral variant FTD
TABLE 95.4 Partial List of Medications Which Can Cause Cognitive Impairment
Sleep aids, cold medications, and antihistamines Anticonvulsants Anticholinergics
with an anticholinergic component: Lamotrigine Benztropine
Diphenhydramine Acetaminophen/Dextromethorphan/Doxylamine Phenobarbital Meclizine
succinate, Ibuprofen/Diphenhydramine Phenytoin Scopolamine
Levetiracetam
Topiramate
Zonisamide
Antihypertensives Anticholinergics Muscle relaxants
Beta-blockers Tolterodine Baclofen
Oxybutynin
Antidepressants Antipsychotics Cardiac
Amitriptyline (anticholinergic property) Quetiapine Digoxin
Imipramine (anticholinergic property) Olanzapine
Risperidone
Aripiprazole
Opiates Hypnotics Immunosuppressants
Oxycodone Zolpidem Tacrolimus
Morphine Eszopiclone Cyclosporine
Hydrocodone
Fentanyl
Propoxyphene
Methadone
Benzodiazepines Antibiotics Mood stabilizer
Alprazolam Metronidazole Lithium
Clonazepam Cefepime
Lorazepam
Diazepam
Temazepam
(bvFTD) or hallucinations or delusions in DLB. The Neuropsychiatric reflexes or other lateralizing signs may suggest a vascular component
Inventory (NPI) can be used to screen for common neuropsychiatric to the dementia. A coexisting peripheral neuropathy may suggest a
manifestations of dementia (Cummings, 1997). metabolic disturbance. Fasciculations can be seen in patients with sus-
pected FTD to suggesting coexisting motor neuron disease. A language
Cognitive Assessment screening exam and testing for apraxia should also be performed. The
Many useful cognitive screening instruments have been developed. presence of a gait abnormality may indicate normal pressure hydro-
Common well validated instruments include the Mini-Mental State cephalus (NPH), parkinsonism, or vascular disease.
Exam (MMSE) (Folstein et al., 1975), the Blessed Orientation Memory
Concentration Test (Katzman et al., 1983), the Kokmen Short Test Laboratory Evaluation
of Mental Status (STMS) (Kokmen et al., 1991), and the Montreal The AAN practice parameter recommends routine assessment for
Cognitive Assessment (MOCA) (Nasreddine et al., 2005). Detailed vitamin B12 deficiency and thyroid hormone abnormalities because
cognitive testing by a neuropsychologist can be very helpful. The neu- these conditions are common, and can affect cognitive function.
ropsychologist provides an in-depth cognitive evaluation by adminis- Treatment of vitamin B12 deficiency and hypothyroidism may not com-
tering a standardized battery of tests. These tests evaluate important pletely reverse cognitive symptoms, but recognition of these conditions
cognitive domains such as attention and concentration, memory, is important. Other routine lab tests include a complete blood cell count,
language, visuospatial abilities, and executive function. They also electrolyte panel, glucose, liver function tests, and creatinine. Screening
gauge the psychiatric contributions to the clinical picture. Patients for syphilis should be done based on clinical suspicion (Knopman et al.,
with different dementias have different strengths and weaknesses on 2001). Special circumstances, including age less than 65 years, seizures,
these tests. The pattern of performance helps determine if the person is rapidly progressive dementia, history of cancer or autoimmune disease,
impaired, the severity of impairment, and the likely brain areas that are suspicion of central nervous system (CNS) infection, constitutional
damaged. Neuropsychology can also be helpful in following a patient’s symptoms, history of drug abuse or immunosuppression, systemic
progression over time. infection, suspicion of vasculitis, or other atypical features, can guide
further laboratory evaluation, including CSF examination. In neurode-
General Neurological Examination generative disease, the cell count, protein, and glucose concentrations
A general neurological exam is a key part of the evaluation of demen- in the CSF are within normal limits and specific markers of AD pathol-
tia. While the general neurological exam is typically normal in early ogy; for example, Aβ42 total and phospho-tau, may be useful.
AD, abnormalities on exam may indicate other neurodegenerative The AAN practice parameter recommends against electroencepha-
processes. The presence of parkinsonism may suggest DLB or another logram (EEG) in the standard evaluation of dementia (Knopman et al.,
parkinsonian dementia. Focal findings on exam such as asymmetric 2001). However, EEG may be very useful in a patient with a history of
seizures, assessment of rapidly progressive dementia, a history of spells, More recently, tau PET imaging and improvement in CSF assays
or suspicion of transient epileptic amnesia (Butler et al., 2007). has allowed detection of both hallmark AD proteins in vivo. This
advance of being able to detect both amyloid and tau in conjunction
Neuroimaging with data from clinical trials, which suggested that almost a quarter of
Structural neuroimaging modalities including computed tomography individuals enrolled in a trial targeting amyloid were considered amy-
(CT) and MRI can identify potentially treatable causes of dementia loid negative (Siemers et al., 2016), led to a new research framework
including subdural hematoma, hydrocephalus, and intracranial neo- proposing that AD should be defined biologically by the presence of
plasm. The AAN practice parameter paper recommends screening with both amyloid and tau either with biomarkers during life or patho-
either CT or MRI to identify these conditions (Knopman et al., 2001). logically with a separation of the clinical syndrome from the disease
In a study evaluating the usefulness of the AAN dementia guidelines, definition. The advantages of this framework include the ability to
3% of dementia patients had a surgically treatable finding on neuroim- classify individuals earlier in the disease process, prevention of indi-
aging (NPH, subdural hematoma, neoplasm). Neuroimaging changed viduals with an amnestic dementia being misclassified as AD dementia
management in 15% of cases and clinical diagnoses in 19%–28% if they have an alternative pathology, and the ability for individuals
(Chui and Zhang, 1997). In the recent “Imaging Dementia-Evidence with an atypical phenotype (nonamnestic) to be classified as AD. In
for Amyloid” Scanning (IDEAS) study, the use of amyloid PET among this research framework, each individual would be characterized by
Medicare beneficiaries with cognitive impairment of unclear etiology 3 biomarker groupings: (1) β-amyloid deposition, (2) pathological
led to a change in diagnosis and clinical management in a significant tau, and (3) neurodegeneration [AT(N)]. In this research framework,
proportion of the participants (Rabinovici et al., 2019). neuritic plaques may be identified by decreased CSF Aβ42 or amyloid
PET positivity and neurofibrillary tangles identified by a positive tau
DSM-5 PET or elevated phospho-tau protein in the CSF (Jack et al., 2018a).
Recently, the DSM-5 was released, updating the prior criteria for The presence of an amyloid biomarker alone without tau would be
dementia. DSM-5 introduces the terms “mild neurocognitive disor- referred to as Alzheimer pathological change and the absence of amy-
der,” which is similar to MCI, and “major neurocognitive disorder,” loid as non-Alzheimer pathological change. The authors cautioned
which is analogous to dementia. Major neurocognitive disorder rep- that this framework is for research at this point in time and should
resents a significant cognitive decline in at least one cognitive domain not be used in routine clinical practice. This framework provides a
that interferes with daily function that is recognized by the individual, universal terminology to allow comparison between research stud-
informant, or clinician and documented by neuropsychological test- ies, avoiding misclassification and potential erroneous enrollment in
ing. Mild neurocognitive disorder represents a cognitive decline which randomized clinical trials of individuals with an amnestic dementia
does not impair daily activities (American Psychiatric Association, syndrome not due to Alzheimer pathology such as hippocampal scle-
2013). DSM-5 recommends a two-tiered approach: (1) syndrome char- rosis (Botha et al., 2018a). A cognitive staging scheme can be applied
acterization as outlined above and (2) an etiological determination. to an individual’s biomarker status (Jack et al., 2018a). This history
of Alzheimer disease definition was reviewed in the 2018 Wartenberg
ALZHEIMER DISEASE lecture (Petersen, 2018). Table 95.5 provides proposed cognitive stages
applied to the new AD biomarker framework.
Background
In 1906 Alois Alzheimer, a German psychiatrist, reported the case of a Alzheimer Epidemiology
woman in her 50s with paranoia and memory loss followed by aphasia Prevalence
whom he evaluated in a psychiatric unit. She eventually lost the ability According to the Alzheimer’s Association in 2018, 5.7 million
to perform motor tasks. At autopsy, gross inspection revealed an atro- Americans have AD dementia (2018) which represents 70% of demen-
phied brain with vascular changes. Microscopic sections prepared with tia in the United States (not autopsy confirmed) (Plassman et al., 2007).
Bielschowsky stain revealed the hallmark AD inclusions which would The prevalence of Alzheimer dementia increases with age from 3% of
later be known as amyloid plaques and neurofibrillary tangles (NFTs). people between the ages of 65 and 74 to 32% of people age 85 and
Although the patient had early onset of symptoms, Alzheimer’s case older (Alzheimer’s disease facts and figures 2018). While MCI is more
summarizes many of the key clinical features of AD dementia. common in men, the prevalence of AD dementia is higher in women.
This in part can be explained by a longer life span in women than men.
Definition of Alzheimer Disease Over Time The lifetime risk of developing Alzheimer dementia from the age of
In 1984, the National Institute on Neurological and Communicative 45 is approximately 10% for men and 20% for women (Alzheimer’s
Disorders and Stroke and the Alzheimer’s Disease and Related disease facts and figures 2018). By 2060, the prevalence will increase to
Disorders Association criteria were created conceptualizing Alzheimer an estimated 15 million individuals in the United States (Brookmeyer
disease as a clinicopathological entity for over 30 years (McKhann et al., 2018).
et al., 1984a). With advancing technology allowing in vivo detection
of amyloid with PET and CSF as well as measurement of neurodegen- Incidence
eration, in 2011 revised AD criteria were proposed by the National Age is the most important risk factor for AD dementia. The incidence
Institute on Aging-Alzheimer’s Association. Individuals were charac- of AD dementia increases with age: 2 new cases per 1000 for individu-
terized by their clinical state (normal, MCI, and dementia) with bio- als age 65 to 74, 11 new cases per 1000 people age 75 to 84, and 37 new
markers of amyloid and neurodegeneration providing the likelihood cases per 1000 people age 85 and older (Alzheimer’s disease facts and
that their clinical state was due to Alzheimer disease. For example, if figures 2018).
amyloid and neurodegeneration biomarkers were present in conjunc-
tion with the clinical syndrome of dementia, the diagnosis of dementia Societal Cost and Future Projections
due to AD with high likelihood could be made (McKhann et al., 2011). Anticipated increases in cost to society for AD dementia are notsus-
But the diagnoses of MCI and dementia due to AD were still clini- tainable. The total payments in 2018 for all individuals with dementia
cal-pathological conditions. are estimated to be $277 billion (Alzheimer’s disease facts and figures
TABLE 95.5 Cognitive Stage

Cognitively Unimpaired Mild Cognitive Impairment (MCI) Dementia
A–T–(N)– Normal Alzheimer disease (AD) biomarkers, cognitively Normal AD biomarkers with MCI Normal AD biomarkers with dementia
unimpaired
A+T– (N) Preclinical Alzheimer pathological change Alzheimer pathological change with MCI Alzheimer pathological change with
dementia
A+T+ (N)– Preclinical Alzheimer disease Alzheimer disease with MCI (Prodromal AD) Alzheimer disease with dementia
A+T+ (N)+
A+T– (N)+ Alzheimer and concomitant suspected non-Alzheimer Alzheimer and concomitant suspected Alzheimer and concomitant suspected
pathological change, cognitively unimpaired non-Alzheimer pathological change with non-Alzheimer pathological change
MCI with dementia
A–T+ (N)– Non-Alzheimer pathological change, cognitively unimpaired Non-Alzheimer pathological change with Non-Alzheimer pathological change with
A–T– (N)+ MCI dementia
A–T+ (N)+
A, Amyloid status; T, tau status; N, neurodegeneration status.
Adapted from Jack, C.R., Jr., Bennett, D.A., Blennow, K., Carrillo, M.C., Dunn, B., Haeberlein, S.B., et al., 2018a. NIA-AA Research Framework:
toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 4, 535–562.
2018). The Alzheimer Association estimates that by 2050 annual costs is associated with vascular brain disease not increased AD pathology
for AD dementia will reach approximately $1.2 trillion (Thies and (Arvanitakis et al., 2006). Nonetheless, a meta-analysis estimated the
Bleiler, 2013). Therefore, the burden on society will continue to be relative risk of dementia related to diabetes was 1.39 (Lu et al., 2009).
enormous unless a prevention or treatment is developed. The Health It has been estimated that a 10% decrease in diabetes prevalence may
and Retirement Study has reported that AD is the costliest chronic dis- decrease the number of worldwide dementia cases by 81,000. Recently,
ease in the United States exceeding those of cancer and heart disease a study has demonstrated that elevated glucose in the absence of
(Hurd et al., 2013). diabetes also increases the risk of dementia (Crane et al., 2013).
Head injury. A meta-analysis of 15 case-control studies
Risk Factors demonstrated an increased risk of AD dementia with prior head
In addition to age and female gender, many other risk factors for AD injury in men (Fleminger et al., 2003). The mechanism is unclear,
dementia have been reported. but after severe head injury, levels of Aβ42 in the CSF decrease, which
Hypertension. After controlling for confounders, systolic blood also occurs in preclinical AD (Franz et al., 2003). The presence of the
pressure (>160 mm Hg) and elevated cholesterol increase risk for AD APOE4 allele may confer a higher risk of dementia after head injury
dementia later in life (Kivipelto et al., 2001). In the Honolulu-Asia (Koponen et al., 2004). In a population-based study, MCI subjects but
Aging Study, the use of beta-blockers for hypertension was associated not normal control subjects with history of head trauma had elevated
with less cognitive decline, especially among diabetics (Gelber et al., brain Aβ deposition (Mielke et al., 2014).
2013). In the Ginkgo Evaluation of Memory Study, the use of a Sleep. The glymphatic system of the brain allows clearance of
diuretic blood pressure medication, angiotensin-1 receptor blocker, or waste products. In mice, it has been shown that during sleep there
angiotensin-converting enzyme inhibitor was associated with reduced is an increase in the interstitial space allowing for increased rate of
risk of AD dementia in those with normal cognition at baseline (Yasar clearance of β-amyloid (Xie et al., 2013b). Emerging evidence suggests
et al., 2013). The relationship between hypertension and dementia is that impaired sleep may alter β-amyloid dynamics in humans (Lucey
complicated. Counterintuitively, some studies have shown that low et al., 2018; Shokri-Kojori et al., 2018). This is an active area of ongoing
blood pressure is more commonly seen in demented patients than high research.
blood pressure (Guo et al., 1996). A parsimonious explanation of this Others. Other risk factors associated with an increased risk of
apparent discrepancy is that the association between hypertension and AD include smoking (Anstey et al., 2007), cerebrovascular disease
cognitive decline is age dependent. Mid-life hypertension and late-life (Pendlebury and Rothwell, 2009), anemia (Hong et al., 2013), and
hypotension are associated with AD dementia (Qiu et al., 2005). The obesity (Profenno et al., 2010).
relative risk of mid-life hypertension and dementia is 1.61 and it has
been estimated that decreasing the prevalence of mid-life hypertension Protective Factors
by 10% could result in a worldwide decrease of 160,000 AD dementia Education/leisure activities/early-life cognitive abilities. In
cases (Barnes and Yaffe, 2011). The recent SPRINT-MIND trial 1990, a study performed in Shanghai demonstrated an association
demonstrated that treating systolic blood pressure to a goal of less between a lower educational attainment and dementia risk (Zhang
than 120 mm Hg compared to a goal of less than 140 mm Hg reduced et al., 1990). Subsequently, several other studies have demonstrated
the risk of mild cognitive impairment by approximately 19%, but the an association between low educational attainment and increased
study did not meet its primary endpoint of showing a reduction in the dementia risk (Qiu et al., 2001; Stern et al., 1994).
risk of dementia (Williamson et al., 2019). In addition to education, participation in certain leisure activities,
Diabetes and elevated glucose. Type 2 diabetes is associated including reading, dancing, playing board games, and playing musical
with hyperinsulinemia. Both insulin and Aβ are substrates for instruments, is associated with a decreased dementia risk (Verghese
insulin-degrading enzyme. Therefore, hyperinsulinemia may result in et al., 2003).
accumulation of Aβ through competing with Aβ for insulin-degrading These studies and others have led to the development of the cog-
enzyme (Qiu and Folstein, 2006). However, at autopsy, type 2 diabetes nitive reserve hypothesis. Which attempts to explain why those with
certain life experiences, including higher educational attainment and Early Presentation
increased leisure activity participation, are more resistant to neurode- Typical AD dementia initially presents with an episodic memory
generative changes (Stern, 2012). impairment reflecting the selective vulnerability of the medial tempo-
Early-life cognitive abilities also may play an important role in ral lobe to AD pathology. Episodic memory relates to our ability to
dementia risk. In the nun study, autobiographical essays from nuns remember information specific to a time and place when that memory
at a mean age of 22 were evaluated for idea density and grammatical was formed (e.g., “What did you eat for dinner? What did you do on a
complexity. Those with low idea density and grammatical complexity trip?”). Recent episodic memory is particularly impaired in early AD.
had lower cognitive scores later in life, and, in a small sample of nuns
who came to autopsy, those with low early-life linguistic ability had AD Pattern of Progression
pathology while those with linguistic talent did not have AD pathol- While episodic memory is the hallmark of early AD, subsequent cog-
ogy (Snowdon et al., 1996). Similarly in 1932, participants in the 1921 nitive decline is heterogeneous as the pathology spreads to the asso-
Scottish birth cohort took a test of intelligence at age 11. Lower men- ciation cortices. While individual presentations vary significantly,
tal ability at age 11 was associated with an increased risk of dementia Feldman and Woodward have described the typical symptom progres-
(Whalley et al., 2000). sion in AD dementia: Mild AD (recent memory impairment, repetitive
Exercise. A Cochrane review of 11 studies of exercise in elderly questions, loss of interest in hobbies, anomia, impaired instrumental
non-demented participants concluded that exercise enhanced cognitive ADLs), moderate AD (aphasia, executive dysfunction, impaired basic
function (Angevaren et al., 2008). In addition, Yaffe and colleagues ADLs), severe AD (agitation, complete loss of independence, sleep dis-
(Yaffe et al., 2001) reported that women with higher baseline levels turbance) (Feldman and Woodward, 2005).
of self-reported physical activity were less likely to decline cognitively.
Similar findings were found in the nurses’ health study (Weuve et al., Common Clinical Features
2004) and a population-based study (Geda et al., 2010). In addition Semantic memory dysfunction can be an early feature of AD but
to epidemiological studies, a single-blind prospective study of occurs after episodic memory involvement. Semantic memory is fac-
physical activity intervention in participants with subjective cognitive tual knowledge not linked to time or space context. Examples include
impairment but not dementia demonstrated modest but significant naming or recalling animals, objects and tools, or landmarks. The
improvement in cognition at 18 months follow-up (Lautenschlager preservation of semantic memory in a subset of early AD cases indi-
et al., 2008). The mechanism of how exercise can improve cognition cates that transentorhinal dysfunction is inadequate to disrupt seman-
is unclear, but exercise and improvement in aerobic fitness correlate tic memory, which likely requires extension of pathology into the
with increased hippocampal volumes (Erickson et al., 2011). Even in temporal neocortex (Hodges and Patterson, 1995). A category fluency
autosomal dominant AD, self-reported exercise of greater than 150 test (asking the subject to generate as many items as possible from a
minutes per week was associated with lower amyloid load compared given category such as fruits, animals, or vegetables) is commonly used
to those who exercised less than 150 minutes per week (Brown et al., as a brief test of semantic knowledge. This not only tests the ability to
2017). remember the names of objects but the ability to search one’s mind for
Diet. In a nested case-control study from the Cardiovascular a category of objects. This test is often impaired early in the course of
Health Study, consumption of 1–6 alcoholic beverages per week was the disease and also tests executive function.
associated with decreased odds of dementia relative to abstinence Executive function (planning, organization, problem solving, set
(Mukamal et al., 2003). In contrast, heavy drinking (>3/day) was not switching) decline occurs in mild AD (Greene et al., 1995). The exec-
associated with a lower AD dementia risk (Luchsinger et al., 2004). In utive dysfunction in AD dementia is mild until later in the disease
fact, it is well described that alcoholic patients can develop dementia course compared to bvFTD.
for multifactorial reasons. Korsakoff syndrome related to thiamine Language disturbance often occurs in the mild-moderate stage of
deficiency is primarily an amnestic disorder. Other neuropsychological AD dementia. Initial complaints often include word-finding difficulty.
features of alcoholics with dementia include impaired letter fluency, In time, other features of aphasia may develop, and in the late states,
fine motor control, and delayed recall with relative preservation of language output can be limited.
recognition (Saxton et al., 2000). Decline in visuospatial skills is common, often manifesting early
Dietary fat intake has been associated with AD dementia risk. with the complaint of becoming lost or being disorientated in unfa-
While intake of saturated fats and trans-unsaturated fats is asso- miliar places.
ciated with a higher risk, intake of unsaturated, unhydrogenated Apraxia often occurs later in the course of typical AD, although it
fats may be protective against AD dementia (Morris et al., 2003a, may be an early feature in atypical AD.
2003b). Weekly fish consumption and increased intake of omega-3 Strikingly, several abilities are preserved until very late in the devel-
fatty acid may also be associated with decreased AD dementia risk. opment of AD dementia. For example, AD dementia patients have
Similarly, adherence to the Mediterranean diet, which recommends preserved motor learning (procedural) (Eslinger and Damasio, 1986),
fish intake, is associated with decreased risk of AD and decreased motor, and sensory skills.
risk of converting from MCI to AD dementia (Scarmeas et al., A useful way to think of the clinical picture of AD dementia is to
2006, 2009). Cognitive outcome data from a clinical trial in which look at the pattern of both deficits and strengths the patient exhibits.
a Mediterranean diet was compared to a control diet demonstrated Patients with AD dementia have episodic memory loss and develop
that a Mediterranean diet supplemented with olive oil or nuts was anomia, executive dysfunction, and visuospatial difficulty in the set-
associated with better cognition than a control diet (Livingston et al., ting of preserved ability to walk, see, hear, and feel. AD dementia is
2017). also characterized by the juxtaposition of “knowing how” (procedural
memory) and “not knowing what” (declarative memory). The clinical
Alzheimer Clinical Features picture of deficits and preserved abilities is explained by the anatom-
AD dementia survival is shorter than predicted based on US popula- ical distribution of the NFT pathology. Arnold et al. (1991) demon-
tion estimates, with a median survival from diagnosis of 4.2 years for strated that tangle burden is greatest in the medial temporal lobe but
men and 5.7 years for women (Larson et al., 2004). spares the primary sensory and motor cortices until very late in the
course, which is why AD dementia patients can see, hear, and move
but not remember. Early AD is characterized by an isolated memory
impairment resulting from significant pathology in the entorhinal cor-
tex and hippocampus, which serves to disconnect the medial temporal
lobe from other cortices. The spread of pathology to other association
cortices results in accumulation of other symptoms: semantic mem-
ory involvement from spread to the anterior temporal lobes, executive
dysfunction from spread to the frontal lobes, and visual-spatial dys-
function from spread to the occipitotemporal lobes. In contrast, the
primary motor and sensory cortices are only affected late in the course.
The preserved basal ganglia and cerebellum are involved in the proce-
dural/motor learning (or knowing how).
Atypical Alzheimer Disease

Occasionally, AD can present with focal cortical syndromes without
memory loss initially. The three most commonly described atypical
presentations are posterior cortical atrophy (PCA), logopenic aphasia
(LPA), and frontal variant of AD. Fig. 95.3 T2 fluid-attenuated inversion recovery magnetic resonance
imaging scans in a patient with posterior cortical atrophy revealing sig-
Posterior Cortical Atrophy nificant parietal and occipital atrophy.
In 1988, Benson used the term posterior cortical atrophy to describe
five cases with progressive dementia involving visual-spatial function, Logopenic Primary Progressive Aphasia
alexia, and partial Balint and Gerstmann syndromes with relatively LPA is one of the primary progressive aphasias. The distinguishing fea-
preserved memory (Benson et al., 1988). Later, autopsy series of PCA tures of LPA include impaired naming, repetition, and word retrieval
revealed Alzheimer pathology as the most common underlying eti- with phonological errors. Motor speech and grammar are spared.
ology. While AD is the most common pathology, other pathologies Gorno-Tempini et al. (2008) have suggested impairment in the pho-
in clinically diagnosed PCA cases include corticobasal degeneration nological loop, which stores and rehearses verbal memory as the basis
and prion disease. PCA patients are often initially referred to optom- of the clinical presentation. In a study by Mesulam et al. (2008), 64%
etry or ophthalmology for difficulty seeing, which may manifest as of logopenic patients had AD pathology at autopsy, and these patients
driving impairment or trouble reading. Not uncommonly, PCA had greater tangle burden in the left hemisphere language areas and
patients undergo procedures such as cataract removal without sig- fewer tangles in the entorhinal cortex when compared to typical AD
nificant benefit, or alternatively, they may be told there is nothing pathology. In a large multicenter study, amyloid pathology was pres-
wrong with their eyes prior to definitive diagnosis. The mean age of ent in 86% of those with LPA compared to 20% of those with non-
onset of PCA is approximately 60 (Tang-Wai et al., 2004). Compared fluent/agrammatic PPA and 16% of those with semantic variant PPA
to typical AD, insight is preserved (Mendez et al., 2002). In a large (Bergeron et al., 2018). Phonological errors may be the strongest pre-
series of 40 PCA cases, complete or partial Balint syndrome (optic dictor of underlying AD pathology (Leyton et al., 2014). Structural
ataxia, oculomotor apraxia, simultanagnosia) was present at diagno- MRI reveals left temporal-parietal atrophy. FDG-PET scans reveal
sis in 88% of patients, complete or partial Gerstmann (left-right con- temporal-parietal hypometabolism and tau PET demonstrates left
fusion, finger agnosia, agraphia, acalculia) was present in 62%, and greater than right temporal and parietal tau deposition (Fig. 95.5, A
visual field loss was present in 48%. Simultanagnosia is characterized and B).
by only being able to see one object at a time while viewing a scene.
Ishihara plates used to assess color perception and complex scenes Behavioral/Frontal or Dysexecutive Variant Alzheimer Disease
are good screening tools for the presence of simultanagnosia. Other Rarely, patients with pathologically confirmed AD present with early
important signs and symptoms include ideomotor apraxia, alexia, impairment on tests of frontal lobe function including verbal fluency
prosopagnosia, hemineglect (sensory or visual), achromatopsia, and and Trails A. These patients may have behavioral and personality
dressing apraxia (Tang-Wai et al., 2004). PCA is associated with the changes similar to patients with FTD. However, those with behavioral
APOE ε4 allele (Carrasquillo et al., 2014). Structural MRI reveals presentation of AD develop apathy as the most common behavioral
parieto-occipital atrophy and FDG-PET demonstrates associated feature, in contrast to hyperorality and perseverative/compulsive
parieto-occipital hypometabolism (Figs. 95.3 and 95.4, respectively). behaviors seen more commonly in bvFTD (Ossenkoppele et al., 2015).
The distribution of amyloid is similar between PCA and typical AD Interestingly, the NFT burden in these patients is increased in the fron-
(Rosenbloom et al., 2011). In contrast, PCA patients have signifi- tal lobes (Johnson et al., 1999).
cantly more tau deposition in the occipital lobe compared to typical
AD (see Fig. 95.4), corresponding to their clinical symptoms (Hof Others
et al., 1990). Adaptive equipment for the blind or those with low sight Other focal presentations with underlying AD pathology include cor-
can be helpful. No randomized controlled trial supports the use of ticobasal syndrome and, rarely, progressive agrammatic aphasia or
any drug therapies in PCA, although acetylcholinesterase inhibitors semantic variant primary progressive aphasia, which are typically due
are commonly used since the most common underlying pathology is to FTLD pathology (Alladi et al., 2007).
AD. Recent consensus criteria (Table 95.6) for the diagnosis of PCA
have been published emphasizing PCA as a clinicoradiological syn- Neuropsychiatric Features of Alzheimer Disease
drome (Crutch et al., 2017). The new classification recognizes that Dementia
PCA can present in a “pure” form or overlap with other degenerative In a study using the Neuropsychiatric Inventory in AD, apathy (72%)
diseases such as corticobasal syndrome. was the most common neuropsychiatric symptom, followed by
Right Lateral Left Lateral Right Medial Left Medial
A Anterior Posterior Superior Inferior
B
Fig. 95.4 A, Top row: Fluorodeoxyglucose-positron emission tomography (PET) statistical stereotactic sur-
face projection map (Cortex ID) in patient with posterior cortical atrophy demonstrating marked left greater
than right occipital-parietal hypometabolism. B, Bottom rows: Tau PET in posterior cortical atrophy demon-
strating posterior tau deposition.
agitation (60%) and anxiety (48%) (Mega et al., 1996). Identification underpinning of AD began many years before the symptoms of demen-
of delusions is important because it often precedes physically aggres- tia presented themselves. Therefore, in 2011, the National Institute on
sive behavior (Gilley et al., 1997). Common delusions in AD include Aging–Alzheimer’s Association (NIA–AA) published revised criteria for
paranoia and infidelity. Identification of neuropsychiatric features is the AD process. In this exercise, a distinction was drawn between the
important because these symptoms result in significant caregiver bur- clinical symptoms of AD and the underlying pathophysiology. That is,
den and can be targeted for treatment (Kaufer et al., 1998). prior to this point, AD was defined as a clinical–pathological entity, but
that caused confusion in the field (Petersen, 2018). Therefore, the NIA–
Diagnostic Criteria AA research criteria characterized the AD clinical spectrum in three
For many years, the most commonly used criteria for the diagnosis of AD phases: dementia, MCI, and preclinical. The dementia due to AD phase
were the National Institute of Aging and Stroke–Alzheimer’s Disease and was quite similar to what had been defined in 1984 but was made more
Related Disorders Association criteria (McKhann et al., 1984b). However, specific and suggested that biomarkers for AD may be useful in the future
over the ensuing years, it became apparent that the pathophysiological when they are validated. The new criteria, however, also recognized a
TABLE 95.6 Posterior Cortical Atrophy A similar condition, sNAP MCI has been described (Knopman et al.,
2013). Fig. 95.6 compares the newest research diagnostic criteria for
Syndrome
AD (Dubois et al., 2014; McKhann et al., 2011) and reports the NIA–
Clinical Features AA criteria, including the 2018 proposed research framework, which
Insidious onset divorces the pathology from the clinical stage. This proposed framework
Gradual progression is a significant departure from the 1984 and 2011 proposals since AD
Prominent early disturbance of visual ± other posterior cognitive functions could only be called a disease if there was biomarker or autopsy evidence
for the presence of amyloid (neuritic plaques) and tau (neurofibrillary
Cognitive Features tangles) independent of clinical state. One implication of this proposal
At least three of the following must be present as early or is that a clinically unimpaired person could be labeled as having AD if
presenting features: there was biomarker evidence for amyloid and tau. Fig. 95.1 reports the
Space perception deficit NIA–AA criteria for MCI due to AD. The International Working Group
Simultanagnosia has also incorporated biomarkers into updated criteria in 2007 (Dubois
Object perception deficit et al., 2007) and 2014 (Dubois et al., 2014).
Constructional dyspraxia
Environmental agnosia Neuropsychology in Alzheimer Disease Dementia
Oculomotor apraxia Neuropsychology provides a more detailed understanding of cognitive
Dressing apraxia constructs, thereby allowing identification of what cognitive functions are
Optic ataxia deficient or preserved. The pattern of neuropsychometric testing abnor-
Alexia malities can assist in predicting underlying anatomy and in the differ-
Left/right disorientation ential diagnosis of dementia. Testing is particularly helpful early in the
Acalculia course. Neuropsychology uses well-developed standards based on nor-
Limb apraxia (not limb-kinetic) mative data that improve clinical utility and predictive value. The NIA
Apperceptive prosopagnosia workgroup consensus criteria of MCI due to AD (Albert et al., 2011) rec-
Agraphia ommend episodic memory evaluation to assist in predicting those with
Homonymous visual field defect MCI at high risk of converting to AD dementia. Memory testing alone
Finger agnosia is insufficient, and simple bedside testing cognitive screens can be insen-
All of the following must be evident:
sitive to early changes of neurodegeneration. The preservation versus
Relatively spared anterograde memory function
impairment in memory subcomponent testing allows for differentiation
Relatively spared speech and nonvisual language functions
among disorders. In brief, learning or encoding refers to the transfer of
Relatively spared executive functions
to-be-learned material from short-term sensory stores into consolidated
Relatively spared behavior and personality
traces in recent memory involving numerous integrated networks. Free
Neuroimaging:
recall pertains to the retrieval of that material without any cues or aids
Predominant occipito-parietal or occipito-temporal atrophy on magnetic
and recognition refers to the identification of the material from among
resonance imaging/hypometabolism on positron emission tomography/
several candidates. A classical memory test such as a verbal memory test
hypoperfusion single-photon emission computed tomography
consists of reading a list of words over multiple trials. An improvement
Adapted from Crutch, S.J., Schott, J.M., Rabinovici, G.D., Murray, M., in encoding over the learning trials (i.e., an increase in number of cor-
Snowden, J.S., van der Flier, W.M., et al., 2017. Consensus classifica- rect words per trial) is found in normal learning. An individual with an
tion of posterior cortical atrophy. Alzheimers Dement. 13, 870–884.. encoding problem may demonstrate a flat learning curve (i.e., the same
number of words per trial). Despite the flat learning curve, an encod-
milder symptomatic stage of the AD process which was termed MCI due ing problem might lead to preserved free recall and recognition of words
to AD (Albert et al., 2011). This stage recognized the growing literature with cues. A retrieval deficit is manifest when the person is unable to
on MCI that had been generated in the previous decade, documenting perform free recall of the material but is able to recall the items when
the existence of a clinical phase of the disease by which people may be retrieval cues are given. For example, if the person remembers the word
mildly impaired from a cognitive perspective, usually with a memory “sweater” and is unable to free recall it but can recall it when cued, “It
disorder, but were otherwise intact in other cognitive domains and were is an item of clothing,” then the person was demonstrating a retrieval
functionally intact (Petersen et al., 2018). The most novel phase of the failure since the word was encoded but not recalled without cues. With
disease process was termed preclinical AD. In this phase, subjects were a retention or consolidation problem, the individual generally encodes
cognitively and functionally normal but harbored the underlying patho- normally with improvement in number of words learned over trials, but
physiological features of AD, such as amyloid deposition. This phase of with delayed recall has significant difficulty recalling words and does not
the disease was meant to generate research on the preclinical aspects of benefit from recognition cuing. Encoding problems may correspond to
the disease process to allow intervention when disease-modifying ther- attentional deficits or a failure of medial temporal lobe structures such as
apies become available. Subsequent research has demonstrated that the hippocampus to facilitate consolidation of the material. This pattern
these research criteria are reasonably accurate and data regarding the of poor learning and consolidation is commonly seen in AD. In contrast,
validation of the biomarkers are accumulating (Jack et al., 2012; Landau a relatively pure retrieval problem would be more characteristic of par-
et al., 2012). The role of biomarkers has been documented using both kinsonian disorders, vascular cognitive impairment, or other disorders
neuroimaging and cerebrospinal fluid measures (Jack et al., 2012; Vos not involving the medial temporal lobe. Other neuropsychometric tests
et al., 2013). Recent work has revealed a group of preclinical subjects can provide discriminating information. For example, category and letter
without the typical AD biomarker profile (i.e., no evidence of Aβ deposi- fluency tests may also provide useful diagnostic pattern in AD. Typically,
tion on PET or in the CSF) but evidence of neurodegeneration by FDG- fluency for semantic categories (e.g., fruits, vegetables, and animals) is
PET or MRI, termed suspected non-Alzheimer disease pathophysiology impaired relative to letter fluency performance (e.g., words beginning
or sNAP given the absence of Aβ deposition (Knopman et al., 2012b). with a certain letter). This discrepancy in verbal fluency performance
A Anterior Posterior Superior Inferior
B
Fig. 95.5 A, Top row: T2 fluid-attenuated inversion recovery magnetic resonance imaging scans in a
patient with logopenic primary progressive aphasia revealing significant left parietal and temporal atrophy
(red arrows). Bottom row: Fluorodeoxyglucose-positron emission tomography (PET) statistical stereotactic
surface projection map (Cortex ID) in patient with logopenic aphasia demonstrating left temporal-parietal
hypometabolism. B, Tau PET in logopenic primary progressive aphasia demonstrating left greater than right
temporal and parietal tau deposition.
tends to reflect temporal lobe involvement in AD pathology and the rela- diagnosis of AD dementia (Hulstaert et al., 1999). More recent studies
tive preservation of subcortical circuitry. Confrontation naming of com- using Aβ42 and tau or phosphorylated tau suggest these biomarkers
mon objects is also impaired in early AD. Executive function tasks may can improve diagnosis in difficult cases and predict conversion from
also be impaired in early AD as evidenced by tasks requiring set-shifting MCI to AD dementia (Hansson et al., 2006; Mattsson et al., 2009; Shaw
and sequencing, including Trail Making Test Part B (Albert, 1996). Tests et al., 2009). The current research framework includes elevated phos-
of visual spatial function including figure copying can also be impaired phorylated tau as evidence of pathological tau accumulation while the
early in AD spectrum disorders. less specific total tau is used as a neurodegenerative biomarker (Jack
et al., 2018a). While these biomarkers can provide important informa-
Biomarkers in Alzheimer Disease tion, normal CSF Aβ42 and tau have been reported in autopsy-proven
Cerebrospinal Fluid Biomarkers AD dementia patients (Brunnstrom et al., 2010). Recent data suggest
The combination of reduction in the CSF Aβ42 and elevation in the that novel CSF markers, for example, neurofilament light protein, may
CSF tau protein has a sensitivity of 85% and specificity of 86% for the be good index of neurodegeneration (Mielke et al., 2019).
Alzheimer disease
1984
NINCDS-ADRDA criteria
Clinical-pathological definition
2011
NIA-AA criteria
Clinical syndrome with biomarkers for
amyloid and neurodegeneration
2014
IWG-2
The presence of dementia not required; therefore,
both MCI and dementia are grouped together.
Separate criteria for atypical AD and mixed AD
2018
NIA-AA framework
Alzheimer’s disease as a biological entity
defined by positive biomarkers for amyloid and tau
clinical spectra independent
Fig. 95.6 Timeline of Criteria and Research Frameworks for Alzhei-

mer Disease (AD). The International Working Group 2 (IWG-2) (Dubois Fig. 95.7 Longitudinal coronal T1 magnetic resonance imaging in a
et al., 2014) criteria do not require the presence of dementia: there- patient that progressed from normal cognition to amnestic mild cog-
fore, both mild cognitive impairment (MCI) and dementia are grouped nitive impairment (aMCI) to dementia due to Alzheimer disease (AD).
together. IWG-2 includes separate criteria for atypical AD and mixed Note progressive hippocampal and cortical atrophy. Top image: Normal
AD. The National Institute on Aging and the Alzheimer Association cognition age 75. Bottom left image: aMCI age 81. Bottom right image:
(NIA-AA) criteria (McKhann et al., 2011): Dementia due to AD criteria Dementia due to AD age 86.
is separated into three subgroups, uncertain, intermediate, and high,
representing the likelihood that the dementia syndrome is due to under-
lying AD pathology. Amnestic presentation refers to decline in learn- The utility of volumetric measurements of the entorhinal cortex,
ing and recall. Nonamnestic presentation refers to decline in language, while promising, is controversial. Although medial temporal lobe
visuospatial function, or executive function. Both sets of criteria include structures become atrophic in early AD and correlate with episodic
exclusionary criteria such as the presence of other types of dementia memory performance, later in the disease atrophy rates are greater
or systemic medical issues that better account for cognitive decline. In
in the temporal, parietal, and frontal cortices and are associated with
the 2018 research framework, the AD is defined purely on biological
deterioration in other cognitive domains including language, praxis,
grounds requiring the presence of an amyloid and tau biomarker sepa-
rate from clinical status. and visuospatial (Frisoni et al., 2010). Medial temporal lobe atrophy
is not specific for AD and can be seen in other degenerative and vas-
cular processes. In particular neurodegenerative hippocampal sclerosis
Neuroimaging Biomarkers of aging can have a similar imaging appearance to Alzheimer demen-
Various neuroimaging biomarkers are sensitive to different stages and tia (Botha et al., 2018b). During the dementia stage, significant global
markers of AD. atrophy occurs typically most significantly in a temporal-parietal dis-
Structural imaging. The AAN practice parameter recommends that tribution with coinciding ventriculomegaly.
a neuroimaging examination, either CT or MRI, be performed at the The presence of white matter hyperintensities observed by FLAIR
time of the initial dementia assessment (Knopman et al., 2001). While or T2 MRI also appears to contribute to cognitive impairment in AD
this recommendation was primarily suggested to exclude reversible and (Provenzano et al., 2013).
treatable causes of dementias, MRI provides much higher resolution Cerebral amyloid angiopathy. Hypointense signal on MRI
than CT and has proven very useful in the differential diagnosis of gradient-echo sequences represents hemosiderin deposition reflective
dementia and as a biomarker of neurodegeneration in AD dementia. of cerebral microbleeds. Newer techniques, such as susceptibility-
Medial temporal lobe atrophy of the hippocampus and entorhinal weighted imaging, are more sensitive for these findings. In the
cortex with concomitant dilatation of the temporal horns is an early Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, cerebral
characteristic of AD dementia (Fig. 95.7) and can predict conversion microbleeds were present in approximately 33% of cases and increased
from normal cognition to MCI and MCI to AD dementia (Jack et al., with Aβ load as measured by amyloid PET (Kantarci et al., 2013).
2000). Reduction in hippocampal volumes correlates with NFT When cerebral microbleeds occur in a lobar distribution in elderly
pathology at autopsy and cognitive decline (Jack et al., 2002). In aMCI, patients, they often represent cerebral amyloid angiopathy (CAA).
atrophy is limited to the medial temporal lobe structures while with AD In a population-based study, β-amyloid load on PET was associated
onset, atrophy spreads to the lateral temporal and parietal cortices. This with lobar but not with deep cerebral microbleeds (Graff-Radford
change corresponds with Braak staging, which is why structural MRI et al., 2019). Identification of coexisting CAA and AD has clinical
serves as a biomarker of neurodegeneration (Braak and Braak, 1991). importance because patients with AD and CAA have worse cognition
Anterior Posterior Superior Inferior
Fig. 95.8 Fluorodeoxyglucose-positron emission tomography statistical stereotactic surface projection map
(Cortex ID) showing marked hypometabolism involving the temporal-parietal junction and posterior cingulate
gyri which is relatively symmetric. Relative preservation of the frontal and occipital lobes consistent with
Alzheimer disease dementia.
and higher mean tangle and plaque rates than patients with just AD
changes alone (Arvanitakis et al., 2011; Pfeifer et al., 2002). Specific
cognitive correlates of CAA include decreased perceptual speed and
episodic memory (Arvanitakis et al., 2011). CAA preferentially involves
the occipital lobe.
Functional imaging. Functional brain imaging using single-
photon emission computed tomography (SPECT) and FDG-PET can
suggest disease specific patterns. While functional imaging studies
have not been endorsed by criteria for MCI or AD due to dementia
(Albert et al., 2011; McKhann et al., 2011), their value is recognized
in selected cases. Especially when the structural imaging scan is not
informative, functional imaging modalities may provide additional A B
useful information (Reiman et al., 1996; Sanchez-Juan et al., 2014).
Decreased blood flow in a temporal-parietal distribution seen on
SPECT correlates with hypometabolism seen on FDG-PET and is sug-
gestive of AD.
In aMCI, hypometabolism is primarily in the hippocampus and
posterior cingulate. In AD dementia, the hypometabolism includes
these regions as well as the temporal-parietal regions (Mosconi et al.,
2008). Recent studies have indicated that FDG-PET can be used as an
aid in the diagnosis of AD dementia, in particular in differentiating AD
from FTD (Foster et al., 2007; Rabinovici et al., 2011), which has led
C D
to the Centers for Medicare and Medicaid Services approving reim-
bursement for evaluating this differential diagnosis. Several studies Fig. 95.9 Top Row: Amyloid Pittsburgh Compound B (PiB)-Positron
have validated the use of FDG-PET as a biomarker in AD, resulting in Emission Tomography Imaging. A, PiB retention is not present. B,
its inclusion as a biomarker in the most recent AD criteria (McKhann Significant PiB retention. Bottom Row: Tau PET in Typical amnestic
et al., 2011). In MCI ADNI participants, FDG-PET predicted con- AD. C, Coronal view of Tau signal in medial temporal lobe. D, Axial view
of Tau PET signal in the bilateral temporal lobes (Courtesy Dr. Val Lowe.)
version to AD dementia (Landau et al., 2010). Of particular interest,
FDG-PET in cognitive normal homozygous carriers for APOE ε4
demonstrates hypometabolism in the posterior in the cingulate, tem- primarily in the frontal and temporal-parietal regions (see Fig. 95.9 for
poral, and parietal cortices (Reiman et al., 1996). Fig. 95.8 demon- examples of PiB-PET imaging). Since its discovery, numerous studies
strates an FDG-PET in a patient with typical AD dementia. have demonstrated possible clinical utilities. PiB-PET outperformed
Amyloid imaging. The development of Pittsburgh Compound B FDG-PET in discriminating FTD from AD (Rabinovici et al., 2011).
(PiB) has allowed measurement of amyloid burden in living subjects PiB binding cross-sectionally correlates with cognitive function
(Klunk et al., 2004). While not currently recommended for routine (Jack et al., 2008). Longitudinally, however, once, symptomatic, the
clinical use, this imaging modality is already being used in clinical deposition of β-amyloid plateaus demonstrating that PiB utility may
trials for identifying preclinical AD, MCI due to AD, and monitoring be greatest in the preclinical stages (Engler et al., 2006).
effectiveness of amyloid-targeted therapies. Appropriate-use criteria In a population-based study of cognitively normal individuals
have been published which make recommendations regarding the over age 70, approximately one-third have significant β-amyloid load
clinical setting in which amyloid PET could be considered (Johnson (Kantarci et al., 2012b). The prevalence of a positive amyloid PET scan
et al., 2013). The deposition of amyloid as measured by PiB-PET occurs among cognitively unimpaired individuals in the general population
increased from 2.7% in individuals between ages 50 and 59 years to Aβ

41% in those individuals between ages 80 and 89 years (Roberts et al., Neurodegeneration
2018). The high rate of amyloid-positive scans in the cognitively normal Cognitive symptoms
population along with the absence of any disease-modifying therapy
would suggest amyloid imaging in cognitively normal elderly individ-
uals should be reserved for research purposes until disease-modifying
therapy is available.
Several F-18 analog amyloid tracers have been developed and
approved for clinical use by the Food and Drug Administration (FDA)
florbetapir, flutemetamol, and florbetaben. The F-18 agents provide
comparable results to PiB imaging, but a longer half-life allows for trans-
portation to clinical centers. Florbetapir performs well compared to
autopsy confirmation (Clark et al., 2011). In the ADNI study, Aβ depo-
sition, as measured with florbetapir, correlated with cognitive decline in
Stage 1 Stage 2 Stage 3 MCI
cognitive normal and MCI participants. In the cognitive normal group
this decline sometimes occurred in the absence of FDG abnormality Fig. 95.10 Hypothetical model for the sequence of biomarkers and
pathological events in the development of Alzheimer disease. Aβ,
(Landau et al., 2012). Multiple studies have demonstrated the prognos-
Amyloid beta; MCI, mild cognitive impairment. (Modified with permis-
tic importance of amyloid PET. The incident risk of developing mild sion from Jack, C.R. Jr., Knopman, D.S., Jagust, W.J., et al., 2010.
cognitive impairment increased greater than twofold among cognitively Hypothetical model of dynamic biomarkers of the Alzheimer’s patholog-
unimpaired individuals who were amyloid PET positive compared to ical cascade. Lancet Neurol. 9, 119–128.)
those who were amyloid PET negative (Roberts et al., 2018).
Task-free functional magnetic resonance imaging. Functional
MRI (fMRI) measures the blood-oxygen-level dependent (BOLD) variant primary progressive aphasia, which is most often associated
signal, essentially relying on the fact that neuronal activation in a with TAR DNA-binding protein (TDP)-43-positive inclusions, tau-
region produces associated increases in blood flow to that same region. PET signal has been seen in areas of atrophy, possibly reflecting off-
Dementia caused by neurodegeneration is caused by the disruption of target binding (Josephs et al., 2018; Makaretz et al., 2018). Tau PET
specific, large-scale neural networks (Seeley et al., 2009). fMRI is one has allowed investigation into how patterns develop with age. In cog-
technique to study these neural networks. The default mode network nitively unimpaired individuals in the preclinical stage of AD, in addi-
(DMN) refers to connected regions of brain that are active when tion to the expected medial temporal tau involvement, tau is present
an individual is at rest or not focused on the external environment in extra-medial temporal regions and extra-temporal regions arguing
(Raichle et al., 2001). In AD, the DMN is selectively targeted. The core against a region-region spread of tau pathology that has been previ-
regions of the brain activated in this default state include the medial ously proposed (Lowe et al., 2018) (see Fig. 95.9 bottom row for exam-
prefrontal cortex, inferior parietal lobule, posterior cingulate gyrus, ples of tau-PET imaging).
hippocampal formation, and lateral temporal cortex. These changes on
fMRI occur early in the disease process. In cognitively normal APOE Longitudinal Tracking of Biomarkers
ε4 subjects, there is a decrease in connectivity relative to controls The advent of biomarkers for tracking the progression of AD has
(Machulda et al., 2011). These changes occur in the absence of brain vastly increased our knowledge about its temporal progression and
amyloidosis, as measured by amyloid PET and Aβ42 levels in the CSF will play a key role in clinical trial design and execution. Several key
(Sheline et al., 2010). Therefore, fMRI changes may be a very early biomarker studies in conjunction with data of unselected autopsies
marker of the pathophysiology of AD. While current use of fMRI in published over a short period of time have provided evidence that
dementia is limited to research, it has provided substantial knowledge the pathophysiological processes underlying AD start decades before
about degenerative disease and is actively being investigated as a cognitive decline. This knowledge has shifted the focus of disease
biomarker. therapies to the presymptomatic or early symptomatic phases of the
Tau imaging. Recently, several tau imaging tracers have been disease. One influential hypothetical model for the sequence of these
developed The FDA approved Tauvid (flortaucipir F18) for patients biomarkers was first proposed by Cliff Jack in 2010 (Jack et al., 2010)
being evaluated for AD. Since tau comprises the other hallmark of the and revised in 2013 (Jack and Holtzman, 2013). This model represents
AD pathological process, neurofibrillary tangles, the ability to image it the pathophysiological processes underlying AD, and is summarized
in vivo would be extremely useful. Tau is also implicated in a variety in Fig. 95.10. The Dominantly Inherited Alzheimer Network (DIAN)
of other disorders and the ability to characterize this protein would be study has provided important information regarding the timing of
advantageous in diagnosis and following putative treatments. biomarkers in autosomal dominant AD largely consistent with the
The presence of tau PET signal in the inferior temporal cortex model described above (Bateman et al., 2012). This sequence can be
is closely linked to clinical symptoms (Johnson et al., 2016). Tau summarized by the following: CSF Aβ42 declines over two decades
PET reliably distinguishes AD dementia from non-AD dementias before clinical symptoms; Aβ-PET abnormalities begin about 15 years
(Ossenkoppele et al., 2018). Since flortaucipir binds to AD-type tau before symptoms; brain volume loss and increased CSF tau also occur
(3R,4R), it is not surprising that tau-PET levels in the temporal pole of 15 years before symptoms; FDG-PET abnormalities occur 10 years
tau mutation (microtubule-associated protein tau [MAPT]) cases were before symptoms (Bateman et al., 2012).
lower than in AD dementia cases, with the exception of tau mutation While this sequence is predictable for dominantly inherited AD, the
cases, whose MAPT mutation occurs outside of exon 10 (V337M and Mayo Clinic Study of Aging has demonstrated that a substantial propor-
R406W) and, therefore, develop AD-like tau and have tau-PET sig- tion of cognitively normal subjects have neurodegeneration biomark-
nal close to the AD dementia levels (Jones et al., 2018a). Many issues ers but not amyloid biomarkers, as was noted earlier in this chapter
exist regarding these tracers, such as specificity for tau and various tau (Jack et al., 2012; Knopman et al., 2012a). In preclinical AD, 42% of
isoforms, but it is a promising technique. For example, in semantic incident Aβ-PET positive cases also have positive neurodegeneration
biomarkers first. This suggests that at least two biomarker profile path- Late-Onset Genes
ways to preclinical AD exist, and some of the cases labeled sNAP are Apolipoprotein E (APOE) is the most important genetic risk factor for
on the AD pathway but with a different biomarker progression (Jack late-onset AD (Corder et al., 1993). APOE has three isoforms (E4 asso-
et al., 2013). In the same framework, progression in MCI to dementia ciated with high risk, E3 associated with neutral risk, and E2 which is
has also been characterized and a similar group of MCI sNAP subjects protective). About 20% of all late-onset AD is thought to be related to
have been identified, implying that neurodegenerative pathologies APOE ε4 (Slooter et al., 1998). APOE ε4 affects AD risk and age of onset
other than AD may be operating in some MCI subjects, and while most in a dose-dependent way; for example, E4 homozygotes have a mean
progress to AD dementia, some do not (Petersen et al., 2013). age of onset of 68 with a lifetime AD risk of 91%; in E4 heterozygotes,
Recently, longitudinal tau-PET studies have demonstrated the rate the mean age of onset is 76 with a 47% lifetime risk (Liu et al., 2013). In
of accumulation of tau over time. Cognitively unimpaired individu- contrast, E4 noncarriers have a mean age of onset of 84 with an approx-
als accumulate tau at a rate of 0.5% per year compared to cognitive imately 20% lifetime frequency (Corder et al., 1993; Liu et al., 2013).
impaired individuals who accumulate at a rate of 3% per year (Jack Trem2 variants have recently been identified as rare risk variants
et al., 2018b). for AD dementia (Guerreiro et al., 2013b). The odds ratio is similar
to APOE ε4 but it is rare, which is why it was not seen in previous
Genetics genome-wide association studies. Its population-attributable risk is
Alzheimer Genetics lower than APOE ε4 due to its lower frequency.
In a large twin study from Sweden based on 392 pairs of twins, the Many other risk loci have been associated with AD risk, but their
genetic component of AD was estimated to be 58%–79% (Gatz et al., overall impact is thought to be small. These include CD33 molecule,
2006). Family history of AD can provide important risk information. ATP-binding cassette, subfamily A, member 7 (ABCA7), sortilin-re-
The lifetime risk of AD dementia in first-degree relatives is approxi- lated receptor L (SORL1), clusterin (CLU), phosphatidylinositol
mately 39% and this risk increases to 54% by age 80 if both parents binding clathrin assembly protein (PICALM), as well as many others
have AD dementia (Lautenschlager et al., 1996). (Guerreiro et al., 2013a).
Early-Onset Genes Genetic Testing

Three rare, early-onset, fully penetrant gene mutations have been Genetic testing for APP, PSEN1, PSEN2, and APOE is commercially
described to cause Alzheimer dementia. While mutations in these genes available in Clinical Laboratory Improvement Amendments (CLIA)
are rare, studying them has been instrumental in our understanding laboratories. Routine genetic testing is not recommended by the
of AD. All three increase brain Aβ levels and form an important part practice parameter of the AAN, but if patients have testing, genetic
of the amyloid hypothesis for AD (discussed later). This provided the counseling prior to testing is essential. Testing may have significant
basis for several animal models and biomarker development including implications for patients and families in terms of family planning,
development of CSF and PET Aβ. financial costs, and risk of depression. Genetic testing currently does
Amyloid precursor protein chromosome 21. Mutations in not change treatment of the patient but may provide opportunities to
amyloid precursor protein (APP) were the first mutation to be participate in research studies such as DIAN.
described to cause AD. Chromosome 21 became a chromosome of
interest for AD, since patients with trisomy 21 (Down syndrome) Alzheimer Pathophysiology
develop AD pathology after age 40. Investigators looked at the brains All three early-onset AD genes (APP, PSEN1, PSEN2) play a role in
of patients with AD dementia and Down syndrome and found Aβ in Aβ metabolism which has provided the foundation for the amyloid
both. Since Aβ is the product of APP (located on chromosome 21), hypothesis of AD. The basic hypothesis is that abnormal Aβ metab-
APP became a candidate gene (Glenner and Wong, 1984; Goate et al., olism altering the Aβ42/Aβ40 ratio in the brain causes Aβ oligomer
1991; Goldgaber et al., 1987; St George-Hyslop et al., 1987). All APP formation and aggregation to form fibrils, which form the amyloid
mutations that cause AD change the Aβ42 to Aβ40 ratio. Recently, plaque. This oligomer formation and aggregation results in a cascade
certain mutations in APP have been described to be protective against of events, including tau protein tangle formation, increased inflamma-
AD (Jonsson et al., 2012) by decreasing the production of Aβ. The mean tory response, and oxidative injury, to cause neurotoxicity and neu-
age of onset for APP mutation families is approximately 50. In addition rodegeneration. More recent work has focused on the pathogenicity
to early age of onset, the clinical presentation of APP mutations carriers of soluble Aβ oligomers with converging basic scientific evidence that
may be distinguished from sporadic AD by the presence of myoclonus, they play a major role in neurotoxicity. For example, human Aβ oligo-
seizures, early dyscalculia, cerebral white matter changes, and even mers injected into the hippocampus of rats inhibit long-term poten-
corticospinal tract signs (Rossor et al., 1993). tiation (Walsh et al., 2002) and result in synaptic dysfunction which
Presenilin 1 chromosome 14. The majority of early-onset familial impairs memory formation (Walsh et al., 2002).
AD cases are mapped to chromosome 14 (Rossor et al., 1993). In 1995, Aβ is derived from APP through proteolytic processing. Aβ is
mutations on chromosome 14 were found in PSEN1 in autosomal produced normally in the body but under normal circumstances
dominant AD families (Sherrington et al., 1995). Interestingly, it is removed efficiently by a number of mechanisms. These include
presenilin is part of the γ secretase complex that cleaves APP (Wolfe breakdown by extracellular proteases, such as insulin-degrading

et al., 1999). Clinical features of PSEN1 families can include significant enzyme, and receptor-mediated endocytosis followed by lysosomal
aphasia in addition to myoclonus and seizures (Lampe et al., 1994). degradation and drainage through the cerebral vasculature and into
Presenilin 2 chromosome 1. PSEN2 was discovered shortly the CSF via the glymphatic system (Xie et al., 2013a).
thereafter (Rogaev et al., 1995). PSEN 2 mutations are the rarest of
the autosomal dominant mutations. PSEN2 is part of the γ secretase Amyloid Hypothesis
complex that cleaves APP. Most of these individuals are descendants The amyloid hypothesis proposes that AD can result from too much
of families from the Volga River region of Russia. Similar to the other Aβ production or a change in ratio with more Aβ42 than Aβ40 pro-
familial early-onset mutations, PSEN2 families have a higher rate of duced, or impaired clearance of Aβ. Understanding APP processing is
seizures than in sporadic AD (Jayadev et al., 2010). central to the amyloid hypothesis (Hardy and Higgins, 1992).
Amyloidogenic Pathway
sAPPβ
Aβ
β
Extracellular
Aβ oligomer Fibril formation
γ
Intracellular Decrease LTP Plaque formation,

AICD and alter inflammation, and
synaptic neuronal loss
APP CTFβ function
Nonamyloidogenic Pathway sAPPα
P3
Nontoxic effects
Extracellular α
Intracellular
AICD
APP CTFα
Fig. 95.11 Amyloid Precursor Protein Processing. Aβ, Amyloid Beta; AICD, APP intracellular domain; APP,
amyloid precursor protein; sAPPα, soluble APP α.
APP is a type 1 protein with the amino terminal in the extracel- Accumulating evidence suggests that a common mechanism across
lular space. APP is cleaved by three enzymes (α, β, and γ secretase) neurodegenerative diseases may include the trans-synaptic spread of
(Selkoe and Schenk, 2003) and can undergo processing either through tau and other misfolded proteins to anatomically connected regions in
the amyloidogenic pathway (γ and β secretases) which produces Aβ, or a prion-like manner where the protein is released and taken up by the
the nonamyloidogenic pathway (α secretase) (Fig. 95.11). anatomically related neuron (Walker et al., 2013).
In the amyloidogenic pathway, APP is first cleaved by β secretase. Recent efforts have been made to investigate how large-scale neural
This cleavage produces a β C-terminal fragment, which stays on the networks may be involved in the pathophysiology of AD and other
membrane and soluble APP Aβ. This β C-terminal fragment is then neurodegenerative disorders. It has long been known that systems of
cleaved by γ secretase in the transmembrane region producing APP connected neurons are selectively vulnerable to neurodegenerative dis-
intracellular domain (AICD) and Aβ peptide, which is then released ease, but the pathophysiology behind this association is debated. In
into extracellular space. PSEN 1 and 2 are part of the γ secretase com- contrast to disease models that emphasize the molecular misfolding of
plex (Iwatsubo, 2004). Other components of the γ secretase complex proteins spreading within connected systems, complex systems models
include nicastrin, APH-1. This aforementioned cleavage occurs by emphasize the causal role of dynamic functional activity within brain
sequential events eventually producing β-amyloid fragments, either systems interacting with molecular physiology (Jones et al., 2016).
Aβ1-42 (about 10%) or Aβ1-40 (about 90%). Aβ can aggregate and
these aggregates may form oligomers which may be toxic. Aβ1-42 has Alzheimer Pathology
a greater tendency to aggregate and is found in greater concentration Alzheimer disease is defined by two pathological findings: extracellular
in plaques, while Aβ1-40 is the predominant form in vascular amyloid plaques composed primarily of amyloid and intraneuronal neurofibril-
deposits. lary tangles composed primarily of hyperphosphorylated tau. Both
In the nonamyloidogenic pathway, APP cleavage is mediated by α involve abnormal conformational changes in proteins. Proteolytic
secretase. This cleavage is in the middle of the β-amyloid peptide above events are critical in APP processing that leads to Aβ. In neurofibrillary
the surface of the membrane, thereby preventing the formation of Aβ. pathology, phosphorylation of tau is a critical event.
This cleavage generates soluble APP α (sAPPα) and α C-terminal frag- Macroscopically, AD is characterized by diffuse brain atrophy
ments, which can also undergo cleavage by γ secretase, producing a including significantly decreased weight at autopsy. Some areas are
nontoxic peptide called P3. preferentially affected, including multimodal association areas, while
APOE functions primarily in the transport of lipids/cholesterol others, like primary motor, somatosensory, auditory, and visual corti-
from astrocytes to neurons. The presence of the APOE ε4 allele is ces, are relatively spared. The limbic areas including hippocampi and
associated with decreased CSF Aβ42 and increased brain Aβ burden cingulate gyrus are severely affected. Substantia nigra (unlike in parkin-
seen on Aβ (Morris et al., 2010). Despite these biomarker changes, the sonian disorders) is relatively spared while locus coeruleus is severely
mechanisms of E4 leading to AD are numerous and include both Aβ- affected. Work from Braak looking at autopsies of young adults sug-
related and Aβ-unrelated mechanisms. Aβ-dependent mechanisms gests the earliest place neurofibrillary tangle pathology occurs is in the
include interfering with cerebral Aβ clearance and promoting Aβ locus ceruleus, with tangles occurring in the third or fourth decades
aggregation. Aβ-independent mechanisms include promoting abnor- without involvement of tangles in the limbic areas or the presence of
mal lipid transport, thereby altering synaptic plasticity and the inflam- amyloid plaques (Braak et al., 2011). Fig. 95.12 summarizes typical
matory response (Liu et al., 2013). examples of Alzheimer pathology.
A B
C D
Fig. 95.12 Alzheimer Disease Pathology. Bielschowsky stain of CA1 of the hippocampus (A) and temporal
cortex (B) demonstrating neurofibrillary tangles and amyloid plaques. C, Tau stain of CA1 of the hippocampus
demonstrating neurofibrillary tangles. D, Aβ stain of the parietal cortex demonstrating plaques. (Courtesy Dr.
Joseph Parisi.)
Amyloid Plaques concentrated around the membrane. Then, tau is organized into
Aβ deposition in the brain occurs in a sequential manner starting in the fibrils as NFTs. When the cell dies, the tangle may be situated extra-
cortex, followed sequentially by the hippocampus, basal ganglia, thala- cellularly. Normal tau is a microtubule-associated protein and is not
mus, and basal forebrain before in the final stages reaching the brainstem visible within the brain. In NFTs, tau has become hyperphosphor-
and cerebellum (Thal et al., 2002). Plaques are complicated heterogeneous ylated and abnormally conformed. This tau can be detected with
lesions composed of extracellular protein deposits and certain cellular immunostains that bind abnormally conformed tau. Braak and Braak
components. Aβ derived from APP is the sine qua non of plaques, which (1991) have described a fairly predictable spread of NFT pathology
are in turn the defining pathological finding in AD. Despite the strong through the brain occurring in six stages which can be reduced to
association of Aβ with plaques, in reality plaques contain many other three, consisting of transentorhinal (stages I, II), limbic (III, IV), and
components. Other associated components of the plaque include APOE, isocortical (V, VI) stages. Braak staging has recently been modified
alpha-1 antitrypsin, complement factors, and immunoglobulins. Plaques to include brainstem regions preceding medial temporal involvement
can be divided into diffuse (Aβ mainly) and neuritic plaques (includes (Braak et al., 2011).
damaged tau containing axons and dendrites, i.e., neurites). Cell compo- Several other associated pathological findings may be seen with AD.
nents seen in plaques include neurites, microglia, and astrocytes. The typ- CAA, often present in leptomeningeal vessels, capillaries, small arte-
ical neuritic plaque has a dense core of Aβ and less compact rim consisting rioles, and middle-sized arteries, is seen in over 80% of AD cases. In
of neurites, microglia, and astrogliosis at the periphery. Diffuse plaques contrast to cerebral plaques consisting primarily of Aβ42, CAA’s major
have less diagnostic specificity and can be seen in a variety of different component is Aβ40. Granulovacuolar bodies, typically found in the
disorders. They contain Aβ but do not stain with tau-containing neurites hippocampus, are small dense granules within the vacuole and can be
and are not associated with synaptic loss, reactive astrocytes, or microglia. labeled with acid phosphatase, tubulin, ubiquitin, and neurofilament.
Hirano bodies (eosinophilic rod bodies), also typically found in the
Neurofibrillary Tangles hippocampus, are often in neuronal processes and contain actin and
The major component of the NFT is tau within neurons and their actin-binding proteins. The significance of granulovacuolar bodies and
cell processes. First, pretangles form in the neuron cytoplasm, often Hirano bodies is incompletely understood.
Clinicopathological Correlations pathology between sites, the amyloid burden is similar. Hippocampal
Numerous studies have shown that dementia duration and severity sparing occurs in approximately 10% of cases (Murray et al., 2011). It
correlate better with NFTs compared to amyloid plaques (Arriagada occurs more often in men and is an early-onset disease with a more
et al., 1992; Grober et al., 1999). aggressive course. These patients are often clinically diagnosed with
frontotemporal dementia, posterior cortical atrophy, or logopenic
Cholinergic Loss aphasia.
Studies of subjects with advanced AD demonstrated depleted cholin-
ergic neurons in the basal forebrain. This finding served as the basis Treatment
for the cholinergic hypothesis, which postulated that memory loss Acetylcholinesterase Inhibitors
in AD was caused by a cholinergic deficit. This hypothesis led to the Acetylcholinesterase inhibitors (AChEIs) are recommended by AAN
development and approval of acetylcholinesterase inhibitors for AD. practice parameter for the treatment of dementia (Doody et al., 2001).
In one study (DeKosky et al., 2002), the loss of choline acetyltrans- The mechanism of action of AChEIs is to improve cholinergic func-
ferase (ChAT) and cholinergic neurons did not occur until late in the tioning in the brains of patients with AD by increasing the concentra-
AD course. tion of acetylcholine through inhibition of acetylcholinesterase.
Tacrine was the first AChEI approved for use in AD but was lim-
Neuropathological Criteria ited by four times a day dosing and strict hepatic function monitoring
The pathological criteria for AD are based not only on the presence requirements due to a risk of toxicity. These limitations in combina-
of the pathological lesions but also the severity and location of the tion with the development of newer drugs resulted in its disappearance
lesions. Original criteria (Khachaturian, 1985) were only plaque based from the market place.
and included all types of plaques. In 1991, modifications were then Donepezil, a reversible AChEI that can be administered with a sin-
made by the Consortium to Establish a Registry for Alzheimer Disease gle daily dose and does not require laboratory monitoring, was the next
(CERAD) (Mirra et al., 1991). These criteria emphasized the impor- AChEI approved by the FDA. Donepezil is initiated at 5 mg per day
tance of neuritic plaques over diffuse plaques but lacked specificity for 28 days and if tolerated can be increased to 10 mg daily. Initial
because NFTs were not included. In 1997, the NIA and the Reagan donepezil studies were 12–24 weeks in duration and demonstrated
Institute criteria were developed which included both neurofibril- improvement on neuropsychological testing and clinician evaluation
lary pathology and neuritic plaques and included probability state- (Burns et al., 1999; Rogers and Friedhoff, 1996; Rogers et al., 1998).
ments (low, intermediate, or high likelihood AD) based on Braak Double-blind placebo-controlled trials of up to 1 year demonstrated
stage and severity of plaques (none, sparse, moderate, or frequent). sustained medication benefit (Winblad et al., 2001). Common side
Most recently, the 2012 criteria incorporated evaluation of coexist- effects include vivid dreaming, diarrhea, and nausea. Education to
ing pathologies and the recognition that AD pathological changes can patients and caregivers about cholinergic mediated gastrointestinal
occur without cognitive decline (Montine et al., 2012). side effects which often attenuate with time can lead to improved drug
The separation of the clinical symptoms from the pathological fea- compliance. Giving the medication in the morning instead of the eve-
tures of AD was an important advancement for the field. Alzheimer ning may decrease the vivid dreams. While not common, serious side
disease is no longer considered a “clinical-pathological” entity; rather effects may include provoking bradycardia and heart block in patients
there are two continua, clinical and pathophysiological. with cardiac conduction disorders. Recently, a 23-mg preparation of
donepezil became available with inconclusive results as to its effective-
TAR DNA-Binding Protein 43 ness (Doody et al., 2012).
TDP 43 deposition was originally thought to be specific for frontotem- Rivastigmine is another AChEI with FDA approval. Rivastigmine
poral lobar degeneration. Recent studies, however, have shown that is initiated at 1.5 mg twice daily, which can be increased by 1.5 mg
TDP-43 pathology occurs in AD and may play an important role in twice daily every 2 weeks to a maximum of 6 mg twice daily. The
neurodegeneration and clinical features (Josephs et al., 2014; Wilson side effects of rivastigmine mirror those of donepezil, although gas-
et al., 2013). trointestinal side effects may be more common (Rosler et al., 1999).
Rivastigmine has been formulated in a patch form and has demon-
Alzheimer Pathology in Aging and Mild Cognitive Impairment strated similar efficacy with decreased side effects (Winblad et al.,
Plaques can be found in cognitively normal individuals. This has been 2007).
termed “pathological aging,” although there is significant evidence that Galantamine is a reversible AChEI. Galantamine is dosed twice
these individuals may have preclinical AD (Dickson et al., 1992). The daily, and should be titrated over 4 weeks. Dosing is initiated at 4
plaques seen in “pathological aging,” unlike neuritic AD plaques, lack mg twice daily, with increases every 2 weeks to 8 mg twice daily and
tau immunoreactivity. NFTs can also be seen with aging but are typ- eventually 12 mg twice daily if tolerated. Galantamine is available
ically restricted to the medial temporal lobe and brainstem in cogni- in a sustained release formulation. The side-effect profile is simi-
tively normal individuals. In addition, cognitively normal individuals lar to donepezil and rivastigmine; however, the FDA recommends
with tau in the entorhinal cortex will have neurons surrounding the caution when using galantamine for MCI due to concerns about an
tau, in contrast to AD where tau will be associated with significant neu- increase in cardiac-related deaths in clinical trials evaluating its use
ronal loss. Not surprisingly, autopsies of patients with MCI typically in MCI.
fall in a transition pathological state between aging and AD dementia,
most commonly Braak stage II or III (Petersen et al., 2006). N-Methyl-d-Aspartate Receptor Antagonist
Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist.
Hippocampal-Sparing Alzheimer Disease It also blocks the 5-hydroxytryptamine-3 receptor. Memantine was
While progression of tangles from the medial temporal to association approved by the FDA for the treatment of moderate to severe AD and
cortex is typical, there is a subgroup of individuals with a high bur- can be used in conjunction with AChEIs (Tariot et al., 2004) or on its
den of cortical tau pathology with relative sparing of the hippocampus. own (Reisberg et al., 2003). Side effects are rare, although confusion
This is termed hippocampal-sparing AD. Despite the difference in tau and dizziness have been reported.
Vitamin E for behavioral disturbance in dementia and have been associated with
In a large double-blind, randomized, placebo-controlled, multicenter increased mortality in dementia patients. In a meta-analysis of ran-
trial, high-dose vitamin E (2000 IU a day) and selegiline delayed domized placebo-controlled trials, the use of atypical antipsychotics in
the progression of moderate AD to severe AD dementia. In con- dementia was associated with an odds ratio of 1.54 for increased mor-
trast, high-dose vitamin E failed to delay progression of MCI to AD tality (Schneider et al., 2005). The FDA has issued a black box warn-
dementia (Petersen et al., 2005). This negative trial in concert with ing for the use of these medications in dementia. After informing the
a meta-analysis which suggested an increase in all-cause mortality patient and families of the increased risk of death, there is a minority
with high-dose vitamin E (Miller et al., 2005) resulted in a decreased of dementia patients in whom the benefits may outweigh the risks. In
enthusiasm for vitamin E in AD dementia. More recently, a large these cases, antipsychotics should be used at the lowest effective dose
double-blind, placebo-controlled, randomized trial involving patients for the shortest period of time necessary. The Citalopram for Agitation
with mild-to-moderate AD dementia demonstrated less decline with in Alzheimer Disease Study demonstrated that the SSRI citalopram
high-dose vitamin E in the primary outcome of the Alzheimer’s given at 30 mg daily improved agitation in AD dementia patients com-
Disease Cooperative Study/Activities of Daily Living, which translated pared to placebo but was associated with prolonged QTc, which led the
to a delay in progression of about 19% per year without an increase authors to conclude that it could not be routinely recommended for
in mortality (Dysken et al., 2014). Further research into the safety of the treatment of agitation (Porsteinsson et al., 2014).
high-dose vitamin E in a dementia population will be needed before it
can be recommended routinely. Patient Safety
Driving
Estrogen Replacement Therapy In 2010, the AAN published a practice parameter on the evalua-
Epidemiological evidence has recognized that postmenopausal women tion and management of driving in dementia patients. This practice
who take estrogen replacement may be at decreased risk of AD. parameter reports that useful indicators of impaired driving perfor-
Randomized controlled trials showed no effect of estrogen on AD risk mance include a Clinical Dementia Rating Scale (CDR) of 0.5 or above,
(Henderson et al., 2000; Mulnard et al., 2000), but there are issues per- MMSE score of ≤ 24, caregiving rating driving safety as unsafe, recent
taining to the time in life the estrogen was administered, e.g., around history of crashes or traffic violation, or aggressive or impulsive per-
menopause or later in life. sonalities (Iverson et al., 2010). Patients with MCI or mild dementia
and no other risk factors for impaired driving may benefit from a driv-
Antiinflammatory Medications ing-risk management strategy that includes regular roadside driving
Converging basic science and epidemiological data suggested that anti- tests, while those with dementia and several risk factors for impaired
inflammatory therapy may decrease the risk of developing AD. Clinical driving should surrender driving privilege (Iverson et al., 2010).
studies using prednisone (Aisen et al., 2000) and nonsteroidal antiin-
flammatory drugs (NSAIDs) (Aisen et al., 2003) have been negative. Medication Supervision
Given the cognitive impairment, medication errors are common when
Treatment of Noncognitive Symptoms in Alzheimer Disease demented patients manage their own medications. The caregiver and
Noncognitive side symptoms of AD play a major role in caregiver patient should be educated to develop an organized system to prevent
burden. Medical conditions such as urinary tract infections can pres- any medication errors.
ent with confusion or agitation in dementia patients and should be
excluded prior to considering other therapies. If possible, nonphar- Other Safety Issues
macological treatment is preferred over pharmacological intervention Dementia patients with a propensity to wander can obtain an identity
to minimize undesirable side effects. Simple nonpharmacological bracelet through the Alzheimer Association. The safety of the home
approaches to neuropsychiatric problems include avoiding prior trig- living situation should be reviewed with the patient and caregiver,
gers, limiting changes to the environment, regular exercise, and shifting including support system need for adaptive equipment at home. While
attention. Other techniques include aromatherapy and music therapy. patients may live at home with a spouse for many years, assisted living
“Sun-downing,” the phenomenon of increased confusion or agitation and nursing homes may need to be considered based on level of care
late in the day, can be particularly problematic. This can occur in the needed, behavioral disturbance, and caregiver burden. During the
hospital, in the nursing home, or at home. Nonpharmacological inter- early stages of cognitive impairment, the healthcare provider should
ventions during waking hours include maximizing patient activity, advise the patient to designate a healthcare durable power of attorney.
exposing the patient to light, and discouraging daytime napping. Prior Also, the healthcare provider should recommend the family help over-
to sleep, extra noise should be minimized. see finances to minimize errors and prevent any exploitation.
Depression commonly accompanies AD. Selective serotonin
reuptake inhibitors (SSRIs) are preferable to tricyclic antidepres- The Future Treatment of Alzheimer Disease
sants because the anticholinergic side effects of tricyclics can exacer- To date, there have been no medications found definitely to modify
bate cognitive decline. Agitation, psychosis, and aggressive behavior the course of disease in AD. A wide array of studies, including those
are also commonly seen in AD. Traditionally, these behaviors were directed at inflammation, hormonal therapy, homocysteine, direct
treated with atypical antipsychotics (risperidone, olanzapine, queti- immunization against Aβ, passive immunization against Aβ, β, and
apine), which have a better side-effect profile than typical antipsychot- γ secretase inhibitors, and those directed against tau, have been neg-
ics such as haloperidol. In 2006, a double-blind, placebo-controlled ative. There are ongoing anti amyloid and anti-tau medications still
trial of atypical antipsychotics in Alzheimer patients demonstrated being studied. However, with all of the present failures, researchers
no significant difference in Clinical Global Impression of Change at have proposed that doctors may have to intervene earlier to modify
12 weeks, although patients in the placebo group stopped medication AD. The biomarker studies in AD may provide such an opportunity.
due to lack of efficacy more than those on olanzapine or quetiapine Biomarker studies indicate that AD pathogenesis starts many years
(Schneider et al., 2006). In addition to the limited effectiveness in ran- before the symptoms occur. At this time, secondary prevention stud-
domized clinical trials, these medications are not approved by the FDA ies are beginning in this pre-symptomatic window. Ongoing studies
include the Anti-Amyloid in Asymptomatic Alzheimer Disease (A4) TABLE 95.7 Clinical Features of Selected
study, the DIAN study, the Alzheimer’s Prevention Initiative studies
Parkinsonian Dementias
on the Columbian autosomal dominant kindred, and the APOE ε4
study as well. The A4 study is a 3-year, double-blind study evaluating Subtype Key Clinical Findings
solanezumab in cognitively normal persons who are florbetapir pos- Dementia with Fluctuations/hypersomnolence
itive. The DIAN study is evaluating solanezumab and gantenerumab Lewy bodies Parkinsonism
versus placebo in unaffected carriers of dominantly inherited gene Visual hallucinations
mutation. REM sleep behavior disorder
Amyloid trials. After early negative trials with amyloid therapy, Progressive supra- Supranuclear gaze palsy
it was felt that two possible reasons for failure were that participants nuclear palsy Axial rigidity
were enrolled based on clinical diagnosis rather than biomarker Gait disorder/frequent falls
status and that the amyloid intervention may have taken place too Bulbar symptoms
late in the disease course. The EXPEDITION 3 trial of solanezumab Corticobasal Asymmetric apraxia, dystonia, myoclonus
in mild cognitive impairment or dementia in individuals with a syndrome Cortical sensory findings, alien hand/limb
positive Aβ biomarker did not reach its primary endpoint of cognitive Rigidity
improvement even though it restricted its criteria to individuals with MSA-C/P Ataxia, parkinsonism, long tract signs, autonomic
early disease and required biomarker positivity for entry (Honig et al., dysfunction
2018). Verubecestat, a β-secretase inhibitor, was tested in mild-to-
moderate Alzheimer dementia and reduced CSF Aβ42 and amyloid MSA-C/P, Multiple system atrophy—cerebellar/parkinsonian type;
PET levels. Verubecestat did not reduce cognitive decline, and the REM, rapid eye movement.
treated groups had a greater decline in hippocampal volume compared
to placebo (Egan et al., 2018). bodies were immunoreactive for alpha-synuclein (Spillantini et al.,
Two Aβ antibodies have demonstrated efficacy in lowering brain 1997), significantly improving recognition of Lewy bodies, leading to
amyloid but whether they can influence cognitive decline remains to improved understanding of the clinical characteristics associated with
be seen (Sevigny et al., 2016). A recent trial using one of these Aβ anti- Lewy body pathology.
bodies, aducanumab, was prematurely stopped due to lack of efficacy Prodromal dementia with Lewy bodies. Prior to cognitive decline,
in participants with MCI due to AD and mild AD dementia but subse- DLB patients often experience several clinical symptoms common to
quent analysis of the full data set reignited interest in Aducanumab and disorders with underlying synuclein pathology. DLB patients may
it continues to be investigated. variably report loss of smell, autonomic dysfunction, and REM sleep
Some have viewed these results as indicating that Aβ-based ther- behavior disorder (RBD) prior to the onset of cognitive symptoms. In
apies should be tried earlier in the disease course while others have a series of patients with RBD who subsequently developed DLB, the
taken these negative trials as impetus to try other non-Aβ-based ther- mean age of onset of RBD was 61.5 while the age of cognitive decline
apeutic approaches. was 68.1 (Boeve et al., 1998). More recently it has been reported that
RBD can precede other symptoms of synucleinopathies by 50 years
NEURODEGENERATIVE DEMENTIAS ASSOCIATED (Claassen et al., 2010), or can occur after cognitive decline has started.
Similar to RBD, autonomic symptoms can precede DLB by many years
WITH PARKINSONISM
(Kaufmann et al., 2004).
The neurodegenerative dementias associated with parkinsonism can Mild cognitive impairment due to dementia with Lewy bodies.
be classified based on the molecular pathology found at autopsy: In a large series of MCI patients, those with naMCI were much more
• Synucleinopathies, which consist of DLB, Parkinson disease likely to develop DLB, with over 80% having either attention or visual-
dementia (PDD), and multisystem atrophy (MSA); and spatial dysfunction (Ferman et al., 2013b). In an autopsy series of MCI
• Tauopathies, which consist of corticobasal degeneration (CBD), patients with underlying DLB or AD pathology, MCI-DLB patients
Guam dementia Parkinson complex, chronic traumatic encepha- were distinguished from MCI-AD patients by the presence of more
lopathy (CTE), progressive supranuclear palsy (PSP), and familial parkinsonism, hallucinations or episodes of delirium, and relatively
FTD with parkinsonism. preserved memory testing (Jicha et al., 2010).
Table 95.7 summarizes key clinical features of parkinsonian Epidemiology. DLB is the second most common cause of
syndromes. degenerative dementia. In autopsy series, DLB accounts for
approximately 20% of dementia cases. Similarly, DLB accounted
Synucleinopathies for approximately 20% of patients referred for dementia to specialty
Dementia With Lewy Bodies clinics in Norway (Aarsland et al., 2008).
In 1961, Okazaki described two male patients with dementia who were The population-based incidence of DLB in France was estimated at
admitted to the hospital and subsequently died and went to autopsy. 112 per 100,000 person-years (Perez et al., 2010).
One of the patients had been hallucinating for over 1 year. Autopsy The majority of DLB patients are male (around 70%) with aver-
of both patients revealed Lewy bodies in the cerebral cortex, brain- age age of onset of approximately 72.5 years old (Boot et al., 2013).
stem, and spinal cord. Okazaki recognized the clinical presentation Compared to AD, DLB patients are more likely to have a history of
with distinctive pathological findings represented a unique disease depression and a positive family history of Parkinson disease (Boot
entity (Okazaki et al., 1961). Lewy bodies are difficult to recognize et al., 2013). The prognosis is different between DLB and AD. DLB
with standard histological sections. Immunohistochemistry with ubiq- patients have a shorter survival compared to AD patients (Williams
uitin in the 1980s led to a greater recognition of the disorder. A major et al., 2006) and are admitted to nursing homes 2 years earlier in the
breakthrough occurred in 1997, when mutations in alpha-synuclein disease course (Rongve et al., 2014).
were shown to be a cause of autosomal dominant Parkinson disease Clinical features. Consortium consensus criteria for the
(Polymeropoulos et al., 1997). The same year it was shown that Lewy diagnosis DLB were published in 2005 and updated in 2017 (McKeith
TABLE 95.8 Consensus Diagnostic Criteria for Dementia With Lewy Bodies
Symptom/Sign Cardinal Manifestations Frequency
Dementia (required criteria) Attentional, frontal-executive, and visuospatial deficits, often worse than in AD 100%
dementia; episodic memory relatively better than in AD dementia
Probable DLB
(a) Presence of 2 or more core clinical features (with or without indicative biomarker)
(b) One core clinical feature plus at least one indicative biomarker
Possible DLB
(a) Presence of 1 core clinical feature (no indicative biomarker)
(b) Presence of 1 or more indicative biomarkers but no core clinical features
Core Features
Fluctuating cognition Variable timing of altered level of attention or arousal; distinct from sundowning 60%–89%
Visual hallucinations Recurrent; typically involve animate subjects; variable degree of insight 50%–75%
Parkinsonian motor signs Spontaneous; rigidity and bradykinesia most common; action tremor more common 50%–90%
than resting tremor
REM sleep behavior disorder Loss of atonia during REM sleep; individuals appear to act out dreams; may be 25%–76%
combative or violent
Indicative Biomarkers
1. Reduced dopamine transporter uptake (SPECT or PET)
2. Low uptake iodine-123-MIBG myocardial scintigraphy
3. Confirmation of REM sleep without atonia on polysomnography
Supportive Clinical Features

1. Neuroleptic sensitivity
2. Postural instability
3. Repeated falls
4. Syncope
5. Autonomic dysfunction
6. Excessive daytime sleepiness
7. Hyposmia
8. Hallucinations (non-auditory)
9. Delusions
10. Apathy, anxiety, and depression
Supportive Biomarkers
1. Preservation of medial temporal lobe volume on CT/MRI
2. Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity and/or the cingulate island sign on FDG-PET imaging
3. Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/theta range
CT, Computed tomography; EEG, electroencephalogram; FDG, fluorodeoxyglucose; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance
imaging; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography.
Modified from McKeith I.G., Boeve, B.F., Dickson, D.W., Halliday, G., Taylor, J.P., Weintraub, D., et al., 2017. Diagnosis and management of
dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 89, 88–100.,
et al., 2005, 2017; Table 95.8). The major change was elevation of the proportion that does not respond to l-dopa is higher than in PD
RBD to a core clinical feature. The cardinal features of DLB can patients (Bonelli et al., 2004).
present in any order but typically RBD precedes cognitive changes Cognitive fluctuations. Fluctuations have been reported to occur
followed shortly thereafter by parkinsonism and hallucinations in up to 89% of DLB patients (Del Ser et al., 2000; McKeith et al., 2004).
(Fields et al., 2011). DLB patients are also notably susceptible to Cognitive fluctuations in DLB resemble delirium but do not have any
delirium, which frequently occurs if they are hospitalized. DLB can provoking cause. Fluctuations are difficult to characterize and several
rarely present as a rapidly progressive dementia (Fields et al., 2011). fluctuations scales have been developed. Fluctuations in DLB can lead
Parkinsonism. Parkinsonism is present in approximately 50% to variable performance on cognitive tests. Despite the difficulty in
of DLB patients at diagnosis, but up to 25% in autopsy series do quantifying them, fluctuations can distinguish DLB from AD. One
not develop parkinsonism (McKeith et al., 2004). The absence of study found that the presence of at least 3 of 4 characteristic fluctuation
parkinsonism is one of the major reasons for misdiagnosis (McKeith features (staring into space, disorganized speech, drowsiness, and
et al., 2000). Parkinsonian features of DLB tend to be symmetrical with napping during the day despite getting adequate sleep) occurred
action tremor greater than rest tremor. Parkinsonian features more in 63% of DLB patients, 12% of AD patients, and 0.5% of normal
severe in DLB than Parkinson disease (PD) include difficulty getting elderly persons, but asking specifically if the patient fluctuates did not
up from a chair, gait difficulty, impaired facial expression, and rigidity distinguish DLB from AD (Ferman et al., 2004). Another fluctuations
(Aarsland et al., 2001). While DLB patients respond to l-dopa therapy, battery found the following four features distinguished DLB from
PDD, vascular dementia, and AD, with sensitivity ranging from 78.6% parkinsonism. In all likelihood, there are multiple genes involved, with
to 80.3% and specificity ranging from 73.9% to 79.3%: most undiscovered.
1. Significant differences in daytime functioning; Neuroimaging in dementia with Lewy bodies. The pathological
2. Somnolence; overlap of AD and DLB results in significant overlap of the imaging
3. Drowsiness; and biomarkers. A multimodal imaging approach (MRI, PiB-PET, FDG-
4. Daytime altered levels of consciousness (Lee et al., 2014). PET) is additive in its ability to distinguish AD from DLB (Kantarci
Hallucinations. Hallucinations in DLB are often detailed, vivid et al., 2012c).
visual images of people and animals. Children and insects are also Structural magnetic resonance imaging. Compared to AD,
common themes. Hallucinations tend to cluster in the evening, and DLB patients have relatively preserved hippocampal volumes and less
patient insight is variable. Hallucinations occur in 63% of autopsy- global atrophy although there is significant overlap. In DLB patients,
confirmed DLB patients and are much more likely to be due to DLB lower hippocampal volumes correlate with higher Braak tangle stage
when they occur in the first 5 years of the dementia (Ferman et al., (Kantarci et al., 2012a), indicating greater coexisting AD pathology.
2013a). The posterior mesopontine region is also significantly smaller in DLB
Rapid eye movement sleep behavior disorder. RBD refers to compared to AD (Kantarci et al., 2012a; Whitwell et al., 2007). The
loss of the normal REM sleep with atonia. RBD can be screened for presence of hippocampal atrophy among DLB patients is associated
by asking “Does the patient act out his or her dreams while sleeping?” with a shorter survival time compared to DLB patients with normal
Polysomnogram is the gold standard for diagnosing RBD. In an autopsy hippocampal volumes (Graff-Radford et al., 2016).
series of patients with RBD, 141 of 172 had Lewy body disease of any Amyloid imaging in dementia with Lewy bodies.
kind (DLB, PDD, or PD) while 19 of 172 had MSA, demonstrating Approximately 50%–80% of DLB patients are amyloid-positive on PiB-
the relationship between synuclein pathology and the presence of RBD PET scans although at lower levels than AD patients and the pattern of
(Boeve et al., 2013). In autopsy-confirmed DLB patients, approximately deposition is similar to AD (Edison et al., 2008; Kantarci et al., 2012c).
76% have RBD (Ferman et al., 2011). Patients who have DLB with RBD Therefore, amyloid PET should not be used to distinguish DLB from
differ from those without RBD. DLB with RBD patients are more likely AD.
to be male, have earlier parkinsonism and hallucinations, and lower Fluorodeoxyglucose positron emission tomography in
Braak tangle staging than those without RBD (Dugger et al., 2012). dementia with Lewy bodies. The FDG-PET pattern of DLB is
RBD improves the diagnosis of DLB. The odds ratio of DLB compared very characteristic, involving parietal-occipital hypometabolism. In
to other causes of dementia improves from 2 to 6 when RBD is added an autopsy-confirmed series, occipital hypometabolism distinguished
to visual hallucinations, parkinsonism, and fluctuations (Ferman et al., DLB from AD dementia with a sensitivity of 90% and specificity of
2011). Other sleep disorders are often comorbid, including obstructive 87% (Minoshima et al., 2001), but it is important to understand
sleep apnea and periodic limb movements of sleep. that cases of atypical AD and late AD may show significant occipital
Neuroleptic sensitivity. DLB patients experience greater hypometabolism. Since occipital hypometabolism does not occur
neuroleptic sensitivity than AD patients. Of DLB patients who receive in all cases, this limits its clinical utility. More recently, the relative
dopamine-blocking antipsychotics (e.g., haloperidol and risperidone), preservation of the posterior cingulate metabolism relative to the
approximately 80% will experience an adverse reaction, with 50% precuneus and cuneus metabolism, termed the “cingulate island,” has
experiencing a severe reaction (McKeith et al., 1992). Symptoms been shown to have the highest specificity in distinguishing DLB from
include worsening motor symptoms, confusion, and agitation. AD (Graff-Radford et al., 2014; Lim et al., 2009).
Autonomic dysfunction. Autonomic symptoms are common Fig. 95.13 demonstrates imaging features of DLB.
in DLB. The most common symptoms are orthostatic hypotension, Dopamine transporter (DaT) scan. Dopamine transporter
urinary incontinence, and erectile dysfunction (Thaisetthawatkul imaging with [123I]-FP-CIT SPECT differentiates DLB from other
et al., 2004). dementias with 78% sensitivity and 90% specificity (McKeith et al.,
Other neuropsychiatric symptoms. Delusions occur in 2007). In DLB patients, there is significantly decreased nigrostriatal
approximately 70% of DLB patients, with 40% developing uptake compared to AD, particularly in the putamen. The 4th
misidentification syndromes (Ballard et al., 1999). Depression, anxiety, consortium criteria for DLB recognized reduced dopamine transporter
and apathy are also frequently seen. uptake in basal ganglia demonstrated by SPECT or PET as an
Falls. Falls are more common in DLB than AD. Falls may be related indicative biomarker of the diagnosis of DLB (McKeith et al., 2017).
to a combination of parkinsonism and autonomic symptoms. Fig. 95.13 demonstrates a dopamine transporter scan in DLB. In an
Neuropsychology. The neuropsychological profile is helpful in autopsy series, approximately 10% of patients with LBD pathology
distinguishing DLB from AD. Compared to AD dementia patients, had a normal dopamine transporter scan with [123I]-FP-CIT SPECT
DLB patients perform worse on tests of visual spatial ability (Mori (Thomas et al., 2017).
et al., 2000) and attention but better on tests of naming and verbal Myocardial iodine-131-meta-iodobenzylguanidine. Myo-
memory (Ferman et al., 1999). cardial iodine-131-meta-iodobenzylguanidine (MIBG) imaging can
Laboratory studies. No proven blood or CSF tests for DLB exist, also help distinguish DLB from other dementias and is considered an
although serum and CSF biomarkers are actively under development. indicative biomarker in the DLB criteria (McKeith et al., 2017; Yoshita
Genetics. The genetics of DLB remain obscure. Genes implicated et al., 2006). MIBG imaging measures postganglionic sympathetic car-
in PD and AD are also implicated in DLB and PDD. In a Belgian diac innervation, which is reduced in DLB compared to AD.
kindred with familial DLB, chromosome 2q35-q36 was mapped as the Pathology. α-Synuclein is the primary protein in Lewy bodies.
region of interest (Meeus et al., 2010). Duplications in the α-synuclein The presence of Lewy bodies and Lewy neurites in limbic and cortical
(SNCA) gene (Kasuga et al., 2010) and mutations in the leucine-rich regions distinguishes DLB from PD, where Lewy bodies are limited to
repeat kinase 2 (LRRK2) gene on chromosome 12 also cause DLB the brainstem. Lewy bodies in the cortex are more difficult to identify.
(Qing et al., 2009). In a multicenter study, glucocerebrosidase (GBA1) In 2003, Braak proposed a staging scheme for synuclein pathology where
mutations were associated with DLB with an odds ratio of 8.28 (Nalls the earliest region involved was the dorsal motor nucleus of the medulla
et al., 2013). GBA1 carriers had an earlier age of onset and worse followed by the pons, midbrain (nigra), basal forebrain, and then cortical

B
Fig. 95.13 A, Left: Fluorodeoxyglucose positron emission tomography (FDG-PET) in dementia with Lewy bod-
ies (DLB) patient demonstrating relative preservation of posterior cingulate (arrow) (e.g., cingulate island sign).
Middle: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) imaging with iodine-
123-ioflupane in patient with DLB. There is markedly decreased striatal accumulation bilaterally, left greater
than right. Right: Normal dopamine transporter imaging. B, FDG-PET statistical stereotactic surface projection
map (Cortex ID) showing occipital hypometabolism in a DLB patient. (DaT imaging courtesy Dr. Bradley Boeve.)
areas, particularly frontal and temporal. Another early region involved improved significantly in neuropsychiatric features and a four-item DLB-
is the olfactory bulb. Synuclein is also present in the striatum of DLB specific subset of the NPI composed of delusions, hallucinations, apathy,
patients, although this was not included in Braak’s staging scheme. and depression subscales (McKeith et al., 2007). In another randomized,
Synuclein pathology in the spinal cord affects the intermediolateral cell double-blind, placebo controlled trial, donepezil 5 or 10 mg improved
column and less often Onuf’s nucleus. There is significant pathological MMSE scores, caregiver burden, and behavioral symptoms in DLB
overlap between AD and DLB. The majority of DLB patients have amyloid patients relative to placebo (Mori et al., 2012a).
plaques at autopsy. Most of the plaques in DLB tend to be diffuse without DLB patients without imaging markers of coexisting AD pathology
associated tau neuritic pathology. Interestingly, plaques may increase (hippocampal atrophy, PiB-PET positivity) are more likely to improve
Lewy body density, suggesting a possible interaction between amyloid with AChEIs compared to those with imaging markers of AD pathol-
and synuclein. In the consortium criteria for DLB, the relative amount of ogy (Graff-Radford et al., 2012).
Lewy body pathology to AD pathology is taken into account to determine
the likelihood of the patient presenting with a clinical syndrome of DLB. Parkinsonism
Fig. 95.14 summarizes the pathological features of DLB. Dopaminergic therapy. Parkinsonism in DLB is l-dopa
Treatment. A systematic approach to DLB patients aids in responsive, although less so than PD. To minimize the risk of inducing
maximizing function. Cognitive symptoms, motor symptoms or exacerbating neuropsychiatric symptoms such as hallucinations,
(parkinsonism, falls), neuropsychiatric symptoms, autonomic l-dopa/carbidopa should be introduced at a low dose and titrated
symptoms, and sleep disorders should all be addressed. Discontinuing slowly. Many medications may exacerbate various symptoms of DLB
medications which can exacerbate cognitive or motor symptoms is an and should be avoided where possible. Specifically, dopamine agonists
important part of the management of DLB patients. These medications are more likely to exacerbate hallucinations and behavioral disorders.
include those with anticholinergica properties, antipsychotic Selegiline may also exacerbate psychosis, and anticholinergics such as
medications with antidopaminergic properties, and benzodiazepines. benztropine and trihexyphenidyl can cause confusion.
Cognitive symptoms Neuropsychiatric features. Depression and anxiety can be
Acetylcholinesterase inhibitor drugs. Compared to AD, DLB treated with SSRIs. As previously noted, it is important to avoid
patients have a greater loss of cholinergic function. The loss of cholinergic anticholinergic agents when selecting an antidepressant.
function with comparatively intact structural integrity has provided the Hallucinations and delusions that do not bother the patient
rationale to suggest that DLB patients may respond better to AChEIs than may not require treatment. First-line therapy for hallucinations
AD dementia patients. In 2000, a double-blind, randomized, controlled and delusions in DLB should be AChEIs, which have been shown
multicenter trial demonstrated that DLB subjects receiving rivastigmine to improve delusions and hallucinations (McKeith et al., 2000c).
A B
C D
Fig. 95.14 Dementia With Lewy Bodies Pathology. Hematoxylin and eosin (H&E) stain of anterior cingulate
cortex (A) and temporal cortex (B) demonstrating Lewy bodies. Alpha-synuclein stain of anterior cingulate
cortex (C) and temporal cortex (D) demonstrating Lewy bodies. (Courtesy Dr. Joseph Parisi.)
Typical antipsychotics are contraindicated in DLB due to severe sen- Sleep disorders. RBD is the most common sleep disorder in DLB,
sitivity and association with increased mortality. Atypical antipsy- but other sleep disorders are common and can be treated. Therefore,
chotics (risperidone, olanzapine, and quetiapine) are associated with patients should be screened for sleep apnea because treatment can
increased mortality in dementia and their use should be avoided if improve daytime alertness. Treatment of RBD should be individualized
possible (Schneider et al., 2005). Pimavanserin was approved to treat to see if the patient is at risk of harming themselves or their bed
Parkinson psychosis by the FDA and has not been approved for use partner. Nonpharmacological treatments include removal of sharp
in DLB. It also carries a black box warning that elderly patients with objects from around the bed, creating barriers between bed partners,
dementia treated with antipsychotics are at increased risk of death. or even bed alarms. Melatonin can improve RBD and is well tolerated.
When the benefits of antipsychotics are felt to outweigh the risks, Clonazepam is often used as a second-line option at low doses, but this
quetiapine and clozapine are often used to minimize the risk of wors- should be monitored carefully as benzodiazepines are typically avoided
ening parkinsonism. The use of clozapine is limited because of the risk in dementia and may increase fall risk.
of agranulocytosis requiring routine blood monitoring. Antipsychotics
should be used at the lowest effective dose for the shortest interval nec- Parkinson Disease Dementia
essary, due to side effects. PDD is distinguished from DLB by the presence of parkinsonism pre-
Autonomic symptoms. Since autonomic symptoms vary ceding cognitive decline for at least 1 year. About 80% of PD patients
significantly among patients, an individualized approach is necessary. will develop dementia (Aarsland and Kurz, 2010). The clinical features
Constipation can be treated by increasing water and fiber intake initially of PDD are otherwise similar to DLB and some authorities have ques-
followed by over-the-counter therapies such as psyllium powder and tioned whether they are distinct entities or different presentations of
rarely prescription therapies. Orthostasis can initially be treated by the spectrum of Lewy body diseases.
lifestyle modifications and limiting drugs that lower blood pressure. There are some pathological differences between PDD and DLB.
As dysautonomia worsens, pharmacological interventions with For example, PDD patients have greater substantia nigra neuronal loss.
midodrine or fludrocortisone may become necessary. In appropriate In addition to treatment of motor symptoms, a recent multicenter
patients, erectile dysfunction can be managed with phosphodiesterase placebo-controlled study of the AChEI rivastigmine in PDD showed an
inhibitors. improvement in cognitive, neuropsychiatric, and functional features,
leading to FDA approval (Emre et al., 2004). An MCI stage of PDD is Pathology. The gross pathology of MSA-P demonstrates
recognized, and similar criteria to MCI due to AD have been suggested degeneration of the putamen and lateral substantia nigra. The
(Litvan et al., 2012). hallmark lesion of MSA is glial cytoplasmic inclusions that consist of
filamentous inclusions of synuclein in oligodendroglia. These can be
Multiple System Atrophy located in the cortex, subcortical areas, cerebellum, spinal cord, and
Multiple system atrophy was known as striatonigral degeneration, dorsal root ganglia.
olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome. Treatment. Treatment is symptomatic, with autonomic dysfunction
Current consensus criteria (Gilman et al., 2008) recognize two types of being most disabling. Early in the course, lifestyle modifications can be
MSA: MSA-P (l-dopa nonresponsive parkinsonism) and MSA-C (cer- effective, including increasing salt and fluid intake, sleeping with the
ebellar ataxia). Approximately 58% of European patients with MSA head of the bed elevated, learning physical maneuvers, and wearing
have MSA-P (Geser et al., 2006) while MSA-C is more common in the compression garments. Later, pharmacological intervention may
Japanese population (84%) (Yabe et al., 2006). Mean age of onset is 54 become necessary with fludrocortisone, midodrine, pyridostigmine, or
(Ben-Shlomo et al., 1997) with mean survival from symptom onset of droxidopa often providing a measure of symptomatic relief although
5.7 years (Bjornsdottir et al., 2013). The average annual incidence rate they may cause supine hypertension. Raising the head of the bed can
of MSA is 3 per 100,000 person-years (Bower et al., 1997). The preva- help mitigate the supine hypertension. A subset of MSA-P patients
lence is estimated at 4.4 cases per 100,000 (Schrag et al., 1999). may respond to l-dopa, but the benefit is often transient and limited,
Patients with pure autonomic failure may evolve into MSA. A pro- with treatment exacerbating orthostatic hypotension. Physical and
spective study of pure autonomic failure found that about one-third occupational therapy can be helpful with gait instability and safety
of patients later met clinical criteria for a synucleinopathy, including evaluation. Referral to a sleep medicine specialist for evaluation
MSA within 4 years of follow-up (Kaufmann et al., 2017). of respiratory stridor should be considered as stridor carries a poor
Clinical characteristics include autonomic dysfunction with any prognosis (Silber and Levine, 2000). Dysphagia should also be
combination of parkinsonism and/or ataxia. Autonomic symptoms monitored.
may manifest as cardiovascular in the form of orthostatic hypo-
tension, urogenital or gastrointestinal dysfunction. Erectile dys- Tauopathies
function is common among male MSA patients. RBD is strongly Corticobasal Degeneration/Corticobasal Syndrome
associated with MSA, reflecting the underlying synuclein pathol- In the 1960s, Rebeiz reported three patients with an asymmetrical
ogy. In MSA-C, ataxia progresses faster than in other degenerative akinetic rigid syndrome and apraxia with unique pathological fea-
ataxias (Klockgether et al., 1998). The parkinsonism in MSA-P typ- tures which was called corticodentatonigral degeneration with neu-
ically lacks the classic rest tremor and l-dopa responsiveness seen ronal achromasia (Rebeiz et al., 1968). Later the name changed to
in PD and progresses more rapidly than in PD (Seppi et al., 2005). corticobasal ganglionic degeneration or corticobasal degeneration.
Other key symptoms associated with MSA include pyramidal signs, The clinical syndrome of progressive asymmetric rigidity and apraxia
stridor, dysarthria, oculomotor dysfunction, pseudobulbar affect, became synonymous with corticobasal degeneration. Subsequent
myoclonus, orofacial dystonia, and dysphagia (Gilman et al., 2008). autopsy series revealed patients with this characteristic clinical syn-
Significant cognitive deficits at diagnosis are rare in MSA. In the drome had h eterogeneous pathology including CBD, PSP p athology,
2nd consensus statement on the diagnosis of multiple system atro- AD pathology, or Creutzfeldt-Jakob disease (CJD) (Boeve et al.,
phy, the presence of dementia was considered a red flag against the 1999). Currently, corticobasal syndrome (CBS) refers to a clinical syn-
diagnosis of MSA (Gilman et al., 2008), although in one clinical drome characterized by asymmetric rigidity, apraxia, and alien limb
series, dementia was diagnosed in 10 of 58 MSA patients with 3 phenomenon variably associated with cortical sensory loss, myoclonus,
of 58 presenting with cognitive symptoms (Kitayama et al., 2009). dystonia, and parkinsonism. This syndrome can be caused by several
Neuropsychological testing can often detect executive deficits and pathologies. The term CBD refers to the distinct pathological entity
slowed processing speed. Common neuropsychiatric symptoms which can present with a variety of clinical syndromes. While CBD is
include depression and anxiety. the most common pathological substrate of CBS, this pathology only
Evaluation. Autonomic dysfunction can be detected by supine accounts for approximately 50% of cases of CBS (Boeve et al., 2003). In
and standing blood pressure, with the drop of 30 mm Hg systolic or the most recent criteria for the diagnosis of CBD, four clinical pheno-
15 mm Hg diastolic required in order to meet diagnostic criteria for types are recognized (corticobasal syndrome, frontal b ehavioral-spatial
probable MSA. Autonomic reflex screen testing may demonstrate syndrome, nonfluent/agrammatic variant of PPA, and PSP-syndrome)
the orthostatic blood pressure drop and other signs of adrenergic or (Armstrong et al., 2013). The mean age of symptom onset is approxi-
cardiovagal failure. Thermoregulatory sweat testing demonstrates mately 64 years, with average disease duration of 6.6 years (Armstrong
anhidrosis in a central pattern. Elevated postvoid residual volumes are et al., 2013). CBS has an incidence rate per year of approximately 0.02
often seen in patients with urological symptoms. cases per 100,000 persons (Winter et al., 2010).
Neuroimaging. The imaging features differ between the types of The key features of CBS are a progressive, asymmetric apraxia
MSA. In MSA-C, atrophy of the pons, cerebellum, or middle cerebellar and rigidity. Cortical features variably associated with CBS include
peduncles is characteristic. On T2-weighted MRI, hyperintensity can cortical sensory loss, alien limb syndrome, mirror movements,
be seen in the pons (“hot cross bun sign”), middle cerebellar peduncles, cognitive impairment, and myoclonus. Motor features associated
and cerebellum. Putaminal abnormalities are more commonly seen with CBS include bradykinesia, dystonia, tremor, and poor l-dopa
in MSA-P with T2-hyperintensity of the lateral putaminal rim or response. Additionally, the hand can form a characteristic fist.
hypointensity of the posterior putamen. Common neuropsychiatric features include depression, disinhi-
FDG-PET findings in MSA include hypometabolism of the basal bition, and obsessive-compulsive features. Capgras and halluci-
ganglia and cerebellum (Eckert et al., 2005). nations are quite rare in CBS relative to other neurodegenerative
Genetics. Recently, mutations in CoQ2 were shown to be diseases (Geda et al., 2007). Most patients with underlying CBD
associated with MSA in Japanese cases (2013), but this mutation was pathology present with cognitive or behavioral symptoms, with
not confirmed in other populations. a significant portion presenting as bvFTD (Lee et al., 2011b).
A B
Fig. 95.15 Corticobasal Degeneration Pathology. A, Tau-positive astrocytic plaque with pleomorphic neu-
ronal inclusions and neurites with tau staining. B, Balloon neuron on hematoxylin and eosin (H&E). (Images
courtesy Dr. Joseph Parisi.)
Neuropsychological testing demonstrates prominent deficits in characterized by unexplained falls, symmetric predominantly axial
executive functions, language, and visual-spatial functions, with rigidity, bradykinesia, poor l-dopa responsiveness, and impaired ver-
relative sparing of episodic memory at presentation (Murray et al., tical gaze, especially downgaze. This typical presentation is also called
2007). Richardson syndrome. Other clinical features include eyelid apraxia,
Structural MRI in CBS often shows asymmetrical frontoparietal dysphagia, abnormal neck posturing, pseudobulbar affect, long tract
atrophy corresponding to the side contralateral to the affected limb. signs, and impaired saccadic pursuits. Five clinical presentations asso-
FDG-PET imaging demonstrates focal asymmetric hypometabolism in ciated with PSP pathology have been described:
the posterior frontal, anterior parietal region. 1. PSP-S (described above).
Pathology. The gross pathology of CBD includes atrophy of 2. PSP-parkinsonism (characterized by limb and axial rigidity,
the superior frontal gyrus, thinning of the corpus callosum, and tremor, l-dopa responsiveness).
loss of pigment of the substantia nigra. CBD is a four-repeat (four 3. PSP-pure akinesia with gait freezing (early gait disorder with sub-
microtubule-binding domains) tauopathy. The pathology in CBD sequent freezing, early micrographia, phonation difficulties, lack of
occurs in both the cortex and white matter. Tau accumulates in certain l-dopa response, or early eye movement abnormalities).
regions including cortex, basal ganglia, basal nucleus of Meynert, 4. PSP-corticobasal syndrome (CBS as previously described).
thalamus, and brainstem (Dickson et al., 2002). Rebeiz described 5. PSP-progressive nonfluent aphasia/apraxia of speech (language
swollen achromatic neurons, now known as ballooned neurons, which and/or speech disorder characterized by agrammatism and/or
are present in CBD but not specific (Rebeiz et al., 1968). The hallmark speech apraxia) (Williams and Lees, 2009).
of CBD is the astrocytic plaque. These plaques are tau positive without In 2017, new criteria for PSP were published by the Movement
amyloid. Research criteria for the pathological diagnosis of CBD Disorder Society recognizing four functional domains (ocular motor
also include tau-reactive gray- and white matter threadlike lesions dysfunction, postural instability, akinesia, and cognitive dysfunction)
(Dickson et al., 2002). Fig. 95.15 summarizes the key pathology of which can predict PSP. Patients can be categorized as probable, possi-
CBD. The clinical presentation is determined by the distribution of ble, or suggestive of PSP based on degree of certainty (Hoglinger et al.,
tau. In autopsy-proven CBD patients, tau deposition in the motor and 2017).
somatosensory cortex was associated with a CBS presentation while Neuropsychiatric features of PSP-S include prominent apathy, dis-
tau deposition in limbic regions and the hindbrain was associated with inhibition, depression, and anxiety (Litvan et al., 1996). Bradyphrenia
PSP syndrome (Kouri et al., 2011). can be prominent and PSP can mimic bvFTD. The annual incidence
The tau genotype consists of two haplotypes, H1 and H2. In typical rate of PSP-S is 5.3 per 100,000 person-years (Bower et al., 1997). The
populations approximately 60% are homozygous for H1/H1, but in prevalence is approximately 6.4 per 100,000 (Schrag et al., 1999).
PSP and CBD over 80% are H1/H1, indicating that being H1 is a risk The disease duration is approximately 7 years. Most patients die
factor for CBD (Houlden et al., 2001). Interestingly, some MAPT gene from complications related to dysphagia. Neuropsychological profile
mutations can cause CBD pathology. includes prominent executive dysfunction. Language and speech diffi-
Treatment. No disease-modifying therapy is available for CBD/ culties can be present or even dominate the clinical presentation.
CBS; therefore, treatment is symptomatic. A minority of patients will Structural MRI demonstrates midbrain atrophy and has been called
have a modest response of rigidity and bradykinesia to dopaminergic the “hummingbird sign” (Kato et al., 2003). A small midbrain to pons
therapy. If myoclonus is problematic, clonazepam, levetiracetam, and ratio may also predict PSP (Massey et al., 2013). Enlargement of the
gabapentin can be considered. Physical and occupational therapy are third ventricle is also described in PSP. The FDG-PET scan reveals
important to prevent falls, provide adaptive equipment, and maximize frontal-subcortical hypometabolism. Midbrain hypometabolism is
function with appropriate exercises. also described and has been called the “pimple sign” (Botha et al.,
2014).
Progressive Supranuclear Palsy Of patients clinically diagnosed with PSP-S, 76% will have PSP at
The nomenclature of PSP is confusing. PSP syndrome (PSP-S) refers autopsy, with CBD, MSA, and DLB accounting for most of the other
to the classical clinical presentation, while PSP pathology refers to pathologies (Josephs and Dickson, 2003). PSP-S caused by CBD dif-
pathological substrate. The classical clinical presentation of PSP-S is fers from PSP-S caused by PSP pathology. PSP-S with underlying CBD
A B
C D
Fig. 95.16 Progressive Supranuclear Palsy Pathology. A, Hematoxylin and eosin (H&E) stain demonstrat-
ing globose neurofibrillary tangle. B, Bielschowsky stain demonstrating globose neurofibrillary tangle. C, Tau
stain demonstrating globose neurofibrillary tangle. D, Neurofilament stain demonstrating ballooned neuron.
(Courtesy Dr. Joseph Parisi.)
pathology is more associated with cognitive behavioral dysfunction body (Alzheimer, 1911). Only later was it recognized that only a small
and tends to have less subthalamic nucleus neuronal loss but more proportion of FTD cases have Pick bodies at autopsy. In 1982, Mesulam
neuronal loss in the medial aspect of the substantia nigra and degen- reported six patients with “slowly progressive aphasia,” and later intro-
eration of the anterior part of the corpus callosum (Kouri et al., 2011). duced the term primary progressive aphasia (PPA) (Mesulam, 1982,
Gross pathological findings with PSP pathology include midbrain, 1987). Brun and Gustafson in Sweden (Gustafson et al., 1990) and
superior cerebellar peduncle, and subthalamic nucleus atrophy. PSP Neary and Snowden in the UK (Neary et al., 1988) termed the group
is a four-repeat tauopathy characterized by globose tangles in the glo- of disorders “frontal lobe dementia of the non-Alzheimer type,” and
bus pallidus, substantia nigra, and subthalamic nucleus. The pathology “dementia of the frontal type,” respectively.
also affects motor cortex, striatum, pontine nuclei, inferior olive, and
dentate nucleus. Tufted astrocytes are also present. The neuronal loss Nomenclature
in PSP correlates with NFTs rather than the astrocytic pathology. Fig. FTD is an encompassing term that refers to a group of clinical syn-
95.16 summarizes the key pathological features of PSP. dromes that are characterized by degeneration of the frontal and tem-
No disease-modifying treatment is available for PSP. Subgroups of poral lobes, while frontotemporal lobar degeneration (FTLD) is an
PSP (PSP-parkinsonism) patients respond to l-dopa therapy. SSRIs encompassing term for the spectrum of pathologies associated with
can be used for depression, anxiety, and pseudobulbar affect. FTD.
Diagnostic Criteria
FRONTOTEMPORAL DEMENTIAS In 1998, consensus criteria were published that recognized three clin-
In 1892, Arnold Pick described a patient with progressive aphasia ical variants of FTD that correlate with FTLD pathologically: FTD,
associated with frontal and temporal lobar atrophy. This was the first progressive nonfluent aphasia (PNFA), and semantic dementia (Neary
description of FTD. In 1911, Alois Alzheimer described the patholog- et al., 1998). More recently updated criteria have been proposed to
ical hallmark of this disorder, a rounded inclusion now called a Pick further characterize FTD variants including bvFTD (Rascovsky et al.,
2011) and the PPA variants (Gorno-Tempini et al., 2011). Currently, considered to aid in the diagnosis (Weintraub et al., 2009). Apraxia
three clinical variants of FTD are recognized: bvFTD, semantic demen- of speech often co-occurs and accounts for some of the appearance of
tia or semantic variant PPA (svPPA), and PNFA. nonfluency. Comprehension for complex sentences can be impaired.
Behavioral symptoms often co-occur but are not the presenting
Frontotemporal Dementia Epidemiology feature. Over time, patients often develop a parkinsonian syndrome.
In a UK-based study of dementia patients aged 45 to 64, the prevalence Semantic variant primary progressive aphasia. svPPA is a fluent
of FTD and AD was the same (15 per 100,000) (Ratnavalli et al., 2002). aphasia characterized by a prominent anomia with loss of single word
In a population-based study in Rochester, MN, the incidence rates meaning. Nouns are particularly difficult to comprehend. Patients
(number of new cases per 100,000 person-years) of FTD were 2.2 for will replace a specific word with a more general word such as “it”
ages 40–49, 3.3 for ages 50–59, and 8.9 for ages 60–69 (Knopman et al., for “telephone.” In most patients repetition is relatively spared, and
2004). While FTD is an early onset dementia, 30% of FTD patients grammar remains intact. The commonest age range of presentation
are estimated to be over the age of 65 (Knopman and Roberts, 2011). in svPPA is between 66 and 70 years of age (Hodges and Patterson,
Median survival from symptom onset among FTD patients is approx- 2007). Surface dyslexia occurs in svPPA, where irregularly pronounced
imately 6 years but FTD with motor neuron disease (FTD-MND) words such as “colonel” and “pint” are pronounced phonetically.
patients have a significantly shorter survival of approximately 3 years svPPA patients also may develop loss of visual object meaning and
(Hodges et al., 2003). prosopagnosia (difficulty recognizing familiar faces) when the right
temporal lobe is more affected than the left. Testing for prosopagnosia
Behavioral Variant Frontotemporal Dementia can be accomplished by showing pictures of famous celebrities and
Clinical Presentation asking the patient to identify the famous face (Tiger Woods) among
The characteristic clinical features of bvFTD include a change in per- distractor (non-famous) faces. To test person knowledge, a follow-up
sonality and behavior such as disinhibition, and executive dysfunction question of asking who, in fact, Tiger Woods is can also be helpful. A
such as poor planning, loss of judgment, difficulty with organization svPPA patient may not know he is a golfer or in professional sports.
and loss of insight. In bvFTD, patients exhibit social isolation, pecu- Over time, svPPA patients commonly develop coexisting behavioral
liar affiliations, antisocial behavior, compulsions, and drug or alcohol issues which overlap with bvFTD. svPPA patients are more likely to
abuse. A change in dietary preference, particularly an increased inter- develop food fads and seek social attention, while bvFTD patients are
est in sweets, may occur, although indiscriminate overeating can also more likely to overeat and become withdrawn (Snowden et al., 2001).
occur. Other features include apathy, decreased pain response, utiliza- Additionally, patients with svPPA tend not to have parkinsonism, a
tion behaviors, and obsessive compulsive and perseverative behaviors. family history of dementia, or associated motor neuron disease. Some
Patients often lack empathy and insight. They may show little concern patients present with nonverbal semantic deficits, typically right greater
for friends or family members. Language deficits occur but are not the than left temporal involvement, do not meet root criteria for PPA, and
presenting feature. The most recent criteria for bvFTD are listed in the term semantic dementia may continue to be most appropriate.
Table 95.9A (Rascovsky et al., 2011). Differentiating features are sum-
marized in Table 95.9B. Amnestic Syndromes
Parkinsonian features are often mild. Motor neuron disease more Occasionally, elderly patients with FTLD pathology can present with
commonly occurs with bvFTD than PPA. Early in the disease course an amnestic syndrome resembling AD.
neuropsychological testing can be completely normal. Typically, neu-
ropsychological testing demonstrates less episodic memory impair-
HIPPOCAMPAL SCLEROSIS OF AGING
ment than patients with semantic dementia or dementia due to AD
(Hodges et al., 1999). Executive function deficits are characteristic Hippocampal sclerosis refers to loss of neurons and gliosis in the
but may be absent. Semantic memory is spared in bvFTD relative to subiculum and CA1 of the hippocampus which is accompanied with
semantic variant PPA and AD dementia (Rogers et al., 2006). TDP-43 pathology. Patients present typically over the age of 75 with
Hodges described a disorder he termed bvFTD phenocopy describ- a progressive amnestic course (Pao et al., 2011). In the elderly, hip-
ing patients who met bvFTD criteria but had no major imaging find- pocampal sclerosis is seen in approximately 13% of autopsy cases. It
ings of FTD and remained clinically stable over time. This disorder may occur as a co-pathology with AD or in isolation (Nag et al., 2015).
may represent lifelong personality quirks and unusual behaviors or, While clinical features of hippocampal sclerosis and AD dementia
alternatively, a subset may represent a slowly progressive bvFTD sec- overlap, the presence of focal medial temporal and posterior cingulate
ondary to a C9ORF72 mutation (Khan et al., 2012). hypometabolism is a promising biomarker to distinguish hippocampal
sclerosis from AD dementia (Botha et al., 2018).
Primary Progressive Aphasias
The primary progressive aphasias refer to a group of disorders where Argyrophilic Grain Disease
neurodegeneration targets the language network. Two variants of PPA Argyrophilic grain (AG) disease is a 4-repeat tauopathy. Patients with
are under the FTD umbrella: PNFA and semantic dementia or svPPA. AG may have an unusually long course of aMCI (Petersen et al., 2006)
The logopenic variant is most frequently caused by AD pathology and or present with an FTD syndrome.
is not considered a type of FTD. Criteria were published for the classi-
fication of the PPA variants (Gorno-Tempini et al., 2011). Frontotemporal Dementia With Motor Neuron Disease
Nonfluent/agrammatic variant primary progressive aphasia. FTD-MND represents approximately 10%–15% of FTDs. Identification
Agrammatic primary progressive aphasia is characterized by of MND in FTD patients is important because of the decreased survival
nonfluent, hesitant speech. Agrammatism occurs and is characterized compared to FTD patients (<3 years). BvFTD with MND is associated
by telegraphic speech, misuse of pronouns, and errors in sentence with a longer survival time compared to a language-dominant FTD-
construction. Word and object knowledge is relatively spared. Early MND phenotype. Traditional teaching reported spared cognition in ALS
in the course, agrammatism may only be evident in writing samples. patients, but recent studies have shown that cognitive impairment and
The Northwestern Anagram Test which focuses on grammar can be subtle executive dysfunction is common in ALS (Phukan et al., 2007).
TABLE 95.9A International Consensus Criteria for Behavioral Variant FTD

I. Neurodegenerative disease. The following symptom must be present to meet criteria for bvFTD:
A. Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by a knowledgeable informant).
II. Possible bvFTD, Three of the following behavioral/cognitive symptoms (A–F) must be present to meet criteria. Ascertainment requires that symptoms be persistent
or recurrent, rather than single or rare events.
A. Early behavioral disinhibition (one of the following symptoms [A.1–A.3] must be present):
A.1. Socially inappropriate behavior
A.2. Loss of manners or decorum
A.3. Impulsive, rash, or careless actions
B. Early apathy or inertia (one of the following symptoms [B.1–B.2] must be present):
B.1. Apathy
B.2. Inertia
C. Early loss of sympathy or empathy (one of the following symptoms [C.1–C.2] must be present):
C.1. Diminished response to other people’s needs and feelings
C.2. Diminished social interest, interrelatedness, or personal warmth
D. Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following symptoms [D.1–D.3] must be present):
D.1. Simple repetitive movements
D.2. Complex, compulsive, or ritualistic behaviors
D.3. Stereotypy of speech
E. Hyperorality and dietary changes (one of the following symptoms [E.1–E.3] must be present):
E.1. Altered food preferences
E.2. Binge eating, increased consumption of alcohol or cigarettes
E.3. Oral exploration or consumption of inedible objects
F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (all of the following symptoms [F.1–F.3]
must be present):
F.1. Deficits in executive tasks
F.2. Relative sparing of episodic memory
F.3. Relative sparing of visuospatial skills
III. Probable bvFTD All of the following symptoms (A–C) must be present to meet criteria:
A. Meets criteria for possible bvFTD
B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores)
C. Imaging results consistent with bvFTD (one of the following [C.1–C.2] must be present):
C.1. Frontal and/or anterior temporal atrophy on MRI or CT
C.2. Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or single-photon emission computed tomography
IV. Behavioral variant FTD with definite FTLD pathology. Criterion A and either criterion B or C must be present to meet criteria:
Meets criteria for possible or probable bvFTD
Histopathological evidence of FTLD on biopsy or at postmortem
Presence of a known pathogenic mutation
V. Exclusionary criteria for bvFTD. Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be
negative for probable bvFTD.
A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders
B. Behavioral disturbance is better accounted for by a psychiatric diagnosis
C. Biomarkers strongly indicative of Alzheimer disease or other neurodegenerative process.
Reprinted with permission from Rascovsky, K., Hodges, J.R., Knopman, D., et al., 2011. Sensitivity of Revised Diagnostic Criteria for the
Behavioural Variant of Frontotemporal Dementia. Brain. 134(Pt 9):2456–77.
TABLE 95.9B Features of Frontotemporal Dementia Subtypes

FTD type BvFTD SvPPA Agrammatic/nonfluent PPA
% of FTD cases 50 25 25
Most common underlying pathology Tau-related or TDP-43 TDP type C Tau-related
Typical anatomy Insula, amygdala, orbitofrontal, anterior L. anterior temporal L. inferior frontal gyrus
cingulate cortex
Expanded Frontotemporal Dementia Syndromes disorders (Boeve et al., 2003; Josephs, 2008). While CBS and PSP-S
Features of bvFTD and PPA are recognized in a subgroup of patients have unique features, there is significant clinical overlap includ-
with progressive apraxia of speech, CBS or PSP-S. Therefore, ing associated frontal lobe dysfunction on neuropsychometric
these disorders are considered in the differential of FTD-related testing.
A A B C D
B
Fig. 95.17 A, Longitudinal serial coronal magnetic resonance imaging (MRI) in patient with bvFTD demon-
strating increasing frontal and temporal atrophy. A, 1 year of symptoms; B, 3 years of symptoms; C, 7 years
of symptoms; D, 9 years of symptoms. B, T2 fluid-attenuated inversion recovery MRI in same patient 7 years
after symptom onset. bvFTD, Behavioral variant frontotemporal dementia. (Courtesy Bradley Boeve.)
Progressive apraxia of speech is a disorder of motor speech plan-

ning. It can occur with agrammatism or on its own. When it occurs in
isolation, it is called primary progressive apraxia of speech (PPAOS)
(Josephs et al., 2012). The speech is characterized by slow rate, sound
distortions, distorted substitutions, and trial-and-error articulatory
movements. The anatomical correlate of PPAOS is atrophy/hypo
metabolism of the lateral premotor area and supplementary motor
cortices. When apraxia of speech occurs with or without agramma-
tism, the pathology is most often tau (Josephs et al., 2006).
Neuroimaging
Structural Magnetic Resonance Imaging
Structural MRI and functional imaging studies provide complemen-
tary information in the diagnosis of FTD. In bvFTD, atrophy occurs
in the anterior cingulate cortex, anterior insula, striatum, amygdala,
hypothalamus, and thalamus comprising the salience network regard-
less of underlying pathological substrate (Perry et al., 2017; Rosen
et al., 2002).
In svPPA, the left anterior temporal pole is the region of greatest
atrophy (Mummery et al., 2000). Other regions that can be involved
include the orbitofrontal region, insula, anterior cingulate right ante-
rior temporal lobe, and hippocampus (Rosen et al., 2002). Agrammatic
PPA is associated with left inferior frontal atrophy (Gorno-Tempini
et al., 2004). When apraxia of speech is present, atrophy is predom-
inantly in the superior premotor and supplementary motor regions Fig. 95.18 T1 coronal magnetic resonance imaging in patient with
(Josephs et al., 2013). Furthermore, in patients with progressive semantic variant primary progressive aphasia (svPPA) demonstrating
apraxia of speech, agrammatic PPA, or both, tests of apraxia of speech asymmetric temporal atrophy and dilation of the collateral sulcus.
correlate with premotor volume while tests of aphasia correlate with
regions of the left hemisphere language network including Broca’s area
(Whitwell et al., 2013). Fig. 95.17 provides an example of longitudinal is characterized by bilateral frontal-temporal hypometabolism.
change on MRI in a patient with bvFTD. Fig. 95.18 shows an MRI in a Agrammatic PPA is associated with the left posterior inferior frontal
patient with svPPA. lobe hypometabolism. svPPA is associated with left anterior tempo-
ral hypometabolism. PPAOS is characterized by a focal hypometabo-
Functional Imaging lism in the supplementary motor area and superior premotor cortex.
FDG-PET has been shown to improve accuracy of diagnosis in Figs. 95.19–95.21 show PET scans for subjects with svPPA, nonfluent/
autopsy-confirmed FTD patients (Foster et al., 2007). BvFTD
agrammatic aphasia, and PPAOS.

(Cortex ID) in a semantic variant primary progressive aphasia (svPPA) patient.
B Anterior Posterior Superior Inferior

Fig. 95.20 A, Top row: Axial magnetic resonance imaging brain in agrammatic aphasia demonstrating left
inferior frontal atrophy. B, Bottom row: Fluorodeoxyglucose-positron emission tomography statistical stereo-
tactic surface projection map (Cortex ID) in patient with progressive agrammatic aphasia showing hypome-
tabolism in the left greater than right frontal lobe. Notice greatest area of hypometabolism near Broca’s area.
PiB-PET of inclusion body myopathy, Paget disease of bone, and frontotem-

PiB-PET has also proven useful in discriminating FTD from AD. PiB- poral dementia. TAR DNA-binding protein 43 mutations have been
PET is more sensitive than FDG-PET on both visual interpretation and reported in patients with FTD with or without MND (Benajiba et al.,
quantitative measures while FDG-PET is more specific only quantita- 2009; Borroni et al., 2009). Less common genes associated with FTD
tively (Rabinovici et al., 2011). include TBK1, TIA1, and FUS.
Tau-PET Frontotemporal Dementia and Parkinsonism Linked to

[18F]-AV-1451 (flortaucipir) was developed to bind to AD-type tau Chromosome 17
which is a mix of 3 microtubule-binding domain repeats (3R-tau) and Frontotemporal dementia and parkinsonism linked to chromosome
4R-tau. FTD syndromes due to 3R-tau such as Pick’s pathology or 4R-tau 17 (FTD-P 17) refers to mutations in either MAPT or progranulin.
such PSP or CBD pathology, therefore, do not bind the current tau PET Microtubule-associated protein tau mutations. The first FTD
ligand well. In FTD cases secondary to MAPT mutations whether the tau gene discovery was MAPT mutations as a cause of behavioral and
PET will be positive depends on where the mutation occurs. Inclusion personality changes associated with parkinsonism (FTD-P 17) (Hutton
of exon 10 in transcripts determines if 3 or 4R-tau is produced. MAPT et al., 1998). Clinical phenotypes vary and can include FTD, PSP-S,
mutations outside of exon 10 (V337M and R406W) produce AD-like and CBS. Despite this discovery, a group of families with FTD linked to
tau (mixed 3R/4R), and, therefore, have tau-PET signal close to the AD chromosome 17 without MAPT mutations or tau pathology remained
dementia levels. Mutations inside exon 10 have lower levels of tau-PET uncharacterized. Mutations in these remaining families were later
SUVR than AD dementia participants (Jones et al., 2018b). linked to progranulin. For MAPT mutations, median age of onset is 45
while the median survival is 7 years. Anteromedial temporal atrophy is
Laboratory Evaluation characteristic on MRI (Fig. 95.22; Whitwell et al., 2009).
In the FTD spectrum disorders serum and CSF studies are normal. Progranulin mutations. In 2006, two groups demonstrated that
Active investigation for the role of serum and CSF biomarkers in pre- these remaining chromosome 17 FTD families have mutations in the
dicting pathology for FTD subtypes is underway. Progranulin serum PGRN gene (Baker et al., 2006; Cruts et al., 2006). Plasma progranulin
levels have shown promise in discriminating those with and with- levels can be used as a diagnostic test to determine when a PGRN
out progranulin mutations (Finch et al., 2009). Some studies have mutation is present (Finch et al., 2009). Low plasma progranulin levels
demonstrated plasma TDP-43 and CSF TDP-43 may predict TDP-43 are detected in both symptomatic and asymptomatic individuals with
pathology although more research is needed to confirm these findings PGRN gene mutations. Significant clinical variability exists between
(Foulds et al., 2008; Steinacker et al., 2008). individuals with the same PGRN mutation, indicating other genetic and
environmental factors play an important role in the clinical phenotype
Genetics (Rademakers et al., 2007). The clinical presentations include bvFTD,
A positive family history occurs in approximately 40% of FTD cases. PPA, AD dementia phenotype, and CBS. The median age of onset is
Several genes associated with FTD have been described. The three approximately 59, with median survival of 6 years (Boeve et al., 2012).
major genes include MAPT, which account for approximately 5%–10% Neuroimaging reveals asymmetric frontal-parietal and posterior
of FTD cases (10%–20% of familial cases), progranulin which accounts temporal atrophy (Fig. 95.23; Boeve et al., 2012; Whitwell et al., 2012).
for 10% of FTD cases, and chromosome 9 open reading frame 72
(C9ORF72) which accounts for approximately 15% (25% of familial Chromosome 9 Open Reading Frame 72
cases) of FTD cases. These genes are dominantly inherited. Several Most recently a noncoding repeat expansion in C9ORF72 was found
other genes have been implicated in FTD, including charged mul- in FTD and ALS patients (DeJesus-Hernandez et al., 2011). In
tivesicular body protein 2B (CHMP2B) on chromosome 3 (Skibinski healthy individuals 2–23 copies of GGGGCC repeat are present. In
et al., 2005) and valosin-containing protein (VCP) mutations on chro- contrast, in FTD/ALS families hundreds to thousands of copies exist.
mosome 9 (Watts et al., 2004). Mutations in VCP cause a syndrome This is the most common cause of familial FTD/ALS. It also accounts
Fig. 95.21 Fluorodeoxyglucose-positron emission tomography statistical stereotactic surface projection

map (Cortex ID) showing hypometabolism in right premotor cortex and right supplementary motor area in a
patient with primary progressive apraxia of speech (PPAOS).
for approximately 6% of sporadic FTD and approximately 25% of have been seen in clinically diagnosed AD, PD, and CBS. Recently,
familial FTD (Majounie et al., 2012). While most patients present C9ORF72 mutations were shown to be the most common cause of
with FTD or ALS, approximately 30% have FTD-MND. BvFTD is the Huntington disease phenocopy (Hensman Moss et al., 2014). Repeat
most common FTD presentation. The clinical phenotype can vary length does not predict phenotype between FTD-MND, ALS, or FTD
widely, including parkinsonism and psychosis. C9ORF72 mutations (van Blitterswijk et al., 2013). Median age (range) of onset is 52, with
median survival of 5 years (Boeve et al., 2012). Neuroimaging reveals
fairly symmetric bilateral frontotemporal atrophy (Fig. 95.24; Boeve
et al., 2012). FDG-PET in a C9ORF72 patient is demonstrated in Fig.
95.25.
Pathology
Gross findings include significant frontal and temporal lobar atrophy.
Pathological diagnoses of FTLD are based on the major deposited pro-
tein in the brain. Three major proteins are associated with FTLD: the
microtubule-associated protein tau (FTLD-tau) (approximately 40%),
the TAR DNA-binding protein of 43 kD (FTLD-TDP) (approximately
50%), and the fused-in-sarcoma protein (FTLD-FUS) (approximately
9%). Approximately 1% remains uncharacterized.
FTLD-tau consists of PSP pathology, CBD, argyrophilic grain dis-
ease (4R tauopathies), globular glial tauopathy, and Pick disease (3R
tauopathy). MAPT mutations are always associated with tau pathol-
ogy. Pick disease is the prototype 3R tauopathy. Pick disease accounts
for less than 5% of all FTLDs. The gross atrophy of Pick disease has
been described as knife edge-like. Pick bodies, circumscribed tau posi-
tive inclusions, are the hallmark pathology of Pick disease. Pick disease
has less neuritic pathology than other tauopathies. The Gallyas silver
stain can distinguish Pick disease from other tauopathies. The inclu-
sions are negative for the Gallyas silver stain and a 4R tau stain. Other
pathological findings in Pick disease include “ballooned neurons.”
Fig. 95.22 T2 fluid-attenuated inversion recovery magnetic resonance CBD and PSP pathology were previously discussed. Characteristic
imaging in frontotemporal dementia patient with microtubule-associated pathology is demonstrated in Fig. 95.26. Globular glial tauopathy is
protein tau (MAPT) mutation with characteristic bitemporal atrophy. characterized by globular tau-reactive oligodendroglial and astrocytic
(Courtesy Dr. Bradley Boeve.) inclusions.
Fig. 95.23 Top 2 rows: Fluorodeoxyglucose-positron emission tomography statistical stereotactic surface
projection map (Cortex ID) in a primary progressive aphasia patient with progranulin mutation showing asym-
metric left greater than right hypometabolism. Bottom row: Corresponding coronal T1 magnetic resonance
imagings in bottom row. Notice asymmetric atrophy and ventricular dilation. (Courtesy Dr. Bradley Boeve.)
FTLD-TDP can be subdivided into types A, B, C, D, and E. Type inclusions, abundant grains, and oligodendroglial inclusions (Lee
A is associated with neuronal inclusions, intranuclear inclusions, and et al., 2017).
dystrophic neurites. Progranulin mutations are associated with FTLD- FTLD-FUS is divided into three rare forms of FTLD: neurofilament
TDP-type A. Type B is associated with neuronal cytoplasmic inclu- inclusion disease, basophilic inclusion disease, and atypical FTLD with
sions. C9ORF72 mutations are associated with FTLD-TDP-type B, less ubiquitin-only immunoreactive changes (aFTLD-U). All three are
likely A, C. C9ORF72 mutation cases also have characteristic cerebel- immunoreactive to FUS. Neurofilament inclusion disease (Josephs
lar inclusions. FTLD-TDP-type B is also associated with FTD-MND. et al., 2003) is a rare cause of FTD that can also be associated with
Type C is associated predominantly with neurites and characteristic MND and parkinsonism. The pathology is characterized by neuronal
Pick body–like neuronal inclusions. Semantic dementia is associated and intranuclear inclusions that are immunoreactive to neurofilament
with TDP type C. VCP mutations are associated with FTLD-TDP type and alpha-internexin (Uchikado et al., 2005). Basophilic inclusion
D pathology with abundant intraneuronal inclusions. TDP type E disease is pathologically characterized by basophilic inclusions on
was recently described in association with a rapidly progressive FTD hematoxylin and eosin (H&E) that are not immunoreactive to inter-
phenotype. Type E was characterized by granulofilamentous neuronal mediate filaments. aFTLD-U does not have inclusions on H&E.
Clinicopathological Correlations
bvFTD is associated most commonly with TDP (usually type A; ∼40%)
or tau pathology (∼40%), with FUS pathology less likely (∼10%). When
bvFTD occurs in tauopathies, the underlying pathologies are in order
of frequency: Pick disease (PiD), CBD, PSP, and argyrophilic grain dis-
ease (AGD) (Josephs et al., 2011). Agrammatic PPA is associated most
commonly with tau (70%) (Josephs et al., 2011) pathology, especially
if apraxia of speech is present (Josephs et al., 2006). CBS and PSP-S are
also most commonly associated with tau pathology, although familial
CBS has been associated with progranulin mutations (Josephs et al.,
2011). FTD-MND is almost always associated with TDP pathology.
svPPA is most commonly associated with TDP pathology (TDP-type
C; 83%), although when it is caused by tau pathology Pick disease is
most likely (Josephs et al., 2011).
Pick disease can present with bvFTD, PPA, or CBS (Boeve et al.,
1999; Piguet et al., 2011). Although Pick disease is typically sporadic,
familial cases can have a tau mutation. Globular glial tauopathies have
a range of clinical presentations, including bvFTD, semantic variant
PPA, PSP-S, CBS, and motor neuron disease.
Patients with FTLD-FUS tend to have a young age of onset (mean
41), stereotypies, hypersexuality, and hyperphagia. Striatal atrophy is a
characteristic imaging feature (Josephs et al., 2010; Urwin et al., 2010).
Pathophysiology
Fig. 95.24 Axial T2 fluid-attenuated inversion recovery magnetic res- TAR DNA-binding protein 43. TDP-43 normally resides in
onance imaging in a frontotemporal dementia patient demonstrating
the nucleus of the cell. In neurodegenerative disease, TDP-43
symmetric atrophy pattern in a patient with chromosome 9 open read-
ing frame 72 mutation.
relocalizes to the cytoplasm, forms inclusions, becomes cleaved,

(Cortex ID) in a patient with chromosome 9 open reading frame 72 mutation demonstrating bifrontal hypo
metabolism.
hyperphosphorylated, and aggregates. TDP-43 has numerous functions sequences make proteins that normally do not exist (Zu et al., 2011).
in the cell and how it is related to neurodegeneration is incompletely This results in different polypeptides, depending on the reading frames.
understood. Functions of TDP-43 include RNA metabolism, including An antibody that recognizes all of these polypeptides was created. All
transcription, splicing, and transport of RNA. stained brains of C9ORF72 patients had these polypeptide inclusions
Microtubule-associated protein tau. The tau protein promotes (Gendron et al., 2013). It is possible that these C9RAN proteins
microtubule stabilization and assembly. Hyperphosphorylation of tau inclusions are toxic although further research is required.
leads to microtubule destabilization under pathological conditions. TMEM106B. Genome-wide association studies (GWAS) in
The tau protein undergoes differential splicing. Inclusion of exon 10 FTLD-TDP patients demonstrated an association with TMEM106B,
in splicing of tau results in four microtubule-binding domains (4R), which is an uncharacterized transmembrane protein (Van Deerlin
while exclusion of exon 10 results in 3 binding domains (3R). In et al., 2010). More recently, it was shown that TMEM106B single
normal adults, there is a 1:1 ratio of 4 and 3 binding domains. Most tau nucleotide polymorphisms may protect against developing FTD in
mutations cluster around the microtubule-binding domain. Mutations progranulin mutation carriers by affecting progranulin levels (Finch
in tau disrupt the binding of tau to the microtubule and enhance tau et al., 2011). The protective variant results in less TMEM106B protein.
aggregation or interfere with splicing, resulting in excessive exon 10 A TMEM106B variant also protects against FTD but not ALS in
inclusion, increasing 4R/3R tau ratio (Rademakers and Hutton, 2007). C9ORF72 mutation carriers (van Blitterswijk et al., 2014).
Progranulin. The progranulin protein is a precursor protein that is
cleaved into granulins. Progranulin functions as a growth factor with Frontotemporal Dementia Treatment
antiinflammatory properties. Granulins may serve as inflammatory There are no FDA-approved medications for the treatment of FTD.
mediators. Progranulin is expressed in neurons and glia. Neuronal While a meta-analysis has suggested benefit for the use of SSRIs in FTD
progranulin regulates synaptic function and has neuroprotective to improve behavioral symptoms, most of the studies included were
and neurotrophic properties. All mutations in progranulin cause a small and uncontrolled (Huey et al., 2006). Since the FDA has issued
reduction in progranulin levels (haploinsufficiency) which may cause a warning that antipsychotic drugs increase risk of death in dementia
a loss of trophic support and neuronal loss. The mechanism by which patients, such agents must be used with caution. Nonpharmacological
progranulin mutations result in TDP pathology is unknown, although interventions including home safety evaluation and removal of weap-
in cells, suppression of progranulin leads to a caspase activation which ons from the home are important. Family education about the disease
leads to TDP-43 accumulation (Zhang et al., 2007). Patients with and caregiver support groups can be helpful. Patients with PPA may
progranulin mutation carriers or svPPA patients have an increased benefit from evaluation and treatment by speech language pathologists
prevalence of associated autoimmune disease and elevated levels of to help with communication strategies.
TNF-alpha, further implicating a relationship between inflammation
and FTD associated with progranulin (Miller et al., 2013). VASCULAR DEMENTIA (VASCULAR COGNITIVE
Chromosome 9 open reading frame 72. The mechanism of how IMPAIRMENT)
hexanucleotide expansions in C9ORF72 cause disease is under active
investigation. Upon expansion in the noncoding region, a decrease in History
C9ORF72 mRNA occurs, resulting in haploinsufficiency. A decrease Our understanding of the interaction among vascular disease, neurode-
in expression of the mRNA transcript may occur through epigenetic generation, and cognition has evolved over time. Binswanger described
events such as DNA and histone methylation, resulting in less protein “encephalitis subcorticalis chronica progressiva” as characterized by
(Belzil et al., 2013). In addition to haploinsufficiency as a mechanism of dementia, stroke, and white matter disease, which Alzheimer demon-
disease, the hexanucleotide repeat undergoes transcription, resulting in strated was secondary to arteriolosclerosis of long perforating arteries.
RNA. This RNA can form nuclear foci which bind and sequester RNA- For many decades, narrowing of the arteries was thought to be the
binding proteins and prevent them from binding their RNA targets. most common cause of dementia and doctors and patients attributed
This process can interrupt splicing. Alternatively, the RNA can undergo dementia to “hardening of the arteries.” Hachinski introduced the term
C9 repeat associated non-ATG translation (C9RAN) where the repeat multi-infarct dementia (MiD), emphasizing prior clinical strokes with
A B
Fig. 95.26 Pick Disease Pathology. A, Bielschowsky stain showing Pick bodies in fascia dentate. B, Tau
stain demonstrating Pick bodies in fascia dentate. (Courtesy Dr. Joseph Parisi.)
focal neurological signs and symptoms and “stepwise” cognitive decline those with mixed pathology (O’Brien et al., 2003). Both multi-infarct
(Hachinski et al., 1974). With advances in neuroimaging, investigators dementia and vascular dementia (VaD) are now subgroups of VCI.
appreciated that multi-infarct was a small part of a wider spectrum of
vascular diseases resulting in cognitive impairment. The term vascular Diagnostic Criteria
cognitive impairment (VCI) was introduced to encompass all forms The American Heart Association and American Stroke Association
of cognitive impairment related to vascular disease including milder (AHA-ASA) released a statement defining the term VCI (Table 95.10;
forms of cognitive impairment not meeting criteria for dementia and Gorelick et al., 2011), but for many years the National Institute of
TABLE 95.10 Vascular Cognitive Impairment

1. The term VCI characterizes all forms of cognitive deficits from VaD to MCI of vascular origin.
2. These criteria cannot be used for subjects who have an active diagnosis of drug or alcohol abuse/dependence. Subjects must be free of any type of substance for
at least 3 months.
3. These criteria cannot be used for subjects with delirium.
Dementia 1. The diagnosis of dementia should be based on a decline in cognitive function from a prior baseline and a deficit in performance in two or more
cognitive domains that are of sufficient severity to affect activities of daily living.
2. The diagnosis of dementia must be based on cognitive testing, and four cognitive domains should be assessed: executive/attention, memory,
language, and visuospatial functions.
3. The deficits in activities of daily living are independent of the motor/sensory sequelae of the vascular event.
Probable VaD 1. There is cognitive impairment and imaging evidence of cerebrovascular disease and
a. There is a clear temporal relationship between a vascular event (e.g., clinical stroke) and onset of cognitive deficits, or
b. There is a clear relationship in the severity and pattern of cognitive impairment and the presence of diffuse, subcortical cerebrovascular
disease pathology.
2. There is no history of gradually progressive cognitive deficits before or after the stroke that suggests the presence of a nonvascular neurode-
generative disorder.
Possible VaD There is cognitive impairment and imaging evidence of cerebrovascular disease but
1. There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g., silent infarcts, subcortical
small-vessel disease) and the cognitive impairment.
2. There is insufficient information for the diagnosis of VaD (e.g., clinical symptoms suggest the presence of vascular disease, but no CT/MRI
studies are available).
3. Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function (e.g.,
annual cognitive evaluations) before the clinical event that caused aphasia could be classified as having probable VaD.
4. There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as
a. A history of other neurodegenerative disorders (e.g., Parkinson disease, progressive supranuclear palsy, dementia with Lewy bodies);
b. The presence of Alzheimer disease biology is confirmed by biomarkers (e.g., PET, CSF, amyloid ligands) or genetic studies (e.g., PS1 mutation); or
c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive function.
VaMCI 1. VaMCI includes the four subtypes proposed for the classification of MCI: amnestic, amnestic plus other domains, nonamnestic single domain,
and nonamnestic multiple domain.
2. The classification of VaMCI must be based on cognitive testing, and a minimum of four cognitive domains should be assessed: executive/
attention, memory, language, and visuospatial functions. The classification should be based on an assumption of decline in cognitive function
from a prior baseline and impairment in at least one cognitive domain.
3. Instrumental activities of daily living could be normal or mildly impaired, independent of the presence of motor/sensory symptoms.
Probable VaMCI 1. There is cognitive impairment and imaging evidence of cerebrovascular disease and
a. There is a clear temporal relationship between a vascular event (e.g., clinical stroke) and onset of cognitive deficits, or
b. There is a clear relationship in the severity and pattern of cognitive impairment and the presence of diffuse, subcortical cerebrovascular
disease pathology.
2. There is no history of gradually progressive cognitive deficits before or after the stroke that suggests the presence of a nonvascular neurode-
generative disorder.
Possible VaMCI There is cognitive impairment and imaging evidence of cerebrovascular disease but
1. There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g., silent infarcts, subcortical
small-vessel disease) and onset of cognitive deficits.
2. There is insufficient information for the diagnosis of VaMCI (e.g., clinical symptoms suggest the presence of vascular disease, but no CT/MRI
studies are available).
3. Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function (e.g.,
annual cognitive evaluations) before the clinical event that caused aphasia could be classified as having probable VaMCI.
4. There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as
a. A history of other neurodegenerative disorders (e.g., Parkinson disease, progressive supranuclear palsy, dementia with Lewy bodies);
b. The presence of Alzheimer disease biology is confirmed by biomarkers (e.g., PET, CSF, amyloid ligands) or genetic studies (e.g., PS1 mutation); or
c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive function.
Unstable VaMCI Subjects with the diagnosis of probable or possible VaMCI whose symptoms revert to normal should be classified as having “unstable VaMCI.”
VaD, Vascular dementia; VaMCI, vascular mild cognitive impairment; VCI, vascular cognitive impairment.
Reprinted with permission from Gorelick, P., Scuteri, A., Black, S.E., et al., 2011, Vascular contributions to cognitive impairment and dementia: a
statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 2672–2713.
Neurological Disorders and Stroke and the Association Internationale result in an amnestic syndrome (Benson et al., 1974), although iso-
pour la Recherche et l’Enseignementen Neurosciences (NINDS- lated left posterior cerebral artery infarctions can produce amnesia as
AIREN) criteria were used for VaD (Roman et al., 1993). The NINDS- well. Common coexisting deficits include visual field cuts. The con-
AIREN criteria rely heavily on symptomatic cerebrovascular disease cept of strategic lesions is highlighted by thalamic infarction where a
including history of stroke, imaging of stroke, and focal exam findings small infarction involving both hippocampal and amygdala pathways
consistent with stroke. These criteria have been shown to be specific, causes significant amnesia, but when the lesion involves only one
but not sensitive, overlooking infarcts that were clinically silent. In pathway the memory impairment is quite mild (Cipolotti et al., 2008;
fact, the clinical diagnosis of “probable VaD” compared to subsequent Graff-Radford et al., 1990). Basal forebrain injury most commonly
pathological confirmation was 20% (Gold et al., 2002). secondary to aneurysm rupture can manifest with amnesia associ-
ated with personality change (Damasio et al., 1985). Other strategi-
Epidemiology cally located infarcts mentioned in the NINDS-AIREN criteria include
In the population-based Rotterdam study with a mean follow-up of those involving the angular gyrus and anterior cerebral artery territory
5.7 years using the conservative NINDS-AIREN criteria, the inci- (Roman et al., 1993). Caudate infarcts may produce a syndrome sim-
dence of vascular dementia was 0.1 per 1000 person-years in those ilar to behavioral variant FTD but with a sudden onset resulting from
aged 60–64 years. The incidence increased with age to 7.0 per 1000 interrupting the connectivity between the caudate and the frontal lobe
person-years in those aged 90–94 years, with a higher risk of VaD in (Graff-Radford et al., 2017).
men (Ruitenberg et al., 2001). In a Rochester, MN population-based
study, approximately 13% of autopsy dementia cases were due to pure Multi-Infarct Dementia
vascular dementia and 12% had significant vascular and AD pathology, MiD reflects traditional thinking that patients with multiple cortical
making vascular disease an important component in at least 25% of strokes develop dementia with an abrupt onset and stepwise deterio-
dementia cases (Knopman et al., 2003). In a PiB-PET study (Lee et al., ration. These patients have focal neurological signs on exam such as
2011a), amyloid imaging was used in 45 patients with subcortical vas- hemiparesis.
cular dementia. Approximately two-thirds of cases were negative for
amyloid deposition, indicating the pure VaD phenotype can be appre- Dementia After Stroke
ciated antemortem. In the Canadian Study of Health and Aging, which sampled 9008
community-based individuals and 1255 institutionalized individuals
Vascular Risk Factors over the age of 65, incident stroke increased the risk of converting from
Interestingly, stroke and Alzheimer dementia share many risk factors cognitively normal to dementia with a hazard ratio of 2.3. Stroke prev-
including diabetes, hypertension, and metabolic syndrome. alence was 6 times higher in those with cognitive impairment relative
to normal, and approximately two-thirds of stroke survivors had cog-
Subtypes nitive impairment or dementia in contrast to 21% of stroke-free indi-
Numerous subtypes of VCI have been proposed, including viduals (Jin et al., 2006). In a population-based study, the incidence of
multi-infarct dementia, subcortical ischemic vascular dementia, dementia after stroke was 9 times greater than expected, and demen-
dementia related to strategic strokes, perfusion-related dementia, hem- tia risk remained double the control population even if there was no
orrhagic stroke-related dementia, dementia associated with arteriopa- dementia the first year after stroke (Kokmen et al., 1996). The sub-
thies, and mixed dementia (O’Brien et al., 2003). type of stroke may be important. In the Secondary Prevention of Small
Subcortical Strokes trial, 47% of subjects had MCI even in the absence
Clinical Presentation of physical disabilities related to the stroke. Therefore, the presence of a
Due to the heterogeneous causes of VCI, there is no typical clinical pre- single stroke serves as a biomarker for more extensive cerebrovascular
sentation. The severity, temporal course, and associated features vary disease (Jacova et al., 2012). Approximately 20% of the population over
widely. VaD patients with large territory stroke may have focal signs on the age of 65 has silent infarctions. In those with normal cognition at
exam (upper motor neuron pattern weakness, hemianopsia, sensory baseline and silent infarction, the risk of dementia is increased signifi-
loss), while those with cerebral small-vessel disease may present with cantly (Vermeer et al., 2003). In a meta-analysis of poststroke dementia
gait disturbance and cognitive slowing. Mixed AD and VaD patients including population- and hospital-based studies, approximately 10%
may present with an amnestic syndrome indistinguishable from typical of patients have dementia prior to first stroke, 10% develop dementia
AD. In one large study that used NINDS-AIREN criteria, patients with shortly after first stroke, and about 33% develop dementia with recur-
large-vessel disease defined as those with strategic or territorial infarcts rent stroke (Pendlebury and Rothwell, 2009). Risk factors for dementia
were compared to those with small-vessel disease defined as those with after stroke include age, diabetes, severity of stroke, and white matter
lacunar strokes and white matter hyperintensity (Staekenborg et al., hyperintensity (Cordoliani-Mackowiak et al., 2003).
2008). A pattern emerged with small-vessel patients manifesting bul-
bar findings and parkinsonism, while large-vessel patients had more Cerebral Small-Vessel Disease
lateralizing language, motor, and sensory findings. The common clini- White Matter Hyperintensity
cal presentation associations with small- and large-vessel presentations White matter hyperintensity, sometimes called leukoaraiosis, was
may be useful in subtyping VCI, with the caveat that many patients initially thought to be of indeterminate significance but is increas-
have coexisting large-vessel and small-vessel disease. ingly recognized as detrimental. In the Cardiac Health Study, white
matter hyperintensity was associated with lower cognitive and lower
Large-Vessel Stroke extremity function (Longstreth et al., 1996). The underlying causes of
Strategic Infarcts white matter hyperintensity are numerous, including arteriolosclerosis
Targeted strokes can present with memory loss. The amnesia can (vascular risk factor related), amyloid angiopathy, genetic (Fabry dis-
be distinguished from the episodic memory loss associated with AD ease, etc.), inflammatory or immune (vasculitides, etc.), venous, and
dementia disease by the sudden onset. The posterior cerebral artery others (postradiation, etc.) (Pantoni, 2010). The Framingham study
provides the blood supply to the posterior medial aspect of the hip- demonstrated, in younger persons (mean age 53), when dementia and
pocampus. Infarction of the bilateral posterior cerebral arteries may CAA are less common, that atherosclerosis risk factors, particularly
hypertension, are strongly related to cerebral white matter changes at autopsy and the most common pathological diagnosis was AD with
(Jeerakathil et al., 2004). Hypertension was also a risk factor for white vascular pathology occurring in 38% of patients (Schneider et al.,
matter hyperintensity in the Cardiac Health Study (Longstreth et al., 2007). The coexistence of vascular pathology modifies clinical expres-
1996). Also in the Framingham study, white matter hyperinten- sion of dementia when AD pathology is present. The presence of coex-
sity volume was associated with incident diagnosis of mild cognitive isting cerebrovascular disease with AD requires a lower AD pathology
impairment (Debette et al., 2010). Specific cognitive functions asso- burden to develop dementia (Nagy et al., 1997). In the nun study, at
ciated with increasing white matter disease burden include executive autopsy those with Alzheimer pathology and lacunar stroke were 20
dysfunction and episodic memory impairment (Maillard et al., 2012). times more likely to be demented during life (Snowdon et al., 1997).
White matter hyperintensity has also been associated with a decline In the Baltimore Longitudinal Study of Aging Autopsy Program, the
in gait (Baezner et al., 2008), progression to disability (Inzitari et al., interaction between cerebrovascular disease and AD pathology in caus-
2009), decreased cognitive speed (Valdes Hernandez Mdel et al., 2013), ing dementia was also assessed. In subjects with a limited degree of AD
and incident depression (Firbank et al., 2012). pathology, the average number of macroscopic infarcts in demented
patients was 2.2, but those with an isolated infarct were not demented
Lacunar Stroke (Troncoso et al., 2008). Despite the interaction between cerebrovas-
Highlighting the overlap between vascular pathologies, white mat- cular disease and AD pathology, an ADNI study reported that ath-
ter hyperintensity is associated with lacunar stroke, but both are erosclerosis risk factors and white matter changes were not related
independently associated with cognition (van der Flier et al., 2005). to Alzheimer-related biomarkers (CSF Aβ42, hippocampal atrophy,
Incident lacunes predict decline in executive functions and psycho- and cognitive tests with memory components) (Lo and Jagust, 2012).
motor speed (Jokinen et al., 2011). Not surprisingly, the location of Similarly, the leukoaraiosis and disability in the elderly study (LADIS)
lacunes appears to play an important role in cognitive outcomes, with demonstrated that t-tau, p-tau, and the different Aβ markers did not
thalamic and putamen lacunes being worse than capsular, caudate, and differ between groups of mild, moderate, and severe white matter
white matter lacunes (Benisty et al., 2009). In the Secondary Prevention hyperintensity (Jonsson et al., 2010).
of Small Subcortical Strokes study, 47% of participants met criteria for
MCI (36% amnestic, 37% amnestic multidomain, 28% nonamnestic) CADASIL
(Jacova et al., 2012). Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is a genetic cerebral small-ves-
Cerebral Amyloid Angiopathy sel disease caused by mutations in the NOTCH3 gene on chromosome
CAA is very common. In the Religious Orders Study, 85% of subjects 19. NOTCH3 codes for a transmembrane receptor located on vascular
had CAA and approximately 25% of demented patients had severe CAA smooth muscle cells. In Scotland, the prevalence has been estimated
(Arvanitakis et al., 2011). The presence of significant CAA was associ- to be 1.98 per 100,000 adults (Razvi et al., 2005). Clinical features
ated with decreased perceptual speed and episodic memory, while mild include migraine headaches, stroke, and dementia. The pattern of
CAA did not correlate to cognitive measures. In the Honolulu-Asia cognitive deficits on neuropsychometric testing includes impaired
Aging Study, the presence of both CAA and AD at autopsy predicted cognitive speed, executive function, and attention (Peters et al., 2005).
worse cognitive scores than AD alone (Pfeifer et al., 2002). Amyloid Neuropsychiatric symptoms are common. MRI reveals significant
angiopathy correlates with extent of white matter hyperintensity on white matter hyperintensity and ischemic lesions, particularly in sub-
MRI (Gurol et al., 2013). Lobar cerebral microbleeds in the elderly cortical regions. Involvement of the anterior temporal pole and exter-
detected on gradient echo or susceptibility weighted MRI sequences nal capsule are characteristic. Microhemorrhage also variably occurs.
can be used to identify CAA during life.
Neuropsychological Testing
Microinfarcts Given the numerous presentations of VCI, no single neuropsychologi-
Microinfarcts contribute to dementia as much as macroscopic infarcts cal profile exists. Nonetheless, a pattern emerges when studying groups
(Troncoso et al., 2008). In an autopsy study, the population attrib- of VCI patients. In an analysis of 27 prior studies, one study found that
utable risk of dementia for microinfarcts was 33% (Sonnen et al., frontal executive function was more impaired in VaD relative to AD
2007). In the Honolulu-Asia Aging Study (White, 2009), in autopsied dementia and verbal memory scores were relatively preserved (Looi
demented or impaired subjects microvascular infarcts were the sole or and Sachdev, 1999). In autopsy-proven AD, memory impairment is
dominant lesion in approximately 33% of subjects while AD pathol- consistently worse than executive function, while in autopsy-proven
ogy was the sole or dominant lesion in 18% of cases. Microinfarcts are VaD the findings are more variable, although the majority of patients
not visible on MRI, but the presence of macroinfarcts, white matter perform poorly on tests of executive function (Reed et al., 2007).
hyperintensity, and hemorrhages correlates with presence of microin- Compared to AD dementia patients, VCI patients have more difficulty
farcts (Longstreth et al., 2009). Recently, it was estimated that identi- with tasks of cognitive speed (Mendez et al., 1997). In a study of 170
fying one or two microinfarcts on nine routine pathological specimens patients with stroke or transient ischemic attack (TIA), those with
indicates a maximum-likelihood estimate of 552 to 1104 microinfarcts cognitive impairment performed worse on tasks of abstraction, men-
(Westover et al., 2013). A recent imaging pathology study demon- tal flexibility, and processing speed relative to those without cognitive
strated microinfarcts increase rate of brain atrophy independent of AD impairment (Sachdev et al., 2004).
pathology on MRI, and this primarily occurs in a watershed distribu-
tion (Raman et al., 2014). Microinfarcts are associated with decreas- Treatment
ing blood pressure, suggesting the pathophysiology of microinfarcts Treatment and prevention of vascular dementia should focus on iden-
requires further investigation (Graff-Radford et al., 1989). tifying and managing hypertension, diabetes mellitus, atrial fibrilla-
tion, and hyperlipidemia. Although aggressive treatment of vascular
Mixed Pathology risk factors is logical to prevent and slow progression of those on the
Mixed pathology is probably the most important subgroup of VCI. In a trajectory to VCI, few prospective trials exist. In the double-blind pla-
recent autopsy series, most demented patients had multiple pathologies cebo-controlled Systolic Hypertension in Europe trial, non-demented
subjects age 60 and older with a baseline systolic blood pressure over wide base and small steps, and turns using multiple steps (piecemeal).
160 mm Hg were randomized to aggressive blood pressure treatment There is no mask-like face, hand tremor, arm rigidity, or impaired fine
or placebo to determine whether blood pressure management could finger movements as in typical Parkinson disease. Postural instability
decrease the incidence of dementia. In the active treatment group and falls are common in NPH. The gait disorder is the feature most
at 2 years, blood pressure was decreased by 8.3 mm Hg on average responsive to treatment.
and the incidence of dementia was reduced from 7.7 to 3.8 cases per
1000 patient-years (Forette et al., 1998). In the Perindopril Protection Cognitive Disorder
against Recurrent Stroke Study, which was a randomized, dou- Stretching of the frontal white matter pathways results in a cognitive
ble-blind, placebo-controlled trial investigating antihypertensive treat- profile characterized by frontal-executive dysfunction, including cog-
ment in patients with prior stroke or TIA, cognitive decline occurred in nitive slowing, impaired abstract thinking, and impaired set-shifting.
9.1% of patients on treatment and in 11.0% on placebo (Tzourio et al., Improvement in cognition is difficult to predict with shunting, but the
2003). In the SPRINT-MIND trial, treating systolic blood pressure to presence of anomia has been associated with less benefit from surgery
a goal of less than 120 mm Hg compared to a goal of less than 140 mm (Graff-Radford et al., 1989). The reason is that anomia is a marker of
Hg reduced the development of mild cognitive impairment at 1 year cortical dementia and indicates the patient may have comorbid neu-
(Group, 2019). rodegenerative disease. In fact, at the average age of shunting, which is
about 75, over 30% of normal persons have AD pathology as measured
Symptomatic Treatment by PiB-PET (Knopman et al., 2013).
AChEIs improve cognitive function to a small degree in patients with
VCI (Birks and Craig, 2013; Malouf and Birks, 2004) but are not FDA Urinary Incontinence
approved for this indication. Since most patients have mixed vascular Urinary urgency may occur very early, while later in the disease course
and Alzheimer pathology, it is reasonable to investigate AChEIs in this incontinence is accompanied by a lack of distress.
population.
Neuropsychiatric symptoms such as depression and pseudobulbar Assessing Comorbidities
affect can respond to SSRIs. Dextromethorphan/quinidine has recently Despite this clinical triad, the diagnosis of NPH remains challenging
been approved by the FDA for treatment of pseudobulbar affect. because the features of NPH are very common in the elderly popu-
lation. Among non-demented patients aged 75–85, gait abnormali-
ties occur in approximately 20% and are related to development of
NORMAL PRESSURE HYDROCEPHALUS dementia (Verghese et al., 2002). Similarly, at age 60 the prevalence of
NPH refers to enlarged ventricles disproportionate to the degree of incontinence is 17% in men and 31% in women (Anger et al., 2006).
cortical atrophy on neuroimaging in patients with a normal opening Therefore, careful evaluation of comorbidities and other diagnoses
pressure on lumbar puncture. Non-communicating hydrocepha- must be made prior to diagnosing NPH. Some possible comorbidi-
lus refers to a condition in which an obstruction of the CSF occurs ties to investigate which can confound the evaluation of NPH by caus-
within the ventricular system. The causes of NPH are heterogeneous. ing cognitive dysfunction or gait disturbance include the presence of
One cause of NPH is impaired absorption of CSF at the arachnoid arthritis, peripheral neuropathy, cervical spondylosis, vestibular dys-
granulations. NPH can be idiopathic or secondary to prior history function, medication use, and visual dysfunction. It is particularly
of subarachnoid hemorrhage, meningitis, or other conditions that important to look for parkinsonian disorders which can be associated
cause inflammation of the arachnoid granulations. Also, a significant with enlarged ventricles. To avoid shunting unnecessarily, some have
minority (10%–20%) of NPH patients have increased head circumfer- advocated a L-dopa challenge to distinguish PD from NPH (Morishita
ence, indicating that a subgroup of NPH patients may have congenital et al., 2010).
hydrocephalus that becomes symptomatic later in life (Krefft et al.,
2004; Wilson and Williams, 2007). Hypertension may also be a risk Neuroimaging
factor (Graff-Radford and Godersky, 1987; Graff-Radford et al., 2013; The hallmark neuroimaging feature is ventricular enlargement out
Krauss et al., 1996). NPH is a rare disease. One Norwegian study esti- of proportion to atrophy. When atrophy is proportionate to ven-
mated the prevalence of NPH to be around 21.9/100,000 and the inci- tricular enlargement, the term ex vacuo hydrocephalus is used. The
dence to be around 5.5/100,000 (Brean and Eide, 2008). A more recent Evans index is used to assess ventriculomegaly. The Evans index is
population-based study in Sweden found the prevalence of probable defined as the maximal diameter of the frontal horns to the larg-
idiopathic NPH was 0.2% in those aged 70–79 years and 5.9% in those est width of the inner tables of the cranium with a ratio of greater
aged 80 years and older, suggesting that the disorder may be more than 0.30 considered consistent with ventriculomegaly (Mori et al.,
common than previously thought (Jaraj et al., 2014). 2012b). Transependymal flow occurs and may be the result of extrav-
While the classical clinical triad of NPH is gait disturbance, urinary asation of CSF into the white matter. This finding appears as white
incontinence, and progressive cognitive impairment, many patients matter hyperintensity capping of the ventricles, but can be mistaken
may have only one or two of these symptoms and still improve with for periventricular white matter hyperintensities. Increased flow rate
shunt surgery. However, the core symptom is gait disturbance and of aqueductal CSF through the third ventricle (Dixon et al., 2002)
shunting patients with hydrocephalus and cognitive impairment alone and radionucleotide cisternography (Vanneste et al., 1992) are prob-
rarely results in improvement (Petersen et al., 1985). The symptoms ably not helpful in predicting shunt responsiveness. Recently, the
are thought to arise from disturbance of white matter pathways sub- MRI imaging finding of disproportionately enlarged subarachnoid
serving frontal lobe function. space hydrocephalus (DESH) was reported. DESH is defined as the
presence of a “tight” convexity in conjunction with enlarged syl-
Gait Disturbance vian fissure and associated hydrocephalus (Mori et al., 2012b). One
Gait disturbance is an early feature in NPH and is sometimes referred important radiological finding is dilation of sulci. These enlarged
to as an apraxic or magnetic gait. This can be misleading because it sulci are indicative of a CSF dynamics disorder and are sometimes
is neither pathognomonic nor typical. The typical gait is slow with a mistaken for focal atrophy.
Fig. 95.27 Top row: Left image reveals enlargement of the sylvian fissures and crowding at the apex consis-
tent with disproportionately enlarged subarachnoid space hydrocephalus. Middle and right images demon-
strate ventricular enlargement and transependymal flow seen in normal pressure hydrocephalus (NPH).
Bottom row: Entrapped sulci seen in NPH (white arrow).
Other helpful features to distinguish NPH from AD dementia test but has a small risk of infection. Other tests that have been used
include an enlarged anterior cingulate sulcus (Adachi et al., 2006) and include intracranial pressure monitoring (Graff-Radford et al., 1989)
narrow precuneus sulci (Ishii et al., 2008). and CSF infusion tests (Boon et al., 1997).
Fig. 95.27 demonstrates many of the hallmark imaging findings in
NPH. Biomarkers
The CSF biomarker profile of NPH is low CSF Aβ42 but normal CSF
Confirmatory Diagnostic Tests t-tau and p-tau similar to controls. Thus the features are in keeping
Since shunting procedures are invasive and associated with possible with AD (low Aβ42) but also in keeping with normals (normal t-tau
serious complications, additional diagnostic tests are recommended and p-tau). Therefore, CSF biomarkers may not be useful in distin-
prior to shunt placement. The best test to see if a shunt will work is a guishing NPH from NPH plus comorbid AD (Kapaki et al., 2007).
temporary shunt. This can be done with either a high-volume lumbar
puncture or external CSF drainage over 1–3 days. The most common Biopsy Studies
approach is a large-volume (30–50cc) lumbar tap test where gait is Many NPH patients have AD pathology found through biopsies or
tested before and within 30 minutes of the tap. Improved gait after CSF autopsies. In a study of 56 probable NPH patients in their mid-70s
has been removed constitutes a positive result and predicts a better who underwent cortical biopsies during shunt surgery, approximately
response to shunting (Wikkelso et al., 1986). Most studies have shown 40% had AD pathology, and patients with a greater amount of amyloid
that this test has a high positive predictive value but lower negative pre- plaque and NFT deposition had more cognitive dysfunction (Golomb
dictive value (Kahlon et al., 2002), indicating some patients who might et al., 2000). Gait improved regardless of biopsy findings. The number
benefit from shunting are missed with only the tap test. A more inva- with AD pathology is similar to what would be expected in that age
sive method is placement of a temporary catheter in the lumbar CSF group. In a population-based study of cognitively normal individuals
space and drainage of CSF at 10 cc per hour for a period of 1–3 days. with a median age of 78 years, approximately 32% had amyloid depo-
This test is reported to be more sensitive than the lumbar puncture sition as measured by PiB-PET (Knopman et al., 2013).
TABLE 95.11 Japanese Diagnostic Criteria of Idiopathic Normal Pressure Hydrocephalus

Possible iNPH (Meets All Five of the Following)
1. Individuals who develop symptoms in their 60s or older.
2. More than one of the clinical triad (cognitive impairment, urinary incontinence, gait disturbance).
3. Ventricular dilation (Evans index > 0.3).
4. Above-mentioned symptoms cannot be completely explained by other neurological or non-neurological disease.
5. Preceding diseases possibly causing ventricular dilation are not obvious, including subarachnoid hemorrhage, meningitis, head injury, congenital hydrocephalus,
and aqueductal stenosis.
Possible iNPH Supportive Features

(a) Small stride, shuffle, instability during walking, and increased instability with turning.
(b) Symptoms progress slowly; however, sometimes an undulating course, including temporal discontinuation of development and exacerbation, is observed.
(c) Gait disorder is the most prevalent feature, followed by cognitive impairment and urinary incontinence.
(d) Cognitive impairment is detected on cognitive tests.
(e) Sylvian fissures and basal cisterns are usually enlarged.
(f) Other neurological diseases such as Parkinson disease, Alzheimer disease, and cerebrovascular disease may coexist; however, all such diseases should be mild.
(g) Periventricular changes are not essential.
(h) Measurement of CSF is useful for differentiation from other dementias.
Probable iNPH (Meets All of the Following Three Features) Definite iNPH
1. Meets criteria for possible iNPH. Improvement of symptoms after the shunt procedure
2. CSF pressure <200 mm H2O and normal CSF content.
3. One of the following three investigational features:
(1) Neuroimaging of narrowing of the sulci and subarachnoid spaces over the
high convexity/midline surface (DESH) in the presence of a gait disturbance
(2) Improvement of symptoms after CSF tap test
(3) Improvement of symptoms after CSF drainage test.
CSF, Cerebrospinal fluid; DESH, disproportionately enlarged subarachnoid space hydrocephalus; iNPH, idiopathic normal pressure hydrocephalus.
Reprinted with permission from Mori, E., Ishikawa, M., Kato, T., et al. 2012. Guidelines for management of idiopathic normal pressure hydrocepha-
lus: second edition. Neurol. Med. Chir. 52, 775–809.
Diagnostic Criteria proposed for a clinical syndrome termed “traumatic encephalopathy

Recently, the Japanese Society of Normal Pressure Hydrocephalus syndrome” (Montenigro et al., 2014), but these criteria will require
published updated guidelines for the diagnosis of NPH (Mori et al., validation before they can be adopted into clinical practice.
2012b; Table 95.11). The pathology of CTE is a tauopathy. CTE typically starts as foci in
the frontal cortex and then spreads to other regions including limbic
CHRONIC TRAUMATIC ENCEPHALOPATHY/POST- structures (McKee et al., 2013). The tau characteristically is perivas-
cular and patchy. The most severe pathology is located at the bottom
TRAUMATIC DEMENTIA of sulci. CTE has also been associated with motor neuron disease and
An article in JAMA in 1928 described the concept of “punch drunk” TDP-43 pathology (McKee et al., 2010). APOE ε4 is thought to be a
in which boxers who received significant head injury later became cog- risk factor for dementia in those with head injury. Among former NFL
nitively impaired (Martland, 1928). “Punch drunk” was also known players, a neurodegenerative cause of death was approximately three
as dementia pugilistica. MacDonald Critchley later introduced the times greater than controls (Lehman et al., 2012).
term CTE. Although CTE has received much attention in the litera-
ture recently, little is known about the pathogenesis. The clinical and
OTHER CAUSES
radiological presentations associated with head trauma are variable.
While the disorder is most often associated with athletes or military Countless causes of dementia have been reported in the literature
veterans who experience head injury, anyone who experiences head because it is a syndromic term. Partial lists of important subtypes of
injury can develop symptoms. Cavum septum pellucidum can occur non-degenerative dementia are listed in Box 95.1.
but is not universal. The mechanism is thought to be related to repet-
itive acceleration-deceleration of the head during concussion or more Autoimmune or Paraneoplastic Dementia
mild head injuries. While some patients have atrophy or hemorrhage Clinical features of autoimmune dementia include a subacute course,
on neuroimaging, the majority demonstrate normal imaging findings. personal or family history of autoimmunity or cancer, and myoclo-
The clinical presentation appears to have two distinct presentations nus. Limbic encephalitis is one form of paraneoplastic/autoimmune
that are age dependent. In a series of 36 individuals with autopsy-con- disorder that can cause a dementia. Predictors of responsiveness to
firmed CTE, those presenting at a young age had a behavioral mood immunotherapy include subacute onset, fluctuating course, tremor,
disorder characterized by violent behavior, aggression, and depression, shorter delay to treatment, seropositivity for certain autoantibod-
while those presenting at an older age presented with cognitive decline ies, pleocytosis in the CSF, and elevated CSF protein (>100 mg/dL)
(memory, executive, attention) (Stern et al., 2013). Currently CTE can (Flanagan et al., 2010). Autoimmune dementias must be kept in the
only be definitely diagnosed at autopsy. Research criteria have been differential diagnosis of rapidly progressive dementias because they
BOX 95.1 Partial List of Non-Degenerative Dementias

Vascular Carbon monoxide poisoning
Vasculitis (primary or secondary) Drugs (see prior table for list of drugs that can affect cognition)
Chronic subdural hematoma
Structural Causes
Infectious Causes Primary or metastatic neoplasm
Syphilis Hydrocephalus
Chronic meningitis
CJD and other prion disease Immune/Inflammatory
Whipple Autoimmune dementia
PML Multiple sclerosis
Sequelae of herpes encephalitis Sarcoidosis
HIV/AIDS-associated dementia Collagen vascular diseases (e.g., systemic lupus erythematosus, Sjögren syn-
Neuro brucellosis drome)
CNS tuberculosis Behçet
Parasitic infections (e.g., cysticercosis)
Lyme disease Neoplastic
Subacute sclerosing panencephalitis Slow-growing neoplasm (e.g., meningioma, pituitary tumors)
Gliomatosis cerebri
Toxic/Metabolic Causes Radiation effect
Hypothyroidism Paraneoplastic syndromes
Liver disease Lymphoma
Kidney disease
Vitamin B12 deficiency Psychiatric
Thiamine deficiency Depression
Vitamin E deficiency
Inherited Disorders
Marchiafava-Bignami disease
Leukodystrophies (e.g., metachromatic leukodystrophy, adrenoleukodystrophy)
Deficiency of nicotinic acid (pellagra)
Krabbe disease
Heavy metal toxicity
Storage disorders: Gaucher disease, Niemann-Pick disease, cerebrotendinous
Parathyroid hormone dysfunction
xanthomatosis, and polysaccharidoses, neuronal ceroid lipofuscinoses
Adrenal and pituitary disorders
Wilson disease
AIDS, acquired immunodeficiency syndrome; CJD, Creutzfeldt-Jakob disease; CNS, central nervous system; HIV, human immunodeficiency; PML, pro-
gressive multifocal leukoencephalopathy.
can mimic CJD and cause an elevated 14-3-3 protein in the CSF, as diseases causing rapidly progressive dementia include FTD-MND,
well as demonstrate cortical diffusion-weighted imaging abnormali- 4R tauopathy, and DLB (Josephs et al., 2009). In a retrospective
ties on MRI (called cortical ribboning) (Geschwind et al., 2008b). In review of brain biopsies referred to the US National Prion Disease
addition to autoimmune dementias associated with specific autoanti- Pathology Surveillance Center for rapidly progressive dementia, 71
bodies, patients with autoimmune conditions such as systemic lupus out of 1106 had a potentially treatable condition (26 immune related,
erythematosus (SLE) or Sjögren syndrome can present with cogni- 25 neoplastic related, 14 infectious, and 6 metabolic [most commonly
tive decline. Neuropsychiatric symptoms occur in up to 90% of SLE Wernicke]) (Chitravas et al., 2011). Chapter 94 reviews this subject in
patients, with cognitive dysfunction (approximately 80%) and mood more detail. A partial list of causes of rapidly progressive dementia is
disorder (43%) being quite common (Ainiala et al., 2001). Sjögren listed in Box 95.2.
syndrome can be associated with a vasculitis and meningoencephalitis.
Dementia and more subtle cognitive dysfunction may also occur.
YOUNG-ONSET DEMENTIA
Other Non-Degenerative Dementias Young-onset dementia has a wide differential diagnosis. Definitions
Rapidly Progressive Dementias vary but typically age of onset before 45 is used to distinguish it
Rapidly progressive dementias typically present over weeks to from early-onset dementia. At the Mayo Clinic, the most common
months, but may still be considered up to 1–2 years after symptom causes were neurodegenerative (31.1%), autoimmune or inflamma-
onset (Paterson et al., 2012). A thorough work-up is important to tory (21.3%), and metabolic (10.6%), with a substantial proportion
identify treatable causes before they are irreversible. At the University remaining unknown (18.7%). Among the neurodegenerative diseases
of California-San Francisco, which is the referral center for rapidly FTD and Huntington disease were most common (Kelley et al., 2008).
progressive dementia, of 178 rapidly progressive dementia cases, When the age range is extended to 65, AD dementia becomes the
approximately 75% of cases were prion disorders, 14.6% neurodegen- most common neurodegenerative cause (Janssen et al., 2003). Given
erative diseases, and 8.4% autoimmune in etiology (Geschwind et al., the number of potentially treatable etiologies, young-onset dementia
2008a). Four cases were infectious with viral encephalitis and three requires a thorough work-up. The nine most common causes in the
were cancer-associated encephalopathies without paraneoplastic anti- papers from Kelley et al. 2008 and Harvey et al. 2003 are listed in
bodies. At the Mayo Clinic, the most common neurodegenerative Table 95.12.
common, but when a person is older, most individuals will have a

BOX 95.2 Partial Differential Diagnoses of
combination of contributing pathologies present, including amyloid,
Rapidly Progressive Dementias tau, alpha-synuclein, TDP-43, and vascular disease. The proportion of
Prion diseases each of these will vary in each person and there are likely many factors
Autoimmune/paraneoplastic disorders contributing to this combination, genetic and lifestyle among them. A
Infections: Viral encephalitis, Whipple disease, fungal meningitis, human challenge for the field lies in our ability to identify these factors in life
immunodeficiency virus-related, Lyme disease, syphilis, tuberculosis as early as possible with the goal of prevention. Biomarkers have taken
Neurodegenerative diseases presenting with rapid time course on a huge role in this regard and progress is being made.
Central nervous system (CNS) vasculitis and other vasculopathies (e.g., Susac As is depicted in Fig. 95.28, ideally we would like to identify a bio-
syndrome, Abeta-related angiitis) marker for each pathological entity and develop therapies for each
Neurosarcoidosis component (Petersen et al., 2018). This would result in combination
Neoplastic: CNS lymphoma, gliomatosis, metastatic disease therapy for each person tailored to that person’s unique biomarker pro-
Toxic/metabolic conditions: Vitamin B1 (thiamine) deficiency, vitamin B12 defi- file. If these therapies were shown to be preventive, early intervention
ciency, alcohol related, uremia, hepatic failure, drug toxicity (e.g., lithium, would be the key. Due to the personal, societal, and economic burden
methotrexate) of these diseases, attempts at prevention or delaying onset and slowing
Wilson disease progression are essential. If a biomarker’s proof of concept could be
Nonconvulsive status epilepticus demonstrated with imaging and CSF measures, extension to involve
Subdural hematoma blood-based biomarkers would be a major step forward. Ultimately,
Primary or secondary hydrocephalus one could imagine a person having a blood panel drawn that would
give the person and the physician a profile of biomarkers for a variety
of neurodegenerative and vascular processes to direct individual ther-
apy programs. While actual prevention may not be feasible, a delay and
Future Directions slowing of the underlying processes would produce huge benefits. A
It has become apparent in recent years that the most common neuro- great deal of research is underway pursuing this approach.
pathology underlying cognitive changes in aging is multifactorial. As
has been discussed above, age is the primary risk factor for virtually The complete reference list is available online at https://expertconsult.
all of the degenerative and vascular diseases. In the early-onset cases, inkling.com.
65 years and younger, a single or a few pathological entities are more
TABLE 95.12 Young-Onset Dementia

Nine Most Common Causes of Dementia (Ages 17–45) Nine Most Common Causes of Dementia (Ages 30–65)
According to Kelley et al. (2008) According to Harvey et al. (2003)
Frontotemporal dementia Alzheimer dementia
Huntington disease Vascular dementia
Multiple sclerosis Frontotemporal dementia
Autoimmune encephalopathy (dementia) Alcohol-related dementia
Neuropsychiatric lupus Dementia with Lewy Bodies
Mitochondrial disease Huntington disease
Storage disease Multiple sclerosis
Prion disease Dementia due to Down syndrome
Vasculitis CBD/prion disease/Parkinson dementia
CBD, corticobasal degeneration.
Rx?
PET/CSF
Rx? Rx?
?CSF Aβ PET/CSF
TDP-43
Hippocampal Tau
sclerosis
Pathology Clinical
Biomarker spectrum
CN - MCI
Therapy -dementia
Alpha
Other
synuclein
?CSF Vascular ?
disease
Rx? Rx?
MRI
Rx?
Petersen, Neurology, 2018, 91: 395-402
©2014 MFMER I slide-29
Fig. 95.28 Clinical spectrum of cognitively unimpaired–mild cognitive impairment–dementia with its multi-
ple potential etiologies. The contribution of Alzheimer disease (AD) is expressed by β-amyloid (Aβ) and tau.
However, the other protein abnormalities, including TDP-43 and β-synuclein, as well as vascular disease may
also contribute to cognitive impairment. Biomarkers for TDP-43, alpha-synuclein and other are under devel-
opment. Treatments may be developed for each pathological entity.
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96
Parkinson Disease and Other
Movement Disorders
Joseph Jankovic
OUTLINE
Movement Disorders and the Basal Ganglia, 1498 Sydenham Chorea and Other Autoimmune Choreas, 1523
Basal Ganglia Anatomy, 1499 Other Choreic Disorders, 1524
Functional Organization of the Basal Ganglia and Other Pathways, Ballism, 1524
1499 Dystonia, 1525
Biochemistry, 1501 Childhood-Onset Generalized Primary Dystonia, 1525
Mechanisms of Neurodegeneration, 1502 Adult-Onset Primary Focal and Segmental Dystonia, 1526
Parkinsonian Disorders, 1504 X-linked Dystonia-Parkinsonism (Lubag), 1527
Parkinson Disease, 1504 Dopa-Responsive Dystonia, 1527
Multiple System Atrophy, 1512 Myoclonus Dystonia (DYT11), 1527
Progressive Supranuclear Palsy, 1513 Rapid-Onset Dystonia Parkinsonism (DYT12), 1527
Corticobasal Degeneration, 1515 Wilson Disease (Hepatolenticular Degeneration), 1527
Dementia with Lewy Bodies, 1515 Neurodegeneration with Brain Iron Accumulation, 1528
Frontotemporal Degeneration with Parkinsonism, 1516 Post-traumatic Dystonia and Peripherally Induced Movement
Parkinsonism-Dementia Complex of Guam, 1516 Disorders, 1528
Guadeloupean Parkinsonism, 1516 Paroxysmal Movement Disorders, 1529
Vascular Parkinsonism, 1516 Tics, 1529
Bilateral Striatopallidodentate Calcification Tourette Syndrome, 1529
(Fahr Disease), 1517 Myoclonus, 1531
Postencephalitic Parkinsonism, 1517 Essential Myoclonus, 1531
Drug-Induced Parkinsonism, 1517 Posthypoxic Myoclonus (Lance-Adams Syndrome), 1531
Toxin-Induced Parkinsonism, 1517 Startle and Hyperekplexia, 1531
Tremor, 1517 Palatal Myoclonus, 1531
Physiological Tremor, 1517 Spinal Myoclonus, 1532
Essential Tremor, 1517 Toxin- and Drug-Induced Myoclonus, 1532
Primary Writing Tremor, 1519 Tardive Dyskinesia, 1532
Orthostatic Tremor, 1519 Classic Tardive Stereotypy, 1532
Neuropathic Tremor, 1519 Tardive Dystonia, 1532
Cerebellar Tremor, 1519 Stereotypies, 1533
Hereditary Geniospasm (Chin Tremor), 1520 Miscellaneous Movement Disorders, 1533
Fragile X Premutation, 1520 Hemifacial Spasm, 1533
Chorea, 1520 Painful Legs–Moving Toes Syndrome, 1534
Huntington Disease, 1520 Stiff Person Syndrome, 1534
Dentatorubral-Pallidoluysian Atrophy, 1523 Functional (Psychogenic) Movement Disorders, 1534
Neuroacanthocytosis and McLeod Syndrome, 1523

MOVEMENT DISORDERS AND THE BASAL implied but not proven. Clinicopathological studies relate the signs
of Parkinson disease (PD) to deficient dopaminergic neurotransmis-
GANGLIA sion in the striatum consequent to the death of dopaminergic neurons
Neurologists often equate movement disorders with disease or dys- in the substantia nigra pars compacta (SNc). Choreic movements in
function of the basal ganglia, so no review of movement disorders Huntington disease (HD) are linked to the death of medium spiny neu-
would be complete without a discussion of these subcortical struc- rons in the caudate and putamen. Hemiballism (HB) is typically asso-
tures and their connections. In some movement disorders such as ciated with structural lesions in the contralateral subthalamic nucleus
parkinsonism, chorea, and ballism, the link to the basal ganglia is sup- (STN) or its afferent or efferent connections. Changes in basal ganglia
ported by clinicopathological, biochemical, functional neuroimaging, neurotransmission are well described in many movement disorders,
and electrophysiological data, whereas in other movement disorders and deepening understanding of basal ganglia neurotransmission has
such as tremor, dystonia, and tics, dysfunction of the basal ganglia is yielded promising symptomatic therapies in many such conditions.
1498
CHAPTER 96 Parkinson Disease and Other Movement Disorders 1499
Functional neuroimaging studies with specific radiopharmaceutical Area Area 6

agents demonstrate abnormal function of basal ganglia structures, All areas of 4 and 6 SMA
and intraoperative electrophysiology studies demonstrate abnormal- cerebral cortex
ities in neuronal firing rates and patterns, particularly in the STN and
globus pallidus (GP) of patients with PD, dystonia, chorea, and other
movement disorders. Animal models including the 1-methyl-4-phe-
nyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, excitotoxic and
transgenic models of HD, and the STN lesion model of HB confirm the
central role of disordered basal ganglia function in these conditions. In
other movement disorders such as dystonia, the link with basal ganglia
function is more complex. For example, although secondary dystonias C, P
may result from structural lesions in the contralateral putamen, other
VA T
sites of pathology include the thalamus, rostral brainstem, and cerebel- GPe GPi
lum. Functional neuroimaging studies in patients with dystonia show
abnormal activation of the lenticular nucleus, but neuroimaging and
physiological studies provide support for additional involvement of
the cortex, brainstem, and cerebellum. In other movement disorders VL I, CM
such as essential tremor (ET), restless legs syndrome (RLS), stiff per-
STN
son syndrome (SPS), hemifacial spasm (HFS), spinal myoclonus, and
painful legs–moving toes syndrome (PLMTS), the dysfunction appears
to lie outside the basal ganglia, such as in the brainstem, cerebellum,
spinal cord, or even in the peripheral nervous system. SC
SNc
Basal Ganglia Anatomy Afferent connections
There is no clear consensus on which structures should be included in Intrinsic connections
the basal ganglia. For the purposes of this discussion, we consider those Efferent connections SNr
structures in the striatopallidal circuits involved in modulation of the Fig. 96.1 Schematic drawing of interconnections between the basal
thalamocortical projection: the caudate nucleus, the putamen, the ganglia and its afferent and efferent connections. CM, Centromedian
external segment of the GP (GPe), and the internal segment of the GP nucleus of thalamus; C,P, caudate, putamen (striatum); GPe, lateral
(external) globus pallidus; GPi, medial (internal) globus pallidus; SC,
(GPi). In addition, the SNc, the substantia nigra pars reticulata (SNr),
superior colliculus; SMA, supplementary motor area; STN, subthalamic
and the STN are included in the basal ganglia (Ellens et al., 2013). The nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra
substantia nigra (SN), a melanin-containing (pigmented) nucleus, pars reticulata; T, thalamus; VA, ventral anterior; VL, ventrolateral.
normally contains about 500,000 dopaminergic neurons. Several tran-
scriptional regulators, including Nurr1, Lmx1a, Lmx1b, Msx1, and
Pitx3, are responsible for the development and maintenance of mid- superior colliculi. The ventral anterior and ventrolateral thalamic
brain dopaminergic neurons (Le et al., 2009). nuclei then project to the motor and premotor cortex. Throughout,
The caudate nucleus is a curved structure that traverses the deep these projections are somatotopically organized (Rodriguez-Oroz
hemisphere at the lateral edge of each lateral ventricle. Its diameter et al., 2009).
is largest at its head, tapering to a small tail. It is continuous with the The basal ganglia has dense internuclear connections (see Fig. 96.1).
putamen at the head and tail. The caudate and putamen together are Five parallel and separate closed circuits through the basal ganglia have
called the striatum, and they form the major target for projections been proposed. These are the motor, oculomotor, dorsolateral pre-
from the cerebral cortex and the SN. The putamen and the GP together frontal, lateral orbitofrontal, and limbic loops (Rodriguez-Oroz et al.,
form a wedge-shaped structure called the lenticular nucleus. The GP is 2009). It is now generally accepted that these loops form three major
divided into two parts, the GPe and the GPi. The GPi is structurally divisions—sensorimotor, associative, and limbic—that are related to
and functionally homologous with the SNr. The SNr and SNc extend motor, cognitive, and emotional functions, respectively (Table 96.1).
the length of the midbrain ventral to the red nucleus and dorsal to the The functions of the sensorimotor striatum are subserved mainly by
cerebral peduncles. The STN is a small lens-shaped structure at the bor- the putamen, which derives its afferent cortical inputs from both motor
der between the cerebrum and the brainstem. The basal ganglia and its cortices. Sensorimotor pathways are somatotopically organized, and
relation to the thalamus and overlying cortex are illustrated in Fig. 96.1. the pathway ultimately terminates in the premotor and primary motor
cortices and the supplementary motor area (SMA). Cognitive func-
Functional Organization of the Basal Ganglia and Other tions are largely mediated by the associative striatum, particularly the
Pathways dorsal caudate nucleus, which receives afferent input from the homo-
Afferent projections to the striatum arise from nearly all areas of the lateral frontal, parietal, temporal, and occipital cortices. Projections
cerebral cortex, the intralaminar nuclei of the thalamus, mesencephalic from this pathway ultimately terminate in the prefrontal cortex. The
SN, and from the brainstem locus coeruleus and raphe nuclei. There is limbic striatum subserves emotional and motivational functions. Its
also a projection from the cerebral cortex to the STN (Eisenstein et al., input derives from the cingulate, temporal, and orbitofrontal cortices,
2014). The major efferent projections are from the GPi and SNr to the the hippocampus, and the amygdala. It mainly comprises the ven-
thalamus and brainstem nuclei such as the pedunculopontine nucleus tral striatum, with ultimate projections to the anterior cingulate and
(PPN). The GPi and SNr project to ventral anterior and ventrolateral medial orbitofrontal cortices (Rodriguez-Oroz et al., 2009). Whether
thalamic nuclei. The GPi also projects to the centromedian thalamic these divisions are interconnected or organized in parallel remains a
nuclei, and the SNr projects to the mediodorsal thalamic nuclei and topic of debate.
TABLE 96.1 Divisions of the Striatum

ORIGIN OF STRIATAL TERMINATION OF BASAL
Division Afferents Striatal Nucleus Ganglia Efferents Function

Sensorimotor Motor cortex Putamen Premotor cortex Movement
Primary motor cortex
Supplementary motor area
Associative Frontal cortex Dorsal caudate Prefrontal cortex Cognition
Parietal cortex
Temporal cortex
Occipital cortex
Limbic Hippocampus Ventral striatum Anterior cingulated cortex Emotion
Amygdala Medial orbitofrontal cortex Motivation
Cingulate cortex
Temporal cortex
Orbitofrontal cortex
Within each basal ganglia circuit lies an additional level of com- pathways serve to balance the facilitation and inhibition of the same
plexity. Each circuit contains two pathways by which striatal activity population of thalamocortical neurons, thus controlling the scale of
is translated into pallidal output. These two pathways are named the movement. A second hypothesis proposes that direct pathway-medi-
direct and indirect pathways, depending on whether striatal outflow ated facilitation and indirect pathway-mediated inhibition of differ-
connects directly with the GPi or first traverses the GPe and STN ent populations of thalamocortical neurons serve to focus movement
before terminating in the GPi. The direct and indirect pathways have in an organization reminiscent of center-surround inhibition. These
opposite effects on outflow neurons of the GPi and SNr (Fig. 96.2, A). hypotheses relate activity in the direct and indirect pathways mainly to
In the motor direct pathway, excitatory neurons from the cerebral rates of firing in the STN and GPi. Thus, death of neurons in the SNc,
cortex synapse on putaminal neurons, which in turn send inhibitory as in nigrostriatal degeneration associated with PD, decreases activity
projections to the GPi and its homolog, the SNr. The GPi/SNr sends in the direct pathway and increases activity in the indirect pathway.
an inhibitory outflow to the thalamus (see Fig. 96.2, B). Activity in These changes cause an increased rate of firing of subthalamic and
the direct pathway disinhibits the thalamus, facilitating the excitatory GPi neurons, with excessive inhibition of thalamocortical pathways,
thalamocortical pathway and enhancing activity in its target, the motor and produce the behavioral manifestations of bradykinesia in PD (Fig.
cortices. Thus, the direct pathway constitutes part of an excitatory cor- 96.3, A).
tical-cortical circuit that likely functions to maintain ongoing motor On the other hand, predominant loss of indirect pathway neu-
activity. In the indirect pathway, excitatory axons from the cerebral rons, as in HD, interferes with suppression of involuntary movements.
cortex synapse on putaminal neurons. These neurons send inhibitory Choreic involuntary movements are the usual result (see Fig. 96.3,
projections to the GPe, and the GPe sends an inhibitory projection to B). Direct electrophysiological recordings of the STN and GP during
the STN. The net effect of these projections is disinhibition of the STN. stereotactic functional neurosurgical procedures confirm that the GPi
The STN in turn has an excitatory projection to the GPi (see Fig. 96.2, and STN are overly active in patients with PD. The activity of these
C). Activity in the indirect pathway thus excites the GPi/SNr, which nuclei returns toward normal with effective pharmacotherapy, and
in turn inhibits the thalamocortical pathway. Thus, the net effect of chorea is associated with lower firing rates of neurons in these nuclei.
increased activity in the indirect pathway is cortical inhibition. There Unfortunately, this model does not completely explain some import-
is growing appreciation of the importance of direct connection from ant features of movement disorders. For example, bradykinesia and
the cortex to the STN, the so-called hyperdirect pathway, and to the chorea coexist in HD and in patients with PD treated with levodopa
thalamus (Coude et al., 2018). (LD). Thalamic lesions that might be expected to worsen parkinsonism
The striatum also receives robust afferent input from the SNc. This by reducing excitatory thalamocortical activity do not do so. Pallidal
projection from the SNc, an important modifier of striatal activity, lesions that might be expected to worsen chorea by decreasing inhibi-
facilitates activity in the direct pathway, mediated via D1 dopamine tion of thalamocortical pathways instead are dramatically effective at
receptors, and inhibits activity in the indirect pathway via D2 dopa- reducing chorea. The model is even more problematic when applied to
mine receptors (see Fig. 96.2, A). dystonia. It has been suggested that in dystonia there is overactivity of
Disorders of the basal ganglia result in prominent motor dysfunc- both the direct and indirect pathways. Yet, intraoperative recordings
tion, though not generally in frank weakness. The absence of direct in dystonia have shown low rates and abnormal patterns of neuronal
primary or secondary sensory input and lack of a major descending firing in the GPi. A simple change in firing rate of the STN or GPi is
pathway below the level of the brainstem suggest that the basal gan- thus insufficient to explain the underlying physiology of dystonia. It is
glia moderates rather than controls movement. The direct pathway is likely that disordered patterns and synchrony of pallidal firing, as well
important in initiation and maintenance of movement, and the indi- as changes in sensorimotor integration and the control of spinal and
rect pathway apparently plays a role in the suppression of extraneous brainstem reflexes, are important. These factors are under investiga-
movement. From this model of basal ganglia connectivity, hypothe- tion, but current models remain useful for understanding the rationale
ses about the motor function of the basal ganglia have been proposed. of pharmacological and ablative surgical procedures for certain move-
One hypothesis is that the relative activities of the direct and indirect ment disorders.
MC SMA PMC MC SMA PMC

glu glu
glu Putamen glu

VA/VL glu Putamen glu
(D2) dopamine (D1) VA/VL
(D2) dopamine (D1)
GABA GPe SN
GABA GABA GPe SN
GABA GABA
GABA
GABA STN GPi
GABA GABA STN GPi
glu GABA
A glu
MC SMA PMC Parkinson disease
glu A
Putamen glu MC SMA PMC
VA/VL glu
dopamine (D1)
glu Putamen glu
VA/VL
GPe SN (D2) dopamine (D1)
GABA
GABA
STN GPi GABA GPe SN
GABA GABA
B GABA
Fig. 96.2 Schematic drawing of internuclear connections of basal gan- GABA STN GPi
GABA
glia, including (A) direct and indirect pathways and (B) direct pathway.
glu
(See Fig. 96.3 for depiction of indirect pathway.) Excitatory pathways
in solid lines, inhibitory pathways in dotted lines. D1, Dopamine D1 Huntington disease
receptor; D2, dopamine D2 receptor; GABA, γ-aminobutyric acid; glu, B
glutamate; GPe, external segment of the globus pallidus; GPi, internal Fig. 96.3 Schematic drawing of functional activities in the direct and
segment of the globus pallidus; MC, motor cortex; PMC, premotor cor- indirect pathways in Parkinson disease (PD) and Huntington disease
tex; SMA, supplementary motor area; SN, substantia nigra; STN, sub- (HD). A, In PD, reduced dopaminergic facilitation of direct pathway and
thalamic nucleus; VA/VL, ventral anterior/ventrolateral thalamic nuclei. inhibition of indirect pathway due to death of dopaminergic neurons
causes increased firing and increased inhibition of thalamocortical path-
ways, producing bradykinesia. B, In HD, loss of striatal neurons leads
Although much of the emphasis has been on GPi and SNr efferents to reduced activity in indirect pathway, causing reduced inhibition of
to the thalamocortical system, there is growing evidence that descend- thalamocortical pathways, with production of excessive or involuntary
ing pathways, particularly to the zona incerta and PPN, are important movements. (See Fig. 96.2 for explanations to abbreviations.) D1, Dopa-
mine D1 receptor; D2, dopamine D2 receptor; GABA, γ-aminobutyric
in movement disorders. The PPN appears to play a role in locomo-
acid; glu, glutamate; GPe, external segment of the globus pallidus; GPi,
tion, muscle tone, and akinesia. A number of other pathways also seem internal segment of the globus pallidus; MC, motor cortex; PMC, pre-
particularly relevant to myoclonus, including a corticolemniscal-thal- motor cortex; SMA, supplementary motor area; SN, substantia nigra;
amocortical circuit and a spinobulbar-spinal circuit that primarily STN, subthalamic nucleus; VA/VL, ventral anterior/ventrolateral thalamic
involves the spinoreticular tracts, nucleus reticularis gigantocellularis nuclei.
of the medullary reticular formation, and the reticulospinal tracts. The
Guillain-Mollaret triangle is a network connecting the red nucleus,
dentate nucleus, and inferior olive, which has been implicated in pala- act to synchronize activity generated by the basal ganglia and cerebel-
tal myoclonus (PM) (also known as palatal tremor) and myorhythmia lum. Indeed, there is a growing body of evidence of communication
(Baizabal-Carvallo et al., 2015). The propriospinal pathways and seg- between the cerebellum and basal ganglia involving γ-aminobutyric
mental spinospinal loops are important in the genesis of propriospinal acid (GABA) and other neurotransmitters (Bostan and Strick, 2018).
and spinal segmental myoclonus, respectively.
It is beyond the scope of this chapter to review all the brain struc- Biochemistry
tures involved in motor control, but there has been considerable recent Our understanding of basal ganglia neurotransmitters and pharmacol-
interest in the lateral habenula, located above the posterior thalamus. ogy is growing rapidly. In addition to dopamine, there are many other
The lateral part of the habenula has an inhibitory influence on the SNc, neurotransmitters that play a role in motor and nonmotor functions
but its exact role in various movement disorders is unknown, although (Stayte and Vissel, 2014; Klein et al., 2014). Along with this growth is
it has been implicated in some mood disorders (Yang et al., 2018). an expanding spectrum of practical applications for pathology, neu-
Another structure that has received some interest, particularly as it roimaging, and therapeutics. For example, catecholamine and amino
relates to ET, is zona incerta. This nucleus appears to be an extension acid neurotransmitters coexist with peptides. This co-localization may
of the reticular nucleus of the thalamus, situated between the thalamus allow histopathological differentiation among medium spiny striatal
and the fields of Forel, with its fiber tracts conveying the pallidal output projection neurons that secrete γ-aminobutyric acid (GABAergic neu-
to the thalamus. Chiefly inhibitory (GABAergic), the zona incerta may rons), further elucidating the specific nature and progress of striatal
TABLE 96.2 Pharmacology of the Basal propionic acid (AMPA), and kainate. The NMDA receptor has been
the focus of particular attention because of its potential role in excito-
Ganglia
toxic neuronal injury. There are also metabotropic glutamate receptors
Pathway Transmitter (Reiner and Levitz, 2018). Glutamate is not only an excitatory neu-
rotransmitter by opening calcium channels, but it is also involved in
Striatal Afferents
many metabolic processes by creating short- and long-term changes
Cerebral cortex → striatum Glutamate
in synaptic excitability that are thought to be fundamental in brain
Cerebral cortex → STN Glutamate
plasticity.
Locus coeruleus → striatum Norepinephrine
GABA, the main inhibitory neurotransmitter in the brain, is syn-
Locus coeruleus → SN Norepinephrine
thesized by glutamic acid decarboxylase (GAD) from glutamate. There
Raphe nuclei → striatum Serotonin
are three classes of GABA receptors, GABAA, GABAB, and GABAc. The
Raphe nuclei → SN Serotonin
subclasses are largely differentiated by their relative sensitivity to ben-
Thalamus → striatum Acetylcholine?
zodiazepines. For example, benzodiazepines can increase the inhib-
SNc → striatum Glutamate?
itory action of a GABAA synapse. GABAA receptors are ligand-gated
Dopamine, cholecystokinin
chloride channels and have many subtypes. The GABAB receptor is a
Intrinsic Connections metabotropic receptor.
Striatal interneurons GABA, acetylcholine Five types (D1 through D5) and two families (D1 and D2) of dopa-
Striatum → GPi Somatostatin, neuropeptide Y mine receptors have been identified (Klein et al., 2019). The D1 family
Striatum → SNr Nitric acid, calretinin of receptor is adenylate cyclase dependent and contains subtypes D1
Striatum → GPe GABA, substance P and D5. D1 receptors reside primarily in the direct pathway, cerebral
GPe → STN GABA, dynorphin, substance P cortex, and limbic system. D2 receptors are located primarily in the
STN → GPi, SNr, GPe GABA, enkephalin, glutamate indirect pathway, cerebral cortex, and limbic system, as well as in the
pituitary gland. There are many types of cholinergic receptors, desig-
Striatal Efferents nated as M1–M5, which mediate both excitatory and inhibitory effects
GPi → thalamus GABA (Liu and Su, 2018). Most striatal cholinergic receptors are musca-
SNr → thalamus GABA rinic. In the norepinephrine system, there are two primary receptor
GABA, γ-Aminobutyric acid; GPe, external segment of the globus palli-
systems, α and β. There are many distinct receptor subtypes of sero-
dus; GPi, internal segment of the globus pallidus; SN, substantia nigra; tonin receptors, including G protein–coupled receptors in the 5-HT1,
SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticu- 5-HT2, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 families and the 5-HT3-
lata; STN, subthalamic nucleus. type ligand-gated ion channels. Adenosine A2A receptors are co-local-
ized with striatal dopamine D2 receptors on GABAergic medium spiny
neurons, which project via the indirect striatopallidal pathway to the
neurodegeneration. Neuroimaging technology has been aided by the GPe. Drugs targeting specific subpopulations of receptors are in use
development of radiopharmaceutical ligands with such discrete targets or under development for movement disorders, but there remains a
as the dopamine transporter on the presynaptic dopamine neuron and knowledge deficit about the relative clinical utility of specific receptor
subpopulations of dopamine receptors on the postsynaptic neuron. agonists and antagonists.
The pharmaceutical industry is searching for ways to provide bet- There is a growing interest in the tetrahydrocannabinol and the
ter-targeted and more physiological stimulation of neurotransmitter cannabinoid system but its role in motor control or various movement
receptors and is expanding its investigations from the primary targets disorders is still not well understood, although there is evidence that
themselves to approaches that may modify responsiveness of the pri- the cannabinoids modulate dopaminergic effects (Bloomfield et al.,
mary targets. 2016; Covey et al., 2017; Kluger et al., 2015). CB1 receptor is the prin-
The major neurotransmitters of the basal ganglia are outlined in cipal receptor in the central nervous system (CNS), particularly abun-
Table 96.2 (see also Fig. 96.2). Most excitatory synapses of the basal dant in the basal ganglia (Davis et al., 2018). TRVP1 (transient receptor
ganglia and its connections—including those from the cerebral cortex potential vanilloid type1) receptors also respond to cannabinoids. The
to the striatum, the STN to the GPi, and the thalamocortical projec- main endogenous ligands for the CB1 receptor are anandamide and
tions—use glutamate. Projections from the striatum to the GPe and 2-arachidonoylglycerol (2-AG).
GPi, from the GPe to the STN, and from the GPi to the thalamus are
inhibitory and employ GABA. Medium spiny GABAergic neurons in
MECHANISMS OF NEURODEGENERATION
the direct pathway co-localize substance P and dynorphin. GABAergic
neurons in the indirect pathway co-localize enkephalin. Dopamine is Many of the neurodegenerative movement disorders share the property
the major neurotransmitter in the nigrostriatal dopamine system; it of neuronal damage caused by the accumulation of aggregation-prone
has excitatory or inhibitory actions depending on the properties of proteins that have toxic effects (Table 96.3). For a protein to function
the stimulated receptor. Acetylcholine is found in large aspiny striatal normally, it must be properly synthesized and folded into its normal
interneurons and the PPN. Norepinephrine, important in the auto- three-dimensional structure. Nascent proteins are aided in folding by
nomic nervous system, is most concentrated in the lateral tegmentum molecular chaperones. Proteins that are not properly folded, are oth-
and locus coeruleus. Serotonin is found in the dorsal raphe nucleus of erwise damaged, or are beyond their useful lives are degraded by the
the brainstem, hippocampus, cerebellum, and spinal cord. ubiquitin-dependent proteasome protein degradation system (Atkin
For each of these neurotransmitters, multiple types of receptors and Paulson, 2014). In the ubiquitin-dependent proteasome system,
may exist. Glutamate is active at a number of types of ligand-gated proteins are first labeled for degradation by attachment of a polyubiq-
ion channel receptors named for their selective agonists: N-methyl- uitin chain (Fig. 96.4). This three-step process involves activation, con-
d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole jugation, and ligation steps catalyzed by three types of enzymes—E1,
TABLE 96.3 Toxic Proteins and Neurodegenerative Movement Disorders

α-Synuclein Tau Polyglutamine Tract
Parkinson disease Four-repeat tau Huntington disease
Diffuse Lewy body disease Progressive supranuclear palsy Spinocerebellar ataxias
Multiple system atrophy Corticobasal degeneration Dentatorubral-pallidoluysian atrophy
Frontotemporal dementia with parkinsonism (chromosome 17)
Parkinsonism dementia complex of Guam
Postencephalitic parkinsonism
U U BOX 96.1 Mechanisms of

U UCHL1 Neurodegeneration Related to Misfolded
U
Protein Stress
U
E1 Loss of protein function
Activation Interaction of the mutant protein with the wild-type protein
Interaction with other proteins, including transcription factors
U
U U Caspase activation
U
E2 U Apoptosis
Conjugation U Suppression of proteasome function
U
U Interference with mitochondrial function
U Oxidative stress
Microglial activation
E3 26S
Ligation Proteasome
Protein
fragments Lewy body–like inclusions, resulting in progressive prion-like spread
Protein
Ubiquinated of neurodegeneration (Recasens et al., 2014). Some potential mech-
protein anisms of neurodegeneration related to misfolded protein stress are
Fig. 96.4 Ubiquitin-Dependent Proteasome Proteolysis. Once a pro- listed in Box 96.1. The mutant protein may be unable to perform a vital
tein is tagged for degradation, it is tagged with a polyubiquitin chain, function or may interfere with the function of the wild-type protein.
a three-step process involving first activation, then conjugation, then Mutant protein, protofibrils, or aggregates might interfere with other
ligation. Ubiquitinated protein enters 26S proteasome, where it is proteins. Interference with transcription factors may be particularly
degraded into protein fragments, and polyubiquitin chain is degraded
important in this regard. Mutant proteins may activate caspases or
back to monomeric ubiquitin. E, Enzyme; U, ubiquitin; UCHL1, ubiquitin
carboxy-terminal hydrolase 1.
in other ways activate the apoptotic cascade. They may interfere with
intracellular transport or other vital processes. They may suppress
activity of the proteasome, enhancing protein aggregation. They may
E2, and E3, respectively. Polyubiquitinated protein enters the 26S interfere with mitochondrial function, making cells more vulnerable to
proteasome, a cylindrical complex of peptidases. The end products of excitotoxicity. In addition to the ubiquitin-proteasome system, lyso-
proteasome action are protein fragments and polyubiquitin. The poly- somes play an important role in degrading intracellular proteins by
ubiquitin is then degraded and recycled to the cellular ubiquitin pool, a process termed autophagy (Chu, 2019). When the function of the
a process requiring enzymatic action by ubiquitin carboxy-terminal ubiquitin proteasome system is not sufficient to clear the accumulat-
hydrolase 1. ing cellular proteins, the autophagy lysosome pathway becomes the
The cascade of pathogenic events linking abnormal protein aggre- other important route for degradation of aggregated/misfolded pro-
gation to cell death is the subject of intense investigation. Although teins as well as sick or abnormal mitochondria. Indeed, mitophagy is
aggregates are the most striking physical change in surviving cells, an increasingly recognized mechanism for removing sick mitochon-
the actual role of the aggregate remains a mystery. Indeed, many now dria and maintaining cellular health (Wang et al., 2019). Accumulation
believe that the formation of aggregates may be a protective mecha- of iron, increased oxidative stress, and microglial activation have also
nism sequestering the wayward protein from vulnerable cell processes been thought to play important roles in the pathogenesis of various
(Espay et al., 2019). Nevertheless, there are now many clinical trials neurodegenerative disorders (Dusek et al., 2012).
designed to suppress α-synuclein as a potential disease-modifying Many neurodegenerative movement disorders can be linked to
strategy (Jankovic, 2019). abnormal synthesis, folding, or degradation of specific proteins or
Misfolded proteins may produce the most mischief as they form protein families and the notion that progression of neurodegenerative
protofibrils. A number of mechanisms have been described. In some disease is mediated via seeding of misfolded proteins has extended to a
cases, these are specifically related to the type of protein, but in many broad range of mutated proteins, including α-synuclein, tau, hunting-
other cases, they are nonspecific mechanisms shared by all the mis- tin, SOD-1, and TDP-43. The synucleinopathies include PD, Lewy body
folded protein diseases. There is growing evidence that preformed disease (LBD), and multiple system atrophy (MSA). The tauopathies
fibrils generated from full-length and truncated recombinant α-synu- include progressive supranuclear palsy (PSP), corticobasal degenera-
clein enter neurons, probably by endocytosis, and act as “seeds” that tion (CBD), familial frontotemporal dementia (FTD) with parkinson-
induce recruitment of soluble endogenous α-synuclein into insoluble ism (FTDP), postencephalitic parkinsonism (PEP), post-traumatic
parkinsonism, and amyotrophic lateral sclerosis (ALS)-PD of Guam.

TABLE 96.4 Hoehn and Yahr Stage
The polyQ disorders include HD, dentatorubral-pallidoluysian atro-
phy (DRPLA), and many spinocerebellar ataxias (Ling et al., 2010; Stage Disease state
Williams and Lees, 2009).
Original Scale
Within the CNS, certain neuronal populations seem selectively I Unilateral involvement only, minimal or no functional
vulnerable to the various pathogenic mechanisms of cell death. This impairment
preferential degeneration of specific neuronal populations ultimately II Bilateral or midline involvement, without impairment of
determines the phenotype of the disorder. Better understanding of the balance
various pathogenic cellular mechanisms and selective vulnerability III First sign of impaired righting reflex, mild to moderate
may lead to neuroprotective therapeutic strategies that favorably mod- disability
ify the natural course of the neurodegenerative disease. IV Fully developed, severely disabling disease; patient still
able to walk and stand unassisted
PARKINSONIAN DISORDERS V Confinement to bed or wheelchair unless aided
Parkinson Disease Modified Scale
In his monograph, The Shaking Palsy (1817), James Parkinson identi- 0 No signs of disease
fied the hallmark features of the illness through descriptions of cases 1 Unilateral disease
observed in the streets of London as well as in his own patients (Obeso 1.5 Unilateral plus axial involvement
et al., 2017). Over time, Parkinson disease or idiopathic PD has replaced 2.0 Bilateral disease without impairment of balance
the original term paralysis agitans as the name for the clinical syndrome 2.5 Mild bilateral disease with recovery on pull test
of asymmetrical parkinsonism, usually with rest tremor, in association 3.0 Mild to moderate bilateral disease, some postural insta-
with the specific pathological findings of depigmentation of the SN due bility, physically independent
to loss of melanin-laden dopaminergic neurons containing eosinophilic 4.0 Severe disability, still able to walk or stand unassisted
cytoplasmic inclusions (Lewy bodies) (see Chapter 24). Dopamine defi- 5.0 Wheelchair bound or bedridden unless aided
ciency in parkinsonian brain was described by Hornykiewicz in 1959,
a discovery that ultimately led to highly effective pharmacotherapy
with LD and direct-acting dopamine agonists (DAs). Recently, genetic
forms of parkinsonism that are clinically indistinguishable from PD In contrast to the rest and re-emergent tremor which may be related
have been linked to mutations in several genes (Rousseaux et al., 2017). to dopamine deficiency, the PD action-postural tremor appears to
The discovery of different genetic forms of parkinsonism with variable correlate with serotonergic deficiency (Jankovic, 2018a). Bradykinesia
penetrance has led to the current concept of PD as a syndrome with and rigidity are often detectable on the symptomatic side (Loane et
genetic and environmental etiologies, but, overall, gene mutations are a al., 2013), and midline signs such as reduced facial expression or mild
rare cause of parkinsonism, particularly in those patients with late-on- contralateral bradykinesia and rigidity may already be present. The
set disease (Deng et al., 2018; Trinh and Farrer, 2013) (Chapter 24). presentation may be delayed if bradykinesia is the earliest symptom,
particularly when the onset is on the nondominant side. The disorder
Epidemiology usually remains asymmetrical throughout much of its course. With
In community-based series, PD accounted for more than 80% of all progression of the illness, generalized bradykinesia may cause
parkinsonism, with a prevalence of approximately 360 per 100,000 and difficulty arising from a chair or turning in bed. Patients typically
an incidence of 18 per 100,000 per year (de Lau and Breteler, 2006). develop stooped posture and in some cases the flexion of the trunk
PD is an age-related disease, showing a gradual increase in prevalence can become quite severe, the so-called camptocormia (see Videos 96.1
beginning after age 50, with a steep increase in prevalence after age 60. and 96.2) (Wijemanne and Jankovic, 2019). Some patients may also
Disease before 30 years of age is rare and often suggests a hereditary develop deformities in the hands and feet which can resemble arthritis,
form of parkinsonism. Prevalence rates in the United States are higher the so-called “striatal deformities” (see Video 96.3) (Wijemanne and
than those in Africa and China, but the role of race remains unclear. Jankovic, 2019). The gait and balance are progressively affected, and falls
Within the United States, race-specific prevalence rates vary, with may occur. Sudden arrests in movement, also called freezing or motor
some studies suggesting a similar prevalence among Whites and Blacks. blocks, soon follow, first with gait initiation, turning and traversing
Unfortunately, Blacks make up only a small fraction of most specialty narrow or crowded environments, and then during walking (see Video
clinic populations and thus are underrepresented in clinic-based stud- 96.4). Bulbar functions deteriorate, impairing communication and
ies and clinical trials. One study showed the world’s highest prevalence nutrition. The tremor-dominant form of PD generally has a more
of PD may be among the Amish in the US Northeast—nearly 6% of favorable clinical course than PD dominated by gait disorder and
those 60 years of age or older, more than three times the reported postural instability (Thenganatt and Jankovic, 2014a).
1%–2% prevalence for the rest of the country (Racette et al., 2009). The Unified Parkinson’s Disease Rating Scale (UPDRS) has been
Clinical features. Typically, the onset and progression of PD used to quantitate the various motor symptoms and signs of PD and to
are gradual. We have developed a screening tool that can be used to chart the course of the disease. This traditional scale, now known as the
detect early symptoms of PD (York et al., 2020). The most common Movement Disorder Society (MDS)-UPDRS, has been revised to clarify
presentation is with rest tremor in one hand, often associated with some ambiguities in the original version and to capture early motor and
decreased arm swing and shoulder pain (Ha and Jankovic, 2012; also nonmotor symptoms associated with PD (http://www.movement-
Jankovic, 2008). Although 4–5 Hz rest tremor is considered the typical disorders.org). The Hoehn and Yahr staging, first described before effec-
tremor of PD, the more troublesome tremor experienced by patients tive dopaminergic treatment became available, outlines the milestones
with PD is postural tremor, either re-emergent tremor occurring after in progression of the illness from mild unilateral symptoms through the
a latency of a few seconds following the assumption of position of end-stage nonambulatory state. A modified version of the Hoehn and
outstretched arms, or the postural tremor of PD (Jankovic, 2016a). Yahr stage is commonly used in contemporary clinical trials (Table 96.4).
Nonmotor symptoms are increasingly recognized as a major cause

BOX 96.2 “Red Flags” Suggesting a
of disability in PD and contribute prominently to declining quality of
life, particularly in the more advanced stages of the disease (Marinus
Diagnosis Other Than Parkinson Disease
et al., 2018). Autonomic symptoms include reduced gastrointestinal Early or prominent dementia
transit time with postprandial bloating and constipation, urinary fre- Symmetrical signs
quency and urgency (sometimes with urge incontinence), impotence, Bulbar dysfunction
disordered sweating, and orthostatic hypotension. Cognitive and Early gait disorder
behavioral changes are also very common. Attention and concentra- Falls within the first year
tion wane. Executive dysfunction with diminished working memory, Wheelchair dependence within 5 years
planning, and organization is common. Global dementia occurs in Early autonomic failure
approximately 30% of patients, increasing in frequency with the age Sleep apnea
of the patient. Those with prominent early executive dysfunction and Inspiratory stridor
more severe motor signs seem particularly at risk. Anxiety, depression, Apraxia
and other mood disorders are common in PD. Sleep disturbance is Alien limb
nearly universal in PD and is multifactorial. Cortical sensory loss
Disordered sleep onset and maintenance lead to fragmentation of
nocturnal sleep. A variety of motor movements including RLS and
periodic leg movements of sleep may be seen, and many patients have for specific PD-related monogenic mutations or by whole-exome
rapid eye movement (REM) sleep behavior disorder (RBD) with active or whole-genome sequencing may be indicated when coupled with
motor movements during REM sleep. The following question was appropriate genetic counseling (Sokol et al., 2017).
found to have 94% sensitivity and 87% specificity in detecting RBD: Neuroimaging studies such as computed tomography (CT) and
“Have you ever been told, or suspected yourself, that you seem to ‘act magnetic resonance imaging (MRI) are usually not very helpful in
out your dreams’ while asleep (for example, punching, flailing your making a diagnosis of PD, because they are generally normal or show
arms in the air, making running movements, etc.)?” (Postuma et al., only incidental abnormalities. Sometimes neuroimaging abnormalities
2012). Some patients with PD have sleep apnea. Vivid dreams and can be useful in suggesting alternative diagnoses such as PSP or MSA
nightmares are very common, particularly in treated patients. Sleep (see below). The radiopharmaceutical 6-[18F]-fluorodopa (F-dopa)
disorders in PD variably relate to the pathological changes of the dis- is taken up by dopaminergic neurons in the SN and metabolized to
ease itself, arousals due to immobility, comorbid primary sleep disor- 6-[18F]-fluorodopamine. Positron emission tomography (PET) scans
ders, and side effects of antiparkinsonian medications. Many patients using this radiopharmaceutical agent show reduced F-dopa uptake in
with PD are excessively sleepy during the day, sometimes with serious dopaminergic nerve terminals in the putamen and caudate propor-
consequences such as unintended sleep episodes while driving. In most tional to the severity of degeneration in the ipsilateral SN and symp-
cases, this excessive daytime drowsiness is related to dopaminergic toms in the contralateral hemibody (Fig. 96.5). Although these tests are
drugs. Fatigue is a common and complex symptom of PD. The dif- used in PD research, they are not readily clinically available at this time.
ferentiation of fatigue from excessive daytime sleepiness, depression, Single-photon emission CT (SPECT) with radioligand that labels the
apathy, and other conditions can be difficult, and there is not yet a dopamine transporter on nerve terminals in the striatum (DaTscan) is
useful body of literature on its assessment and treatment. a very helpful tool in differentiating PD from ET, drug-induced par-
Clinicopathological studies have found that the clinical variable kinsonism (DIP), or functional (psychogenic) parkinsonism (Isaacson
that best predicts the typical pathological changes of PD, in the absence et al., 2017; Jankovic, 2011). Since most atypical parkinsonian disor-
of other diagnoses known to cause parkinsonism, is an asymmet- ders have striatal dopaminergic denervation, DaTscan is not helpful in
rical illness with rest tremor along with rigidity or bradykinesia and differentiating these disorders from PD. Routine electrophysiological
marked improvement with LD, motor fluctuations, dyskinesias, and testing is not helpful in the diagnosis of PD.
hyposmia (Adler et al., 2014). Misdiagnosed cases generally are found
to have MSA, PSP, or subcortical vascular disease. When making the Pathology
diagnosis of early PD, the clinician should be aware of a number of The most striking pathological changes in PD occur in the SNc. The SN
red flags (Box 96.2) (see Chapter 24). Cognitive impairment within appears pale to the naked eye. Microscopic changes include neuronal
the first year should raise the possibility of Alzheimer disease (AD), loss, gliosis, and the presence of extracellular pigment. Surviving neu-
dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), PSP, rons may show characteristic cytoplasmic inclusions (Fig. 96.6). These
or FTDP. Symmetrical or prominent midline or bulbar signs suggest inclusions, called Lewy bodies, have a dense eosinophilic core and a
MSA or PSP. Early gait disorder with falls points to the diagnosis of pale halo (except for those located in the cortex) (Jellinger, 2012). They
PSP or to subcortical vascular disease. Dependence on a wheelchair contain hyperphosphorylated neurofilament proteins, lipids, iron,
within 5 years of onset is suggestive of PSP or MSA. Early orthostatic ubiquitin, and α-synuclein. Pigmented nuclei elsewhere in the brain-
hypotension or incontinence points to the autonomic dysfunction of stem, including the locus coeruleus, dorsal motor nucleus of the vagus,
MSA. Severe sleep apnea, inspiratory stridor, or involuntary sighing and others, may also show Lewy bodies and characteristic degenerative
also suggests MSA. Apraxia, alien limb, or cortical sensory loss is typ- changes. The substantia innominata and intermediolateral cell column
ically seen in CBS. in the spinal cord also are affected. Patients with PD and dementia
Routine laboratory studies are not helpful in the diagnosis of PD, show more diffuse Lewy body pathology or comorbid AD. Even the
and their use should be reserved for patients with atypical features. myenteric intestinal and cardiac plexus of patients with PD may con-
There is a growing interest in serums and cerebrospinal fluid (CSF) tain Lewy bodies, showing that PD is not just a CNS disease.
biomarkers that may differentiate between PD and atypical parkinson- A staging system introduced by Braak (Goedert et al., 2013) has
ism. In this regard, several studies have found that neurofilament light been developed to characterize the progression of neuropatholog-
chain (NFL) protein levels have been found elevated in the serum and ical changes associated with PD. According to Braak staging, during
CSF of patients with atypical parkinsonism but not in PD (Marques the presymptomatic stages (1 and 2), the PD-related inclusion body
et al., 2019). When genetic causes (see below) are suspected, testing pathology remains confined to the medulla oblongata and olfactory
A B
Fig. 96.5 Positron emission tomography scan with [11C]RTI-32,
which labels the presynaptic dopamine trans-
porter in a normal control (A) and a subject with early Parkinson disease (PD) (B). There is asymmetrically reduced
uptake in PD, indicating asymmetrical loss of presynaptic dopaminergic neurons. (Courtesy Mark Guttman, MD.)
olfactory, sleep, and autonomic involvement in patients with PD, the

staging proposal has been challenged for many reasons and inconsis-
tencies, such as absence of cell counts to correlate with the described
synuclein pathology, absence of immunohistochemistry to identify
neuronal types, absence of observed asymmetry in the pathological
findings that would correlate with the well-recognized asymmetry of
clinical findings, absence of bulbar symptoms as early features of PD,
and the observation that brain synucleinopathy consistent with Braak
stages 4 and 6 has been found in individuals without any neurologi-
cal signs. Although the Braak hypothesis and the central role of α-sy-
nuclein in the pathogenesis of PD have been challenged (Espay et al.,
2019) these concepts provide a useful framework for understanding
A the progression of neurodegeneration in PD.
Etiology
Studies of large numbers of patients with PD have suggested that PD is
a multifactorial illness with likely genetic and environmental determi-
nants (Rousseaux et al., 2017; Jankovic and Tan, 2020). Twin studies
suggest that heredity plays a relatively small role in the population at
large, but the hereditary component is greater if one twin has disease
onset at younger than age 50. Moreover, PET studies of twins suggest
that most monozygotic twins of patients with PD show subclinical
declines in dopamine innervation, strengthening the evidence for a
significant hereditary contribution irrespective of age at onset.
Although the majority of cases of PD appear to be sporadic, it is
B becoming increasingly evident that genetic factors play an import-
Fig. 96.6 Brainstem Lewy Bodies. A, Hematoxylin and eosin-stained ant role in the pathogenesis of PD, particularly if onset is earlier than
section of substantia nigra with a pigmented neuron containing two age 50 (see Chapter 24). Some 20%–25% of patients have at least
Lewy bodies. Each is an eosinophilic cytoplasmic inclusion with a halo, one first-degree relative with PD, and first-degree relatives are two
displacing neuromelanin. B, α-Synuclein-immunostained Lewy body in a to three times as likely as relatives of controls to develop PD. The
neuron of the substantia nigra; α-synuclein protein is stained red in this most cogent evidence for genetic contribution to the pathogene-
preparation. (Courtesy Elizabeth Cochran, MD.) sis of PD has been provided by reports of large multicase kindreds
with dominantly inherited autopsy-proven PD. A genome scan in
bulb. In stages 3 and 4, the SN and other nuclear grays of the mid- the Contursi kindred of Greek-Italian origin found a genetic marker
brain and basal forebrain are the focus of initially subtle and then on chromosome 4q21-q23 linked to the PD phenotype. Subsequent
severe changes, and the illness reaches its symptomatic phase. In the studies identified at least three different mutations in the α-synuclein
end stages (5 and 6), the pathological process encroaches upon the tel- gene (SNCA), the first monogenetic form of PD, designated PARK1
encephalic cortex. Although the Braak hypothesis is supported by early (see Table 24.1). In addition to the typical PD features, this family
exhibited dementia, severe central hypoventilation, orthostatic hypo- ranging from Lewy body and tau neurofibrillary tangle pathology
tension, prominent myoclonus, urinary incontinence, and patholog- to no pathological changes. The gene responsible for PARK8 on
ical involvement of the brainstem pigmented nuclei, hippocampus, 12p11.2-q13.1, called LRRK2 (leucine-rich repeat kinase 2), belongs
and temporal neocortex. Later, the application of quantitative real- to the ROCO protein family and includes a protein kinase domain of
time PCR amplification of the SNCA gene showed that some families the MAPKKK class and several other major functional domains. The
with a PD phenotype, originally designated as PARK4, had duplica- gene product, a protein called dardarin (from Basque word dardara,
tion and triplication of the gene, with marked increase in the amount meaning “tremor”), is a novel protein that probably functions as a
of α-synuclein protein. Thus, an overexpression of α-synuclein may cytoplasmic kinase involved in phosphorylation of proteins such as
lead to neurodegenerative disease, with features overlapping with PD, α-synuclein and tau. LRRK2 is closely associated with a variety of
DLB, and MSA. Based on screening, the entire coding region of the membrane and vesicular structures, membrane-bound organelles,
gene in a large number of PD patients shows that mutation in the and microtubules, suggesting its role in vesicular transport and
SNCA gene is a rare cause of PD. membrane and protein turnover, including the lysosomal degra-
Discovery of a linkage between an autosomal recessive, young-onset, dation pathway. This mutation has been found to be particularly
LD-responsive form of PD to a locus on chromosome 6q25.2-27 led frequent in PD patients of North African origin and in Ashkenazi
to subsequent identification of numerous mutations in the gene called Jewish patients (Inzelber et al., 2014). The penetrance is quite vari-
parkin (PARK2). This 500-kb, 12-exon gene encodes a 465-amino acid able, and many elderly individuals have the mutation but no signs
protein with E3 ubiquitin-ligase activity through interaction with the of PD have been reported.
ubiquitin-conjugating enzyme UbcH7 (E2). Associated with the Golgi It is beyond the scope of this chapter to discuss all the various
complex, the parkin protein has also been thought to be involved in genetic causes of PD but the reader is referred to Chapter 24 and other
vesicular transport. Parkin strongly binds to a variety of proteins and reviews on this topic (Deng et al., 2018). The variable penetrance and
microtubules, a disruption of which in patients with parkin mutations growing number of causative and susceptibility genes, coupled with
affects vesicular transport and may contribute to the nigrostriatal a growing number of commercially available DNA tests, has obvious
degeneration. Whereas normal parkin is involved in ubiquitination and implications for genetic counseling (Sokol et al., 2017).
subsequent degradation of certain proteins by proteasomes, mutated Evidence for environmental causes of PD comes primarily from
parkin protein loses this activity and thus may lead to an accumulation two sources: the fortuitous discovery of parkinsonism in parenteral
of proteins, causing a selective neural cell death without formation of drug users exposed to the contaminant MPTP and epidemiological
Lewy bodies. In addition to typical PD features, patients with PARK2 associations of sporadic PD or other parkinsonisms with certain life-
exhibit a variety of atypical features such as hyperreflexia, dystonia, style or occupational exposures. The discovery that a handful of drug
leg tremor, autonomic dysfunction, sensory axonal peripheral neu- addicts had developed a severe LD-responsive form of parkinsonism
ropathy, marked sleep benefit, LD-induced dyskinesias, psychosis, and following parenteral administration of a meperidine analog contam-
other behavioral and psychiatric problems. Although PARK2 has been inated with the mitochondrial protoxin MPTP suggested that envi-
identified in patients with late age at onset, up to half of patients with ronmental toxins might cause PD. The discovery of MPTP-induced
onset of PD before age 40 years have parkin mutations. parkinsonism in humans was a sentinel event in our understanding of
A growing number of novel genes have been implicated in the the disease because it pointed to a class of environmental toxins that
pathogenesis of PD (Deng et al., 2018; Trinh and Farrer, 2013) (see might be important in sporadic disease. Although MPTP spawned
Chapter 24). In addition to α-synuclein (SNCA gene), there are many the development of reproducible models of disease in many kinds
other monogenetic causes of PD (see Table 24.1) (Deng et al., 2018) of animals, its role in human disease is limited to the cluster of cases
Mutations in the PTEN-induced putative kinase 1 (PINK1) gene on in drug addicts and a few others. Intriguing studies have confirmed
chromosome 1p36 were identified in autosomal recessive families with that certain pesticides (e.g., paraquat, rotenone) can reproduce the
early-onset parkinsonism (PARK6). The PINK1 gene codes for a puta- pathology of PD in animals, but their role in human disease remains
tive serine-threonine kinase located in the mitochondria, thus provid- undefined.
ing further support for the role of oxidative stress in the pathogenesis Epidemiological studies suggest that exposure to environmental
of PD. The mean age at onset is in the fourth decade, and the course metals or organic toxins may be associated with an increased risk of
is quite benign, associated with LD-induced dyskinesias. These clinical PD or an earlier age at onset. Case-controlled studies have suggested
features are similar to those of another autosomal recessive form of that the risk of PD is increased in persons who have worked in the agri-
PD (PARK7) localized to the same chromosomal region in the DJ-1 cultural industry, have been exposed to pesticides, or have sustained
gene. Besides slow progression and good, prolonged response to LD, significant head injury. Whether exposure to welding predisposes to
patients with a DJ-1 mutation may exhibit blepharospasm, leg dysto- earlier onset of PD, possibly as a result of manganese poisoning, is con-
nia, anxiety, and parkinsonism-dementia-ALS complex. In contrast to troversial (Jankovic, 2005). On the other hand, the risk of PD seems
parkin mutations that may account for up to 50% of young-onset PD, lower in those with a high dietary intake of antioxidant-rich foods,
the DJ-1 mutations account for approximately 1% of all young-onset as well as caffeine drinkers and those who have smoked cigarettes.
PD cases. Although PD and cancer are two distinct diseases that result from
Another locus mapped to 12p11.23-q13.11 (PARK8) was ini- either degeneration or over-proliferation, respectively, several recent
tially identified in a Japanese family with typical PD inherited in an studies have provided evidence that while PD provides some type of
autosomal dominant pattern with incomplete penetrance and has biological protection against most types of cancers, the disease confers
been subsequently found to be the most common form of famil- increased risk for other cancers such as melanoma. The relationship
ial adult-onset PD (Marras et al., 2016). The course of the disease between PD and melanoma is being explored, but the higher frequency
is relatively benign, usually presenting with unilateral hand or leg of melanoma does not appear to be due to LD. It is possible that high
tremor without cognitive deficit; the patients respond well to LD. concentrations of α-synuclein in the skin of patients with PD may
Other clinical phenotypes have included parkinsonism with demen- increase their risk of melanoma by inhibiting tyrosine hydroxylase, an
tia, hallucinations, dysautonomia, amyotrophy, or both and other- enzyme involved in dopamine and melanin biosynthesis or by some
wise typical ET. Autopsy studies demonstrate variable pathology, other mechanism (Pan et al., 2012).
Treatment anticholinergics, amantadine, LD, MAO inhibitors (MAOIs), catechol-

Before discussing specific treatment strategies for PD, it is important O-methyltransferase inhibitors (COMTIs), and DAs (Jankovic et al.,
to recognize that the quantitative assessment of clinical symptoms and 2014; Obeso et al., 2017). Anticholinergics such as trihexyphenidyl
progression of the course is an essential component of any therapeutic and benztropine antagonize the effects of acetylcholine at muscarinic
trial (Jankovic, 2008; Jankovic and Tan, 2020 Jankovic and Tan, 2020). receptors postsynaptic to striatal interneurons. They reduce tremor
In addition to sensitive clinical rating scales (e.g., MDS-UPDRS), and rigidity but have no effects on bradykinesia. Toxicity relates to
reliable diagnostic, presymptomatic, and progression biomarkers are antagonism of acetylcholine at central receptors, causing confusion,
needed (Marek et al., 2018; Wu et al., 2011). and peripheral receptors, causing blurred vision, dry mouth,
Neuroprotective or disease-modifying therapies for Parkinson constipation, and urine retention. Although amantadine has been
disease. A preclinical period lasting years, its slow progression rate, available for nearly 4 decades (it was originally marketed as an anti-
and our increasing understanding of disease etiopathogenesis make PD influenza, antiviral agent), its antiparkinsonian mechanisms have
an ideal candidate for neuroprotective therapeutic strategies. However, been poorly understood. It has been thought to stimulate release of
double-blind placebo-controlled trials designed to explore therapies endogenous dopamine stores, block reuptake of dopamine from
that may have favorable disease-modifying effects and slow disease the synaptic cleft, and have anticholinergic properties. However,
progression have been thus far disappointing. The first “neuroprotective” amantadine has been found to have antiglutamatergic properties and
trial, DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of as such is the only antiparkinsonian drug that improves LD-induced
Parkinsonism), randomized patients with early PD to treatment with dyskinesia. Extended release formulation of amantadine has been
placebo, tocopherol, selegiline (deprenyl), or both, using the time until found to improve not only dyskinesia but also motor fluctuations
the patients needed potent symptomatic dopaminergic therapy, LD, (Pahwa et al., 2017).
as a proxy endpoint for disease progression. The selective monoamine Combining LD with carbidopa, an aromatic acid decarboxylase
oxidase (MAO-B) inhibitor, selegiline, successfully delayed this endpoint, inhibitor that prevents its peripheral metabolism, markedly reduces its
but interpretation of the study was contaminated by the drug’s mild peripheral adverse effects, particularly nausea. The global antiparkinso-
symptomatic antiparkinsonian and antidepressant properties, as well as nian efficacy of LD is so dramatic and predictable that a positive thera-
the potential effects of its amphetamine metabolites. Although disease- peutic response is used to define the disease itself. Adverse effects of LD
modifying effects of selegiline have been suggested by some clinical trials, include nausea and vomiting, orthostatic hypotension, sedation, confu-
further studies are needed before it can be concluded that selegiline is sion, sleep disturbance, alterations of dream phenomena, hallucinations,
neuroprotective in PD. Another MAO-B inhibitor, rasagiline, has been and dyskinesias (see Video 96.6). Many studies have concluded that DAs
shown to have modest symptomatic benefit (Jankovic et al., 2014), such as pramipexole, ropinirole, and rotigotine, when introduced early
but its effects on disease progression are also still being debated. In a in the course of PD treatment, may delay LD-related complications
randomized multicenter, double-blind, placebo-controlled, parallel- such as motor fluctuations and dyskinesias. But evidence is lacking to
group study prospectively examining rasagiline’s potential disease- support the hypothesis that early introduction of DAs slows progres-
modifying effects (ADAGIO [Attenuation of Disease Progression with sion of the disease or even improves long-term quality of life (Espay
Azilect Given Once-Daily]), delayed-start design was used to assess and Lang, 2017). The PROUD study (Pramipexole on Underlying
the potential disease-modifying effects of rasagiline (Olanow et al., Disease), which assessed early versus delayed pramipexole treatment
2009). A total of 1176 patients with early untreated PD (mean time in early PD, involved 535 untreated PD patients who were randomized
from diagnosis, 4.5 months) from 129 centers in 14 countries were to double-blind placebo or pramipexole (1.5 mg/day) for 6–9 months
randomized into 4 treatment groups (either 1 or 2 mg/day, early-start and continued with pramipexole for up to 15 months. The researchers
versus delayed-start treatment, 9 months each). Early-start treatment found no difference in UPDRS (−0.4 UPDRS units) or PDQ-39 scores
consisted of 72 weeks of rasagiline (either 1 or 2 mg once daily), and in the 411 patients who completed the 15-month study, but at the end of
delayed-start treatment consisted of 36 weeks of placebo followed by the placebo-controlled phase, the difference in adjusted means was −4.8
36 weeks of rasagiline (either 1 or 2 mg once daily [active treatment UPDRS units (95% confidence interval [CT], −6.3, −3.2; P < .0001), and
phase]). The primary analyses of the trial were based on change in total there was a significant difference in PDQ-39 (P = .0001), both in favor
UPDRS score and included slope superiority of rasagiline over placebo of pramipexole (Schapira et al., 2010). Furthermore, many studies have
in the placebo-controlled phase, change from baseline to week 72, and shown that LD is more effective than DAs in reducing motor symptoms
noninferiority of early-start versus delayed-start slopes during weeks in early as well as advanced stages of PD (PD MED Collaborative Group,
48 through 72 of the active phase. The 1-mg dose group met all three 2014). In a pragmatic, open-label, randomized trial involving 1620
endpoints, but there was no observable benefit with the higher 2-mg patients with a newly diagnosed PD randomized to receive a DA (N =
dose, although when analyzing the upper quartile group, the 2-mg dose 632), a monoamine oxidase inhibitor (N = 460), or LD (N = 528), after
group met all the primary endpoints. Some possible explanations for median follow-up of 3 years there was a slightly better (1.8 points) PDQ-
the seemingly confusing outcome include early symptomatic treatment 39 mobility score with LD than with the other two treatments (PD MED
helping some compensatory mechanism, cumulative symptomatic Collaborative Group, 2014). Although the study suggested small but
effect, and other possibilities. persistent benefits when PD patients were initially treated with LD com-
Development of neuroprotective strategies has been challenging, pared with LD-sparing therapy, the study did not adequately address
partly because of lack of reliable and sensitive biomarkers of progression whether patients with young-onset PD should be treated differently than
(Jankovic and Sherer, 2014; Jankovic and Tan, 2020). Animal models are those with late-onset PD. Despite the findings from the PD MED study,
essential in preclinical testing of potential symptomatic and neuropro- most parkinsonologists would probably still employ LD-sparing strategy
tective therapies (Le et al., 2014). One of the most exciting developments in patients with young-onset PD.
of potential neuroprotective or disease-modifying therapies is the use Because of various adverse effects related to their ergot struc-
of α-synuclein monoclonal antibodies to reduce α-synuclein formation ture, particularly fibroproliferative lesions of heart valves, lung, and
and rescue dying neurons (Savitt and Jankovic, 2019a; Tran et al., 2014). other tissues, bromocriptine, pergolide, and cabergoline have been
Symptomatic treatment of Parkinson disease. Many types discontinued from clinical use. Apomorphine, a nonergoline DA, is
of medications are available for symptomatic treatment of PD: water soluble and lipophilic and is therefore suitable for intravenous,
subcutaneous, sublingual, intranasal, or transdermal administration. within 2 years after initiation of LD therapy. Wearing off results from
Apomorphine is available as an acute intermittent subcutaneous loss of DA storage in the striatum as a result of loss of nigrostriatal ter-
injection, as a rapid rescue from hypomobility off episodes (end-of- minals. Experiments in animal models relate the development of dys-
dose wearing off and unpredictable on/off episodes) associated with kinesia to changes in striatal glutamate receptor sensitivity consequent
advanced PD. DAs cause side effects similar to those of LD, although to pulsatile stimulation of striatal dopamine receptors. Continuous
orthostatic hypotension, sleepiness, and hallucinations are more com- dopamine receptor stimulation with LD or with long-acting DAs pre-
mon or severe. Continuous apomorphine infusion has been found to vents or reverses this phenomenon.
meaningfully reduce off time in PD patients who experience trouble- In eliciting a description of the patient’s response to medication, it
some motor fluctuations (Katzenschlager et al., 2018). is important to understand the severity of symptoms in the morning
One major concern with DAs is the relatively high frequency on arising and the latency, magnitude, and duration of benefit from
of a variety of behavioral problems that include pathological gam- each dose of LD. Information about the onset of motor and nonmotor
bling, compulsive shopping and eating, hypersexuality, and other symptoms during wearing off as well as the phenomenology, timing,
impulse-control disorders (ICD) (Zhang et al., 2019). Patients with and distribution of dyskinesia. The usefulness of historical informa-
PD who experience ICD seem to have a variety of associated psychi- tion may be augmented by careful patient education on symptom
atric symptoms, such as psychoticism, interpersonal sensitivity, obses- recognition and the development of a shared vocabulary. Completing
sive-compulsive symptoms, and depression (Jaakkola et al., 2014) and motor diaries (Fig. 96.7) helps both the patient and the treating physi-
seem to be prone to dopamine dysregulation syndrome, an addictive cian recognize patterns of motor response and adjust the medications
behavior and excessive use of dopaminergic medication (Warren et al., accordingly.
2017). Wearing off is the most common type of motor fluctuation. It refers
Selegiline and rasagiline block MAO-B-dependent dopamine deg- to the return of parkinsonian symptoms following the previous dose
radation and have modest effects in potentiating the action of LD. in advance of the next scheduled antiparkinsonian dose. On/off is the
These drugs are now used very infrequently, but some clinicians pre- unpredictable reappearance of parkinsonism at a time when central
scribe these MAO-B inhibitors as the initial pharmacological agents levels of antiparkinsonian drugs are expected to be within the target
in newly diagnosed patients in an attempt to delay LD therapy. This therapeutic range. Delayed on is a prolongation of the time required
approach is in part supported by the ADAGIO study (Olanow et al., for the central antiparkinsonian drug effect to appear. Dose failure is
2009). COMTIs (entacapone and tolcapone) block peripheral degra- a complete failure to develop a favorable response to an incremen-
dation of peripheral LD and central degradation of LD and dopamine tal dopaminergic dose. This may be related to protein intake which
(tolcapone), increasing central LD and dopamine levels. Hepatotoxicity interferes with the transport of LD across the intestinal wall as a result
associated with tolcapone has limited its use. Triple-combination ther- of competition for facilitated transport by large amounts of neu-
apy containing LD, carbidopa, and entacapone is available for patients tral amino acids. A variety of dyskinesias can further complicate the
with moderately advanced PD. The primary role of COMTIs is to pro- response to LD. Peak-dose dyskinesias are usually choreiform or ste-
long the effects of LD, so they are useful as adjunctive drugs for patients reotypical movements, such as head bobbing movement of the head
who experience LD-related motor fluctuations. Besides increasing or choreic movements of limbs and trunk, present at the peak of the
LD-related dyskinesias, COMTIs may cause nausea, postural hypo- therapeutic response. Off-period dystonia usually appears in the more
tension, diarrhea, and orange discoloration of urine, but they are severely affected foot in the morning before the first daily doses, some-
generally well tolerated. There is no evidence that COMTIs prevent times reappearing during wearing off. Diphasic dyskinesias are usually
or delay the onset of LD-related motor complications. Symptomatic large-amplitude dyskinetic movements of the lower body during the
pharmacological treatment should begin when the patient is noticing time of increasing and decreasing LD levels.
functional, occupational, or social disability related to PD symptoms. Armed with a few basic principles and a commonsense approach,
Prospective studies have suggested that approximately 70% of patients the clinician can usually smooth out fluctuations for most patients
with PD will require symptomatic therapy within 2 years of disease with appropriate selection of drugs and dose (Jankovic and Poewe,
onset. Less potent therapies such as selegiline, rasagiline, amantadine, 2012) (Figs. 96.8 and 96.9). Delay to onset of therapeutic benefit can be
and DAs may be useful for initial therapy, particularly in patients with hastened by taking the medication on an empty stomach (if tolerated
young-onset PD, but LD should be used when more potent therapy without nausea), avoiding or reducing protein intake, or by crushing
is indicated or in patients with late-onset disease. The argument that the LD tablet and mixing it with a carbonated beverage. The duration
LD might be toxic to dopaminergic neurons is based on (1) the rec- of benefit increases when the individual dose is increased or dopamine
ognition that dopamine metabolites increase oxidative stress and (2) metabolism is blocked with an MAO-B or COMTIs. This, however,
the observation that LD is toxic to cultures of mesencephalic neurons may increase the risk of dyskinesia and the patient may do better on
in vivo. There is, however, no in vivo evidence from animal or human smaller, more frequent LD doses. Thus fractionation of LD dose is usu-
studies that LD accelerates disease progression, and it is difficult to rec- ally the initial strategy in an attempt to smooth out fluctuations and
oncile the potential of dopamine toxicity with the obvious fact that prevent wearing off symptoms.
the drug prolongs life in patients with PD. A 9-month study called In addition to the fluctuating response, some patients, particularly
the Earlier versus Later L-DOPA (ELLDOPA) trial compared differ- those with advanced disease, may acquire LD-resistant motor symp-
ent doses of LD with placebo and found no evidence of LD toxicity toms such as freezing, progressive gait dysfunction, dysarthria and
(Jankovic and Poewe, 2012). Nevertheless, as a result of “LD phobia,” dysphagia, and recurrent falling due to loss of balance and postural
many patients and physicians still unnecessarily delay LD therapy in instability. Other features of advanced illness (cognitive impairment,
patients who would clearly benefit from symptomatic relief (Espay and autonomic dysfunction, psychiatric complications) may limit the types
Jankovic, 2017). and dosage of tolerated medications. Freezing, sudden immobility of
Clinical experience with LD treatment of PD indicates that there the feet while walking, often with falls, may be seen in either the off
is a progressive increase in the prevalence of drug-related motor fluc- or the on period. Although off-period freezing may improve with
tuations (wearing off, dyskinesia) over time, and that about half of optimization of medications, on-period freezing is usually resistant to
patients experience wearing off, and a third experience dyskinesias pharmacological treatment. Physical therapy, including strategies that
Time Medication Meal Asleep Off On Dyskinesia
Midnight – 1:00 A X
1:00 – 2:00 A X
2:00 – 3:00 A X
3:00 – 4:00 A X
4:00 – 5:00 A X
5:00 – 6:00 A X
6:00 – 7:00 A 1 Sinemet

X X
½ Mirapex
7:00 – 8:00 A X
8:00 – 9:00 A X X
9:00 – 10:00 A X
10:00 – 11:00 A X
11:00 – noon 1 Sinemet

X X
½ Mirapex
1:00 – 2:00 P X
2:00 – 3:00 P X X
3:00 – 4:00 P 1 Sinemet X
4:00 – 5:00 P X
5:00 – 6:00 P X X X
6:00 – 7:00 P X
7:00 – 8:00 P ½ Sinemet X
8:00 – 9:00 P X X
9:00 – 10:00 P X X
10:00 – 11:00 P X
11:00 – midnight X
Fig. 96.7 Sample Diary in Parkinson Disease. For each hour, the patient indicates whether and which
antiparkinsonian drugs he or she has taken, then places a mark to indicate motor state for most of the hour.
utilize sensory cues, such as stepping over a horizontal laser beam, may clozapine. Also, pimavanserin, a non-dopaminergic and selective sero-
be helpful. Dysarthria and dysphagia are often treated by speech thera- tonin inverse agonist with high affinity at the 5-HT2A receptor has
pists, although documentation of improvement from these techniques been found to be effective in the treatment of psychosis and hallucina-
is scant. tions related to dopaminergic therapy (Cummings et al., 2014).
Cognitive impairment increases mainly with the age of the patient Cholinesterase inhibitors, in addition to improving cognitive func-
and with disease severity. Preliminary reports suggest that cholines- tion, may reduce hallucinations in some patients. Sleep disorders may
terase inhibitors might be useful in PD-associated dementia, but these respond to hypnosedatives, tricyclic antidepressants, mirtazapine,
studies require confirmation in carefully controlled trials. Orthostatic trazodone, quetiapine, or nighttime dopaminergic therapy. Excessive
hypotension can be managed conservatively with salt supplemen- daytime sleepiness may respond to methylphenidate, modafinil, or
tation, fludrocortisone, midodrine, and droxidopa for orthostatic armodafinil.
hypotension (Kaufmann et al., 2014). Urological medications may Surgical treatment of Parkinson disease. Despite optimal medical
improve bladder dysfunction, and dietary changes along with medica- therapy, many patients with moderate to advanced disease have a poor
tions such as linaclotide and lubiprostone may improve constipation. quality of life because of fluctuating response, troublesome dyskinesia,
Hallucinations occur in approximately 30% of treated patients; a loss or LD-unresponsive symptoms. Palliative surgical approaches such
of insight that the visions are not real or the appearance of psychotic as stereotactic destruction of physiologically defined overactive
thinking signals a particularly disabling complication. Hallucinations brain nuclei (thalamotomy, pallidotomy) have been replaced by
often improve with atypical antipsychotics such as quetiapine and deep brain stimulation (DBS) using implanted pulse generators. The
Treatment of motor symptoms of Parkinson disease
Diagnosis of PD
Established Uncertain
Functional impairment? DAT or VMAT imaging
Yes
Consider alternative
Minimal or Dx and Rx
none
Mild sxs or young Troublesome sxs or elderly
Exercise ± MAOB-I Anticholinergics,

(selegiline, rasagiline) BoNT for tremor
Disease progression
Initiate DA therapy
(pramipexole, ropinirole, rotigotine) Initiate levodopa
Disease progression
Entacapone, opicapone, amantadine,

safinamide, istradefylline, apomorphine,
Add or increase levodopa
inhalable levodopa
Experimental
therapeutics
Motor complications
Dose adjustments,
DBS or FUS continuous levodopa
or DA delivery
Fig. 96.8 Treatment of Motor Symptoms of Parkinson Disease. Algorithm for the treatment of Parkinson
disease (PD). BoNT = botulinum neurotoxin; DA, Dopamine agonist; DAT, dopamine transporter; DBS, deep
brain stimulation; Dx, diagnosis; FUS, focused ultrasound; MAOB-1,monoamine oxidase inhibitor type 1;
MAOI, monoamine oxidase inhibitor; Rx, treatment; VMAT2, vesicular monoamine transporter 2.
chief advantage of DBS over ablative lesioning is that the stimulation vs. 11%). In a follow-up analysis of the Veterans Affairs Cooperative
parameters can be customized to the needs of the patient to optimize Studies Program outcomes, STN and GPi DBS were analyzed after 24
the benefits. With improvements in technology the outcomes of DBS months in 299 patients, and there were no differences in mean changes
will likely continue to improve (Okun, 2019). in the motor (Part III) UPDRS between the two targets (Follett et al.,
Thalamic DBS is most frequently used to control high-amplitude 2010). Patients undergoing STN required a lower dose of DAs than
tremor (either PD or ET), but STN or GPi are the most frequent tar- those undergoing pallidal stimulation (P = .02), and visuomotor pro-
gets for DBS treatment of patients with PD with disabling LD-related cessing speed declined more after STN than after GPi stimulation (P =
complications. To address the question whether optimal medical .03). On the other hand, there was worsening of depression after STN
therapy or DBS provides more robust improvement, 255 patients at DBS, but mood improved after GPi DBS (P = .02). Slightly more than
seven Veterans Affairs and six university hospitals were enrolled in a half of the patients experienced serious adverse events, but there was
randomized controlled trial designed to compare the effects of DBS no difference in the frequency of these events between the two groups.
(STN, n = 60; or GPi, n = 61) and “best medical therapy” (n = 134) Based on these and other studies, there is emerging evidence that GPi
after 6 months of treatment (Weaver et al., 2009). Patients treated with DBS may be particularly suitable for patients who may have trouble-
DBS gained a mean of 4.6 hours/day of on time without troubling some dyskinesias as well as mild cognitive or behavioral impairment,
dyskinesia, compared to 0 hours/day for patients who received best whereas bilateral STN DBS may be the surgical choice for patients
medical therapy (P < .001). Furthermore, motor function improved who are cognitively intact but in whom reduction in LD dosage is the
by 5 or more points on the motor UPDRS in 71% of DBS and 32% primary goal. While DBS is a proven effective therapeutic strategy,
of medical therapy patients. This was accompanied by improvements its success depends on the appropriate selection of patients and the
in the majority of PD-related HRQOL (health-related quality of life) experience and skill of the stereotactic surgeon in order to optimize
measures and only minimal decrement in neurocognitive testing. the results and minimize complications. Advances in DBS technology,
The overall risk of experiencing a serious adverse event, however, was such as the use of adaptive stimulation, improving connectivity, direc-
3.8 times higher in the DBS than in the medical therapy group (40% tional stimulation (Pollo et al., 2014), and searching for new targets,
Treatment of motor complications in Parkinson disease
Levodopa therapy
Fractionate levodopa or use
ER formulations
Add:
MAOI (rasagiline, selegiline,
Dyskinesias Motor fluctuations safinamide)
DA agonist (ER or
transdermal formulations)
A2A antagonist
(istradefylline)
Discontinue sinemet CR,
MAOI, entacapone
Reduce levodopa
Severe motor fluctuations SC or sublingual apomorphine,
inhalable levodopa rescue
continuous infusions:
Add amantadine or LCIG
amantadine ER, LCIG SC infusion apomorphine
No improvement
Consider:
zonisamide, clozapine,
quetiapine, topiramate,
levetiracetam STN or GPi DBS
Fig. 96.9 Treatment of Levodopa-Related Motor Complications in Parkinson Disease. A2A, Adenosine
A2A receptor; COMTI, catechol-o-methyl-transferase inhibitor; CR, Controlled release; DA, Dopamine ago-
nist; DBS, deep brain stimulation; ER, extended release; GPi, globus pallidus interna; LCIG, levodopa-carbi-
dopa infusion gel; MAOI, monoamine oxidase inhibitor; SC, subcutaneous; STN, subthalamic nucleus.
will undoubtedly provide additional benefits from this procedure and hypotension (75%), sexual dysfunction (64%), RBD (54%), sweating
reduce complications (Baizabal-Carvallo et al., 2012). It should be dysfunction (40%), sleep apnea (37%), and nocturnal stridor (30%)
noted that there is a trend toward recommending DBS earlier in the (Iodice et al., 2012). In contrast to PD, MSA-P usually presents with
course of PD (Charles et al., 2014). symmetrical parkinsonism, often without tremor, with early instability
Unilateral focused ultrasound lesioning of the STN or thalamus and falls. Most patients become wheelchair bound within 5 years after
(in tremor-dominant forms of PD) has been found to be beneficial in onset (see Video 96.12).
some patients, particularly if the symptoms are markedly asymmet- Several clinical studies have addressed differentiating between
ric (Bond et al., 2017; Martínez-Fernández et al., 2018). Finally, spinal MSA-P and parkinsonism, and a collection of “red flags” has been
cord stimulation is increasingly being explored in patients with PD generated and recently validated as having high diagnostic specificity
who are most troubled by their gait disorder (Samotus et al., 2018). (Stefanova et al., 2009). The red flags were grouped into six catego-
ries: (1) early instability, (2) rapid progression, (3) abnormal postures
Multiple System Atrophy (includes Pisa syndrome, disproportionate anterocollis, and/or con-
MSA is a neurodegenerative disorder manifested by dysautono- tractures of hands or feet) (Fig. 96.10), (4) bulbar dysfunction (includes
mia and various combinations of parkinsonism and ataxia (Krismer severe dysphonia, dysarthria, and/or dysphagia), (5) respiratory dys-
and Wenning, 2017; Stamelou et al., 2013). Originally referred to as function (includes diurnal or nocturnal inspiratory stridor and/or
Shy-Drager syndrome, MSA is subdivided into two major categories inspiratory sighs) (Mehanna and Jankovic, 2010), and (6) emotional
according to the predominant clinical manifestation. Predominantly incontinence (includes inappropriate crying and/or laughing). They
parkinsonian MSA (MSA-P) replaces the term striatonigral degenera- proposed that a combination of two out of these six red-flag catego-
tion. Cerebellar MSA (MSA-C) replaces the now obsolete term olivo- ries be used as additional criteria for the diagnosis of probable MSA-P.
pontocerebellar atrophy. Other characteristic features of MSA include early hypokinetic dysar-
MSA is considerably less common than PD, with a prevalence of thria, distal myoclonus, and cold hands and feet with bluish discolor-
4–5 per 100,000, compared to 360 per 100,000 for PD. This sporadic ation of the distal extremities. MSA patients also have more autonomic
neurodegenerative disorder with a mean age at onset of 54 years may symptoms at baseline and more progression to global anhidrosis than
be difficult to differentiate from PD, particularly in the early stages. patients with PD (Iodice et al., 2012). The autonomic symptoms (par-
The most common signs of dysautonomia in pathologically confirmed ticularly sexual dysfunction) and RBD may precede the onset of motor
cases are bladder dysfunction (89%), particularly urinary incontinence symptoms by years or even decades. About 10% of patients originally
(44%) and urinary retention (26%), bowel dysfunction (77%), partic- diagnosed with pure autonomic failure eventually transition to MSA
ularly constipation (46%) and fecal incontinence (27%), orthostatic (Singer et al., 2017). Patients with MSA-C have parkinsonism with
Fig. 96.11 Glial cytoplasmic inclusions in basal ganglia, immunostained

with α-synuclein—typical of multiple system atrophy. (Courtesy Eliza-
beth Cochran, MD.)
cord. Glial cytoplasmic inclusions containing α-synuclein (Fig. 96.11)

are the most characteristic histological features linking the different
types of MSA. Neuron-to-oligodendrocyte transfer of α-synuclein by
prion-like spread, leading to oligodendroglial and myelin dysfunction
associated with chronic neuroinflammation, has been suggested to
lead to the MSA pattern of neurodegeneration (Jellinger, 2014). There
is a severe depletion of cholinergic neurons in the PPN and laterodor-
Fig. 96.10 Patient with multiple system atrophy showing anterocollis sal tegmental nucleus. The etiology of MSA remains unknown, but
and Pisa sign. genetic factors do not seem to play an important role.
Treatment of MSA is difficult (Castro et al., 2017; Stamelou et al.,
prominent cerebellar signs, especially wide-based ataxic gait. Although 2013). There are no specific interventions, and symptomatic therapies
there may be a positive response to LD, this is generally relatively short provide only partial relief of disability. Parkinsonism may respond to
lived and often associated with facial and oromandibular dyskinesia. LD, particularly early in the disease course, but the results are not dra-
In a prospective study of 141 patients with moderately severe MSA matic or sustained. DAs are not helpful and may be poorly tolerated
(mean age at symptom onset 56.2± 8.4 years) who had a median sur- because of orthostatic hypotension. There is no effective treatment for
vival of 9.8 years (95% CI 8.1–11.4), shorter survival was suggested by the cerebellar signs. Orthostatic hypotension may improve with non-
the parkinsonian variant of MSA and incomplete bladder emptying, pharmacological measures such as liberal salt and water intake, com-
and shorter symptom duration at baseline and absent LD response pression stockings, and sleeping with the head up, but most patients
predicted rapid progression (Wenning et al., 2013). require pharmacotherapy with fludrocortisone, midodrine, droxi-
Clinical tests of autonomic dysfunction may be helpful in diagnosis dopa, or other agents (Kaufmann et al., 2014). Treatment of ortho-
or treatment (Mostile and Jankovic, 2010). Testing of cardiovascular static hypotension often worsens supine hypertension. Even in the best
reflexes such as heart rate variability at rest and during forced respira- hands, MSA has a poor prognosis, with a mean survival of 7–9 years.
tion, as well as blood pressure changes during head-up tilt, may help
establish a clinical diagnosis of MSA. A lack of responsiveness of growth Progressive Supranuclear Palsy
hormone to clonidine challenges and denervation on rectal sphincter First described in 1964 by Steele, Richardson, and Olszewski as a pro-
electromyography (EMG) are also characteristic findings. T2-weighted gressive illness characterized by vertical supranuclear ophthalmople-
MRI brain scans may show a hyperintense rim at the lateral edge of gia, axial rigidity, pseudobulbar palsy, and mild dementia, PSP has
the dorsolateral putamen, with decreased signal within the putamen. evolved into a broad spectrum of syndromes with different patho-
Cruciform hyperintensity within the pons, the so-called hot-cross- logical substrates (Boxer et al., 2017; Höglinger et al., 2017; Stamelou
bun sign, may also be a helpful marker (Brooks et al., 2009). PET scan et al., 2013). In addition to the classic Richardson syndrome, other
with [11C]PMP that images subcortical acetyl cholinesterase (AChE) subtypes include PSP-parkinsonism (with features suggestive of PD),
activity was significantly more decreased in MSA-P and PSP than in pure akinesia with gait freezing, CBS, non-fluent variant primary pro-
PD, possibly reflecting greater impairment in the pontine cholinergic gressive aphasia, behavioral variant FTD, and PSP presenting with
group (PPN); this may account for the greater gait disturbances in cerebellar ataxia (Boxer et al., 2017). In addition, based on four core
the early stages of these two disorders compared to PD (Gilman et al., clinical features of PSP (oculomotor dysfunction, postural instability,
2010). There is a need for development of highly specific and sensitive akinesia, and cognitive dysfunction) other variants of PSP have been
biomarkers that support the diagnosis and track the progression of the described. These include PSP with predominant ocular motor dys-
disease. In this regard, NFL protein levels have been found elevated in function (PSP-OM), with predominant postural instability (PSP-PI),
the serum and CSF of patients with MSA but not in PD but this does with predominant parkinsonism (PSP-P), with predominant frontal
not differentiate between MSA and other forms of atypical parkinson- presentation (PSP-F), with progressive gait freezing (PSP-PGF), with
ism (Marques et al., 2019). predominant corticobasal syndrome (PSP-CBS), with predominant
At autopsy, MSA brains show neuronal loss and gliosis in the stria- speech and language disorder (PSP-SL), with predominant ataxia
tum, SN, locus coeruleus, inferior olive, pontine nuclei, Purkinje cells, (PSP-C), and with predominant primary lateral sclerosis (PSP-PLS)
intermediolateral cell column, and the Onuf nucleus in the sacral spinal (Boxer et al., 2017; Höglinger et al., 2017).
Fig. 96.12 Typical facial expression of a patient with progressive supra-

nuclear palsy, illustrating worried or surprised appearance, with fur-
rowed brow and fixed expression of lower face.
After vascular parkinsonism (Mehanna and Jankovic, 2013), which

can also have PSP-like features, PSP represents the third most com-
mon cause of parkinsonism, but it is still a relatively rare disease, with
prevalence estimates ranging from 1.39 to 6.4 per 100,000. Men are
affected more often than women. B
The diagnosis of PSP is made based on clinical criteria (Höglinger Fig. 96.13 Globose neurofibrillary tangle and tufted astrocytes in pro-
et al., 2017; Stamelou et al., 2013). PSP typically begins with a gait dis- gressive supranuclear palsy (PSP). A, Tau-immunostained globose neu-
order and falling in the sixth to seventh decades of life. Patients develop rofibrillary tangles in neurons of globus pallidus. B, Gallyas silver-stained
an akinetic rigid state with symmetrical signs and prominent axial rigid- tufted astrocytes in globus pallidus of patient with PSP.
ity. In contrast to the flexed posture of patients with PD, those with PSP
may have an extended trunk or retrocolic neck posture. A characteristic In contrast to PD, patients with PSP tend to have a more broad-based
facial appearance features a wide-eyed stare, furrowing of the forehead gait with knee extension, and instead of turning en bloc they tend to pivot
with frowning expression (“procerus sign”), and deepening of other facial on their toes and sometimes even cross their legs, which contributes to
creases, allowing experienced clinicians to make an instant diagnosis (Fig. frequent falls (Jankovic, 2015a). Atypical presentations are often seen,
96.12; see also Videos 96.7–96.11). Pseudobulbar palsy with dysarthria especially pure akinesia manifested by severe motor blocks while walking
and dysphagia lend the patient a characteristic dysarthria with spasticity, (freezing). PSP is rapidly progressive; by the fourth year of illness, half
hypokinesia, and ataxia and often “silent” aspiration. Frontal lobe fea- of patients need assistance for walking and have troublesome dysarthria
tures are common. There is striking executive dysfunction early in the and visual symptoms. Dysphagia becomes prominent shortly thereafter.
disease course; concrete thought, difficulty shifting set, decreased verbal There are no diagnostic tests for PSP, but elevated serum and CSF
fluency, and personality changes such as impulsivity and poor judgment levels of NFL have been found in patients with PSP compared to those
are nearly universal. One of the characteristic, although not specific signs with PD (Marques et al., 2019). Although not diagnostic, NFL can
of PSP is the applause sign, which is manifested by persistence of applaud- serve as a possible biomarker. Typical MRI signs of PSP include mid-
ing by the patient beyond the number of claps performed by the exam- brain atrophy, increased signal in the midbrain and GP, atrophy or
iner. This is highly correlated with impairments in executive, visuospatial, increased signal in the red nucleus, third ventricle dilation, and atro-
and language function as well as measures of disease severity (Schönecker phy of the frontal or temporal lobes. On the midsagittal view of the
et al., 2019). A progressive apathetic state ensues, but true dementia may MRI, as a result of atrophy of the rostral midbrain tegmentum, the
not be prominent until the advanced stages of the disease. The presence most rostral midbrain, the midbrain tegmentum, the pontine base,
of square wave jerks should suggest the diagnosis of PSP, although this and the cerebellum appear to correspond to the bill, head, body, and
neuro-ophthalmological sign may also be observed, but much less fre- wing, respectively, of a hummingbird or a penguin.
quently, in other parkinsonian disorders (Waln and Jankovic, 2018). At autopsy, the midbrain in PSP is atrophied, and the sylvian
Abnormal vertical saccades, best demonstrated by examination for opti- aqueduct is dilated. The SN is depigmented and appears orange and
cokinetic nystagmus, compared to horizontal saccades, is one of the ear- shrunken. The locus coeruleus may also show some depigmentation,
liest ophthalmological signs of PSP. Typically, the vertical saccades are but this is less prominent than in idiopathic PD. Other structures may
more impaired when the opticokinetic tape moves in an upward rather also show atrophy, most notably the frontal lobe, STN, and superior cer-
than downward direction. Electro-oculographic recordings in PSP show ebellar peduncle. Histopathologically, the degenerative process involves
decreased amplitude and normal latency of horizontal saccadic eye move- mainly the basal ganglia, diencephalons, and brainstem. Pathological
ments. Although considered a clinical hallmark of PSP, supranuclear ver- findings include neuronal loss, gliosis, neurofibrillary tangles, and gran-
tical gaze palsy may not appear until later in the disease course, and some ulovacuolar degeneration in neurons of the brainstem. There are tufted
patients may never develop gaze palsy. Another neuro-ophthalmological astrocytes in the motor cortex and the striatum, and the typical neuro-
sign in PSP is blepharospasm with or without apraxia of eyelid opening nal lesion is the globose neurofibrillary tangle, made up of hyperphos-
(Waln and Jankovic, 2018). phorylated four-repeat tau protein filaments (Fig. 96.13).
On the basis of an analysis of 103 pathologically confirmed con- had AD, and the remaining five had other non-tau pathologies. Forty-
secutive cases of PSP, PSP was divided into two categories: Richardson two percent of CBD cases presented clinically with a PSP phenotype,
syndrome, characterized by the typical features described in the origi- and 29% of CBS cases had underlying PSP pathology. The authors
nal report, and PSP-P, in which the clinical features overlap with PD suggested the CBD-Richardson syndrome for the overlap cases and
and the course is more benign (Williams and Lees, 2009). The lat- concluded that CBD “is a discrete clinico-pathological entity but with
ter group, representing about a quarter of all patients with PSP, has a broader clinical spectrum than was originally proposed” (Ling et al.,
less tau pathology than the classic Richardson syndrome. The mean 2010).
4R-tau/3R-tau ratio of the isoform composition of insoluble tan- CBD is one of the least common and most asymmetrical forms of
gle-tau isolated from the pons was significantly higher in Richardson atypical parkinsonism (Stamelou et al., 2013). The mean age at onset is
syndrome (2.84) than in PSP-P syndrome (1.63). 60–64 years. In its most recognizable form, it is predominantly a motor
PSP almost always occurs sporadically, yet an increasing number of disease, but its presentation is clinically heterogeneous. In addition
familial cases suggests a genetic etiology in some cases. Pedigrees with to parkinsonism with strikingly asymmetrical rigidity, CBD patients
apparent dominant and recessive inheritance have been described. often exhibit asymmetrical dystonia, myoclonus, apraxia, alien limb,
Affected families may show phenotypical heterogeneity, with some and cortical sensory loss. They may also present with primary progres-
affected persons showing dementia, dystonia, gait disorder, or tics. sive aphasia and may evolve into global dementia (see Videos 96.13–
Mutations in the tau gene have been reported in patients with a familial 96.16) (Lee et al., 2011).
PSP-like illness, but these have been quite rare, and mutations are not Patients with CBS have asymmetrical and often focal cortical atro-
believed responsible for most PSP cases. However, patients with PSP phy on MRI, with widening of the sylvian and interhemispheric fis-
are homozygous for a common haplotype that contains a normally sures and dilation of frontal, parietal, and temporal sulci (Josephs,
occurring polymorphism in the tau intron immediately preceding 2017). Fluorodeoxyglucose PET scans show asymmetrical hypometab-
exon 10. There is growing support for the notion of altered regulation olism in the thalamus and motor cortex. SPECT scans show marked
of tau gene expression in PSP. Genetic polymorphisms are increasingly asymmetry of cortical blood flow.
being identified, some of which might increase risk for PSP via effects At autopsy, patients with a clinical syndrome consistent with CBD
on tau. No toxic, viral, or other environmental risk factors have been have gross brain atrophy. Typical microscopic changes are tau-positive
described. neuronal and glial lesions, especially gray and white matter astrocytic
Dopaminergic agents, particularly LD, may provide temporary plaques and threadlike lesions, and neuronal loss in the cortex and SN.
improvement in bradykinesia in approximately 40% of patients, but The inclusions are formed of hyperphosphorylated four-repeat tau.
LD usually does not improve dysarthria, gait, or balance problems. Overlap with other conditions including AD, PSP, PD, FTDP, and hip-
No other drug has been shown to provide any meaningful improve- pocampal sclerosis is common (Ling et al., 2010).
ment in symptoms of PSP. A randomized placebo-controlled trial As with other tauopathies, the etiology of CBD is unknown. There
of donepezil showed modest cognitive improvements but poor tol- are no familial forms of the illness, and no mutations in the tau gene
erability. Amitriptyline may be helpful in improving pseudobulbar have been identified. There is clinical and pathological overlap with
affect and emotional incontinence. Botulinum toxin injections may other tauopathies, and patients with CBD share a similar tau haplotype
be useful to treat blepharospasm or retrocolic neck posture in PSP. with patients with PSP.
The prognosis of PSP is poor, with serious impact on quality of life There is no treatment for the degenerative process. Parkinsonian
and a median duration of survival of approximately 8 years. It is features do not seem to respond to LD or other dopaminergic drugs.
possible that future strategies targeting toxic tau, currently investi- Benzodiazepines, particularly clonazepam, may help myoclonus.
gated in other tauopathies, may also exert disease-modifying effects Botulinum toxin injections may improve focal dystonia early in the
in PSP. disease and help relieve pain and facilitate care in advanced disease.
The prognosis is poor, with a reported median survival after onset of
Corticobasal Degeneration about 7 years.
In 1967, Rebeiz and colleagues described three patients with akinetic
rigidity, apraxia, dystonia, tremor, and aphasia, who at autopsy had Dementia with Lewy Bodies
pale achromatic ballooned neurons similar to those seen in Pick dis- DLB is the second most prevalent degenerative dementia after AD. In
ease. The condition was named corticodentatonigral degeneration with one study, among 542 incident cases of parkinsonism, 64 had DLB and
neuronal achromasia in 1989 but has since become known simply as 46 had PD dementia (PDD); the pathology was consistent with the
corticobasal degeneration. Although CBD generally brings to mind a clinical diagnosis in 24 of 31 patients (77.4%) who underwent autopsy
particular motor syndrome of asymmetrical rigidity, apraxia, and cor- (Savica et al., 2013). DLB is a progressive dementia characterized espe-
tical sensory dysfunction, its underlying pathological features may be cially by fluctuating cognitive impairment, prominent disruption of
seen in other clinical syndromes including PSP, progressive aphasia, attention and visuospatial abilities, visual hallucinations, and par-
and FTDP. One study based on 35 cases from the Queen Square Brain kinsonism (see Video 96.5). RBD and depression are also very com-
Bank, in which there were 21 clinically diagnosed cases of CBS and 19 mon. These behavioral symptoms are typically present at least 1 year
pathologically diagnosed with CBD, was designed to address the clini- prior to the onset of motor (parkinsonian) features (McKeith et al.,
cal and pathological overlap between CBD and PSP (Ling et al., 2010). 2017). Patients with DLB are extremely sensitive to dopamine recep-
Of 19 pathologically confirmed CBD cases, only five had been diag- tor antagonists and experience severe parkinsonism when treated with
nosed correctly in life (sensitivity =26.3%). All had a unilateral pre- neuroleptics.
sentation, a clumsy useless limb, limb apraxia, and myoclonus; four Characteristic pathological changes include cortical and brain-
had cortical sensory impairment and focal limb dystonia, and three stem (SN) Lewy bodies. Spongiform changes, neurofibrillary tangles,
had an alien limb. Eight cases of CBD had been clinically diagnosed and dystrophic Lewy neuritis may also be seen, and overlap with AD
as PSP, all of whom had vertical supranuclear palsy, and seven had is considerable. Treatment of DLB is difficult but medications used
falls within the first 2 years. Of 21 cases with CBS, only five had CBD in the treatment of both PD and dementia are often employed here.
(positive predictive value = 23.8%); six others had PSP pathology, five Although antiparkinsonian agents are used to treat parkinsonian
signs, the degree of sensitivity of parkinsonian signs to dopaminer- (PDC). Some had both motor neuron disease and PDC. Early in
gic therapy has not been well defined. Psychiatric and behavioral its course, PDC appears variably like PD, atypical parkinsonism, or
symptoms may improve with atypical antipsychotics, and cholin- PSP; however, in the end stages, it most resembles PSP. Familial
esterase inhibitors such as rivastigmine may improve delusions and aggregation of cases has been noted, but prior attempts to elucidate
hallucinations. a hereditary basis to the illness proved fruitless. A similar constel-
PD dementia is defined as cognitive impairment that includes lation of ALS and PDC has been reported on the Kii peninsula of
cognitive and motor slowing, executive dysfunction, and impaired Japan.
memory retrieval. The relationship of PDD to AD and other dement- Pathologically, the disorder is characterized by neuronal degen-
ing disorders such as DLB has not yet been well defined. Although eration and abundant neurofibrillary tangles in the brain and
some investigators suggest that clear clinicopathological separation spinal cord. A recent reanalysis of a patient registry suggests that
is possible between the three disorders, the differences in neuro- both the spouses and the offspring of persons with PDC have a
pathological and neurochemical characteristics suggest that there is significantly higher risk of themselves developing ALS-PDC, sug-
a continuum. gesting both environmental and genetic risk factors. The critical
age for exposure to the environmental factor was adolescence or
Frontotemporal Degeneration with Parkinsonism early adulthood. Despite extensive analysis of the diet and other
Frontotemporal degeneration is a group of disorders character- environmental factors, the etiology of PDC of Guam remains
ized by behavioral changes and neuropsychological evidence of unknown, although neurotoxic damage from the cycad nut has
frontal lobe dysfunction. They include PSP, CBD, Pick disease, been implicated.
pallidopontonigral degeneration, disinhibition-dementia-parkin-
sonism-amyotrophy, familial multiple system tauopathy with pre- Guadeloupean Parkinsonism
senile dementia, familial subcortical gliosis, FTD, FTD with ALS, A form of atypical parkinsonism has been described in the French
FTD with inclusion body myopathy, and FTDP-17. In up to 60% of West Indies. The so-called Guadeloupean parkinsonism shows clin-
patients with FTD, there is a positive family history. Genetic loci on ical features of LD-unresponsive parkinsonism, postural instability
chromosomes 17 (FTDP-17), 9 (FTD with ALS; FTD with inclusion with early falls, and pseudobulbar palsy. More than 25% of these
body myositis), and 3 (FTD) have been described. The prototype patients have a phenotype like that of PSP. The etiology of this form
of FTDP is an inherited parkinsonism-dementia disorder, initially of parkinsonism is unknown, but exposure to dietary or other envi-
described as Wilhelmsen-Lynch disease (disinhibition-dementia-par- ronmental toxins is suspected. The disease may be associated with
kinsonism-amyotrophy complex) and subsequently found to be due the use of indigenous plants (Annona muricata [synonyms: soursop,
to mutations in the tau gene on chromosome 17q21. Although tau corossol, guanabana, graviola, and sweetsop]) that contain the mito-
mutations account for many of these diseases, similar phenotypes chondrial complex I and dopaminergic neuronal toxins, reticuline
have been attributed to mutations in other genes such as p97 (also and coreximine.
known as valosin-containing protein) on chromosome 9p21-p12,
CHMP2B (charged multivesicular body protein 2B) on the peri- Vascular Parkinsonism
centromeric region of chromosome 3, and progranulin (PGRN) on After PD, vascular parkinsonism is the second most common form of
chromosome 17q21 (1.5 Mb centromeric of tau). Plasma and CSF parkinsonism encountered in movement disorders clinics, accounting
levels of progranulin have been found to be reduced nearly fourfold for 8% of all parkinsonian patients (Mehanna and Jankovic, 2013).
in affected and unaffected subjects with PGRN mutations, and low Vascular changes on imaging studies are common, but the cause and
(75% reduction) plasma progranulin levels may be used as a screen- effect are not always clearly established. Among stroke patients, par-
ing tool for PGRN mutations. kinsonism is more common in patients with lacunar stroke. Adult-
There is considerable phenotypical, genotypical, and pathological onset diabetes, chronic hypertension, and hyperlipidemia seem to be
heterogeneity in FTDP (Spillantini and Goedert, 2013). The disor- the most common risk factors associated with vascular parkinsonism
der most often begins in the 50s or 60s with personality and behav- (De Pablo-Fernandez et al., 2018). Vascular parkinsonism usually
ioral changes that include disinhibition and aggressiveness as well as presents as “lower body parkinsonism” with a broad-based shuffling
frontal executive dysfunction. Other common signs include social gait and prominent start and terminal hesitation, as well as freezing
misconduct, stereotyped verbalizations, impaired recent memory, (see Videos 96.17 and 96.18). Postural instability and a history of falls
and parkinsonism. Some families present with early parkinsonism. are common. Many patients have dementia and corticospinal find-
Many mutations have been reported in the tau gene. They comprise ings of incontinence. In a systematic review of 25 articles, patients
mainly three groups: mutations in the coding region for a microtu- with vascular parkinsonism were older, had a shorter duration of ill-
bule-binding domain, resulting in a dysfunctional protein; mutations ness, presented with symmetrical gait difficulties, were less respon-
outside the microtubule-binding domains; and mutations that alter sive to LD, and were more prone to postural instability, falls, and
the ratio of three- to four-repeat tau isoforms. Pathological findings dementia (Kalra et al., 2010). Pyramidal signs, pseudobulbar palsy,
include tau-positive neuronal and glial inclusions distributed vari- and incontinence were more common in vascular parkinsonism, but
ably throughout the brain. In patients with prominent parkinsonism, tremor was not a main feature. Structural neuroimaging was abnor-
there is severe neuronal loss in the SN. The response of parkinsonism mal in 90%–100% of vascular cases, compared to 12%–43% of PD
to symptomatic treatment is not known. The prognosis is poor, with cases. In contrast to PD, there is usually no abnormality in presynap-
death occurring within 10 years. tic striatal dopamine transporters as measured by SPECT in vascular
parkinsonism.
Parkinsonism-Dementia Complex of Guam The pathology includes subcortical vascular disease with preserva-
A high incidence of an ALS-like illness among the Chamorros, tion of dopaminergic cells in the SN. There is a growing body of evi-
indigenous people of Guam, was noticed more than 50 years ago. In dence that microstructural changes of normal-appearing white matter
the same population, a smaller number of people had a syndrome of are common in the brains of patients with vascular parkinsonism
parkinsonism with dementia, the parkinsonism-dementia complex (Salsone et al., 2019; van Veluw et al., 2017).
The symptoms of vascular parkinsonism are unlikely to show a antagonists flunarizine and cinnarizine, which are not marketed in the
significant response to LD, but a therapeutic trial is worth pursuing United States. DIP generally appears subacutely after weeks to months
because as many as half of patients improve. Physical therapy may also of therapy. Although it is reversible, DIP may resolve very slowly over
be useful. a period of up to 6 months, and symptomatic treatment with anti-
cholinergics, amantadine, or LD may be required. Occasionally, par-
Bilateral Striatopallidodentate Calcification kinsonism does not resolve, suggesting that the offending drug likely
(Fahr Disease) has unmasked an underlying parkinsonism. The use of antipsychotic
Calcification of the basal ganglia has many causes. It is an incidental medications is a strong predictor of subsequent PD and patients taking
finding in up to 1% of all CT brain scans. Basal ganglia calcifications neuroleptics may be five times more likely to begin antiparkinsonian
can also be seen in infectious, metabolic, and genetic disorders affect- medications than nonusers. In some cases of DIP when the offend-
ing this brain region. There are familial and sporadic forms. When ing dopamine receptor blocking drug is discontinued TD may emerge
symptoms occur, they usually begin in adulthood between age 30 and (Savitt and Jankovic, 2018).
60 years. Cognitive dysfunction, seizures, cerebellar signs, dysarthria,
pyramidal signs, psychiatric illness, gait disorder, and sensory impair- Toxin-Induced Parkinsonism
ment are common. About half of symptomatic patients have move- In 1982, a number of young California drug addicts developed acute
ment disorders. Among these, parkinsonism and chorea are most and severe parkinsonism after intravenous injection of a synthetic
common. Fewer than 10% of patients have tremor, dystonia, atheto- heroin contaminated by MPTP. Subsequent study showed that the
sis, or orofacial dyskinesia. The presence of symptoms correlates with offending toxin was the metabolic product of MPTP produced by
the amount of calcification. Calcification is most often seen in the GP monoamine oxidase, 1-methyl-4-phenyl-propionoxypiperidine
but may also occur in the caudate, putamen, dentate, thalamus, and (MPP+). Postmortem examination in patients 10 years after the origi-
cerebral white matter, as well as internal capsules. Calcium is depos- nal exposure showed severe loss of SN neurons without Lewy body for-
ited in the perivascular extracellular space. Dominant and recessive mation. Interestingly, despite the 10-year interval between exposure to
inheritance patterns with many different gene mutations have been the toxin and death, there was evidence of an active neurodegenerative
described (Deng et al., 2015). There is no specific treatment other than process that included extracellular melanin and active neuronopha-
symptomatic management. gia. This suggests that intracellular mechanisms may promote neu-
rodegeneration after a distant environmental insult. MPTP-induced
Postencephalitic Parkinsonism parkinsonism is responsive to LD, but the response is complicated by
Between 1916 and 1927, a worldwide epidemic of encephalitis lethar- early development of motor fluctuations and dyskinesias, which may
gica killed approximately 250,000 persons and left an additional become severe, and psychiatric complications such as hallucinations.
250,000 with chronic disability. These survivors of the acute illness Cognitive function usually remains intact.
developed parkinsonism, usually within 10 years of the infection. PEP Acute carbon monoxide poisoning is associated with parkinson-
resembles PD, although more prominent behavioral and sleep abnor- ism. MRI scans show high-intensity white-matter lesions and necrosis
malities occur early in the disease course, extraocular movements are of the GP bilaterally. Cognitive signs including decreased short-term
often abnormal, and oculogyric crises are common. Other common memory, attention, and concentration are common. Patients with
movement disorders include chorea, dystonia, tics, and myoclonus. neurological sequelae of carbon monoxide intoxication may experi-
Pyramidal tract signs are common. The pathological appearance of ence gradual clinical and radiological improvement over months to
PEP includes degeneration of SN neurons, with neurofibrillary tangles years.
in surviving neurons. Although the etiology is presumed to be a virus, Manganese toxicity is associated with LD-unresponsive sym-
none has ever been identified. There have been no subsequent epidem- metrical parkinsonism with dystonic features such as oculogyric cri-
ics of encephalitis lethargica, although sporadic cases of PEP are occa- sis. The disorder may progress for years after cessation of exposure
sionally reported. The symptoms of PEP tend to be responsive to LD, (Jankovic, 2005). Striatal MRI T2-weighted hyperintensity may be
but behavioral complications such as hallucinations and delusions are present during the acute phase of poisoning. F-dopa PET scans in sub-
common, limiting therapy. jects with manganism show normal presynaptic dopamine function,
suggesting postsynaptic pathology. The fungicide maneb (manganese
Drug-Induced Parkinsonism ethylene-bis-dithiocarbamate) has also been shown to induce a toxic
Dopamine receptor-blocking drugs reproduce the major clinical fea- parkinsonism.
tures of PD, although signs are usually symmetrical, and the tremor
is more often present during posture holding than at rest (Savitt and TREMOR
Jankovic, 2018; Ward and Citrome, 2018). The most common causes
of DIP are the typical neuroleptic antipsychotic drugs, antidopami- Physiological Tremor
nergic antiemetics, and drugs that deplete presynaptic nerve terminals A fine tremor of the outstretched limbs is a universal finding.
of dopamine, such as reserpine, tetrabenazine, deutetrabenazine, and Physiological tremor appears to originate in the heartbeat, mechanical
valbenazine. Despite the marketing efforts by the drug manufactur- properties of the limbs, firing of motoneurons, and synchronization of
ers to minimize the risk of tardive dyskinesia (TD) with the atypical spindle feedback. Its frequency ranges from 7 to 12 Hz. It is usually not
(third-generation) neuroleptics, all these drugs have been reported noticeable except with electrophysiological recording, but its ampli-
to cause TD. Among the newer, or atypical, antipsychotics, the rela- tude is accentuated by fatigue, anxiety, fear, excitement, stimulant use,
tive propensity to cause DIP is as follows: risperidone = ziprasidone and medical conditions such as hyperthyroidism (Box 96.3).
> olanzapine > quetiapine > clozapine. This ranking reflects their
respective affinity for the D2 receptor. A number of other drugs have Essential Tremor
been associated with DIP: aripiprazole and other new atypical neuro- Epidemiology and Clinical Features
leptics (Peña et al., 2011), selective serotonin reuptake inhibitors, lith- ET is one of the most common movement disorders. In popu-
ium, phenytoin, methyldopa, valproic acid, and the calcium channel lation-based studies, the prevalence increases steadily with age,
BOX 96.3 Physiological Classification of

Tremor
Mechanical Oscillations
Physiological tremor
Oscillations Based on Reflexes

Neuropathic tremor
Oscillations Due to Central Neuronal Pacemakers

Palatal tremor
Essential tremor Right hand Left hand
Orthostatic tremor Fig. 96.14 Writing sample from a man with asymmetrical postural and
Parkinsonian rest tremor action tremor of essential tremor.
Holmes tremor
Oscillations Due to Disturbances in Feed-Forward/

Feedback Loops A striking improvement after ingestion of a small amount of
Cerebellar tremor ethanol is seen in 50% of patients and may be helpful in diagnosis
Holmes tremor (Mostile and Jankovic, 2010). Over time, the tremor worsens, causing
increasing functional disability. Only a fraction of affected persons
seek medical attention, and there is often a long latency from onset
occurring in up to 10% of patients older than 60 years of age. Meta- to presentation for care. At the time of diagnosis, nearly all patients
analysis of epidemiological studies has found the prevalence of ET to with ET have significant social, functional, or occupational disabil-
range between 0.01% and 20.5%, but the pooled prevalence is 0.9% ity, and as many as 25% must make occupational adjustments as a
(Louis and Ferreira, 2010). In its purest form, ET is a monosymp- result of tremor-related disability. ET is thought to be a monosymp-
tomatic illness characterized by gradually increasing-amplitude pos- tomatic illness without changes in cognition, strength, coordination,
tural and kinetic tremor of the forearms and hands (with or without or muscle tone, and the results of the neurological examination are
involvement of other body parts) in the absence of endogenous or usually normal. However, detailed studies of patients with ET have
exogenous triggers or other neurological signs. In clinic-based series, demonstrated frontostriatal cognitive deficits, changes in tandem
as many as 50% of patients exhibiting ET do not conform to this gait, and other (albeit subtle) evidence of cerebellar dysfunction. The
clinical picture, suggesting substantial heterogeneity and an overlap worsening of ET over time likely relates to two phenomena. First,
in some cases with dystonia and parkinsonism (Fekete and Jankovic, the frequency of tremor in ET decreases over time, and its ampli-
2011). The clinical definition of ET is problematic because there are tude increases. This results from decreased attenuation of lower-fre-
no pathological, biochemical, genetic, or other established and val- quency tremor secondary to age-related changes in the mechanical
idated diagnostic criteria. The Movement Disorders Society issued properties of limbs and muscle. A second possible contributor is true
a “consensus statement” on classification of tremors (Bhatia et al., progression of the underlying disorder. According to recent studies,
2018). It defined ET as isolated tremor syndrome of bilateral upper the severity of ET relates to disease duration independent of aging
limb action tremor at least 3 years’ duration with or without tremor and age-related changes in mechanical properties of the muscles and
in other locations (e.g., head, voice, or lower limbs), absence of other limbs.
neurological signs, such as dystonia, ataxia, or parkinsonism. They The diagnosis of ET is made by history and physical examination.
acknowledged that patients frequently have a family history, of trem- A tremor rating scale known as The Essential Tremor Rating Assessment
ors and small doses of alcohol may improve the tremor, but they felt Scale (TETRAS) has been developed by the Tremor Research Group to
that these clinical features are not consistent enough to be included in assess ET and has been found to correlate well with quantitative assess-
the definition of ET. They also introduced the term “ET-Plus,” a new ments using the kinesia system (Mostile et al., 2010).
tentatively and uncertainly defined entity characterized by the pres-
ence of additional neurological signs other than action tremor. This Etiology
has engendered much controversy, and many believe that ET-Plus is As many as two-thirds of patients give a positive family history of
more common than ET. tremor, and first-degree relatives of patients with ET are 5–10 times
There seems to be a bimodal distribution for age at onset, peaking more likely to have ET than first-degree relatives of control subjects.
in the 2nd and 6th decade of life. The typical patient becomes aware Direct questioning or examination of first-degree relatives increases
of a barely perceptible postural or action tremor, usually in the distal the yield of family history to as high as 96%. In some families, pedi-
arms and hands. The head and lower limbs are less commonly affected. gree analysis suggests ET is an autosomal dominant trait, with virtually
Head tremor (titubation) is milder than limb tremor and is predomi- complete penetrance by age 50 years. Twin studies suggest both hered-
nantly of a side-to-side, “no-no” type. Head tremor is often associated itary and environmental factors are important in disease expression.
with cervical dystonia and some patients with head tremor merely have Hereditary ET is genetically heterogeneous, with several described loci
dystonic tremor as a manifestation of their cervical dystonia without including ETM1 (FET1) on chromosome 3, ETM2 on chromosome
associated ET (Merola et al., 2019). Tremor of the face, trunk, and 2, a D3 receptor gene (DRD3) localized on 3q13.3, and a locus on
voice may also be present in patients with ET. The kinetic tremor is chromosome 6p23 (Kuhlenbäumer et al., 2014). One study involving
typically higher in amplitude than the postural tremor (Fig. 96.14). a North American population demonstrated a significant association
In contrast to PD where the handwriting is small, the handwriting in between a LINGO1 variant and ET, but further studies are needed
patients with ET is tremulous. before this association can be confirmed (Deng et al., 2019).
The mechanism of disease production in these genetic disorders the Clinical Rating Scale for Tremor (CRST) as the primary endpoint
remains unknown, and no consistent pathological structural changes along with several secondary outcomes the on-medication median
have been found in postmortem brain or nervous tissue, although cer- tremor scores improved 62% after active treatment and 22% after
ebellar degeneration and Lewy bodies have been found in a few autop- sham procedures (P = .04).
sied brains (Fekete and Jankovic, 2011; Louis et al., 2013). A number of
lines of evidence point to cerebellar dysfunction in ET; abnormal tan- Primary Writing Tremor
dem gait is one example. The tremor may resolve following ipsilateral Primary writing tremor is a rare condition characterized by a 4- to
cerebellar lesions. Motor control studies show evidence of abnormal 7-Hz tremor in the hand while assuming a writing posture or during
production of ballistic movements in a pattern that suggests abnormal- the writing task itself. Most patients are men. About one-third have a
ities in cerebellar timing. PET scans have shown evidence of bilaterally positive family history of writing tremor, and a similar number give a
increased cerebellar activity at rest and during tremor. The demonstra- history of improvement after ethanol ingestion. Surface EMG shows
tion of reduced N-acetyl-l-aspartate (NAA) relative to total creatine isolated extensor tremor, alternating tremor in flexors and extensors,
in the cerebellar cortex by magnetic resonance spectroscopy (MRS) or co-contraction of flexors and extensors. Writing tremor may be
suggests that the cerebellar disorder may be degenerative. difficult to distinguish clinically from ET and from task-specific or
writing dystonia. Primary writing tremor is not usually associated
Treatment with the phenomenon of overflow, typically seen in dystonia, and
Patients with mild ET whose main source of disability is tremor electrophysiological studies suggest it is distinct from both condi-
during meals and whose tremors respond to ethanol often benefit tions. Accelerometry suggests that the primary writing tremor reflects
from a cocktail before meals. The two most commonly used phar- the normal rhythmic movement of writing, but the amplitude of the
macological treatments are β-adrenergic blockers and primidone. movements is enhanced. The tremor may respond to β-adrenergic
Placebo-controlled studies have shown that β-adrenergic blockers blockade or primidone or anticholinergic medications, but botulinum
(e.g., 120–320 mg of propranolol per day) reduce tremor amplitude toxin injections provide the most benefit. Thalamic DBS has also been
in 40%–50% of patients. Common side effects of these beta-blocker reported effective in some cases.
drugs include bradycardia, fatigue, nausea, diarrhea, rash, impotence,
and depression. Beta-blockers are contraindicated in patients with con- Orthostatic Tremor
gestive heart failure, asthma, third-degree atrioventricular block, and Orthostatic tremor consists of a high-frequency (14–18 Hz) isomet-
diabetes. Primidone improves ET about 50% in short-term controlled ric tremor in the legs during standing (see Video 96.21) (Yaltho and
trials and has been suggested to be more effective for head tremor than Ondo, 2014). Patients may not be aware of the tremor but complain of
other agents. Because of the risk of acute side effects such as vertigo, unsteadiness and vibration or discomfort in the legs that are relieved
nausea, and unsteadiness, primidone is usually started at a dose of 25 by leaning against a stationary object, by walking, or by sitting down.
mg at bedtime and then titrated as tolerated to its effective dose range Leaning on the arms may precipitate a similar frequency tremor
of 50–350 mg daily. It can be given as a single nighttime dose or in in the arms, and a tremor of the closed jaw has also been reported.
divided-dose increments. Long-term primidone therapy is usually well Orthostatic tremor may be visible or palpable and can be confirmed
tolerated. Propranolol and primidone combination therapy may be by the appearance on EMG of high-frequency tremor when standing.
more effective than either agent alone. A double-blind placebo-con- Unlike parkinsonian tremors and ETs, orthostatic tremor shows sig-
trolled study of topiramate found that this antiepileptic drug may nificant side-to-side coherence, suggesting a central generator. PET
reduce ET. Other drugs such as alprazolam, gabapentin, pregabalin, scans have shown increased resting cerebellar activity similar to that
clonazepam, acetazolamide, and nimodipine may also provide bene- seen in ET. A recent study has suggested that coherent high-frequency
fit in some patients with ET. Botulinum toxin injection in the wrist tremor in the legs may be a normal response to perceived unsteadiness
flexors in patients with prominent hand tremor and into cervical mus- when standing still, and that orthostatic tremor may be an exaggera-
cles in patients with head tremor provided a meaningful reduction in tion of this response. Clonazepam is thought to be the most effective
the amplitude of the tremor for about 3–4 months after each injection pharmacological treatment, although there are reports of benefit from
(Mittal et al., 2019a; Niemann and Jankovic, 2018). The pipeline of LD and gabapentin.
experimental therapeutics is beginning to expand and includes various
tremor suppression devices, peripheral nerve stimulation and drugs Neuropathic Tremor
that modulate GABA type A receptors and calcium-activated potas- Tremors associated with neuropathy are usually postural and
sium channels, and Cav3 T-type calcium channel blockers. kinetic tremors with a frequency between 3 and 6 cycles per second.
Thalamic DBS has been reported to suppress contralateral tremor Demyelinating neuropathies have a particular association with tremor.
as much as 75% in up to 90% of cases, and bilateral stimulation can The diagnosis is made when a typical tremor affects a person with
be performed safely with long-lasting benefits, although dysarthria neuropathy in the absence of other tremorgenic neurological disor-
and gait and balance problems may occur, particularly with bilateral ders. The pathophysiology of neuropathic tremor is believed to be
stimulation (see Video 96.19) (Baizabal-Carvallo et al., 2014). Adverse disordered feedback control related to abnormal peripheral sensory
effects are relatively rare and may include intracranial hematoma, post- input. Some patients develop tremor after a peripheral injury, some-
operative seizures, dysarthria, paresthesia, dysequilibrium, headaches, times associated with abnormal posture as well as reflex sympathetic
dyspraxia, and word-finding difficulty. Problems with the stimulator dystrophy or complex regional pain syndrome. The mechanism of
itself are relatively uncommon but include lead fracture or migration this peripherally induced movement disorder is not understood.
and failure of the impulse generator. Reoperation may be necessary to Pharmacological treatment is usually disappointing, but some patients
correct device-related adverse effects. DBS should be considered for respond to beta-blockers or clonazepam.
cognitively intact, otherwise healthy patients with disabling medica-
tion-resistant tremor. Unilateral focused ultrasound thalamotomy was Cerebellar Tremor
evaluated in 27 patients with troublesome ET, who were randomized The tremor typically associated with cerebellar disease is a slow tremor
(2:1) to compare this with sham procedures (Bond et al., 2017). Using that is absent during rest but appears and progressively increases in
amplitude with movement, particularly with fine adjustments required Clinical Features
for a precise movement. Sitting or standing unsupported may induce When clinical illness begins, it does so gradually, and it is best to define
a tremor of the trunk and head (titubation). A variant of cerebellar a “zone” rather than a time of onset. Patients with HD may present
outflow tremor is known as Holmes tremor, or rubral tremor (Raina with motor signs, particularly chorea (about 60%), with behavioral
et al., 2016). This tremor is present during rest, posture holding, and signs (about 15%), or with both motor and behavioral signs (about
action. At rest, it is slower and less rhythmic than parkinsonian rest 25%). Patients themselves may be unaware or unconcerned about early
tremor. Holmes tremor results from acquired structural lesions in the cognitive and motor changes. Concerned family members often bring
ipsilateral cerebellar dentate nucleus and superior cerebellar pedun- them to medical attention. A change in the ability to generate saccadic
cle. The usual causes are multiple sclerosis, stroke, and head injury. eye movements and their speed is often the earliest sign. Eventually,
Pharmacological treatment of Holmes tremor is difficult, although a blink or head thrust may be required to initiate saccadic eye move-
some patients respond to LD. Thalamotomy or thalamic DBS may be ments. The motor disorder usually begins with clumsiness and fidgeti-
useful in some cases (Oliveria et al., 2017) (see Video 96.20). ness that evolves into chorea. The presence and severity of chorea vary
markedly from person to person and over time. Some patients, partic-
Hereditary Geniospasm (Chin Tremor) ularly in early stages of the disease, are able to camouflage their chorea
Hereditary geniospasm is characterized by involuntary vertical move- by incorporating the involuntary movements into seemingly volitional
ment of the tip of the chin with quivering and mouth movements. gestures such as touching their face or adjusting glasses (parakinesia).
Geniospasm may be spontaneous or stress induced. Trembling Chorea may not be recognized initially by family members or other
becomes apparent in infancy or early life. Trembling episodes last min- observers. In addition to chorea, patients with HD have bradykinesia
utes. The attacks become somewhat less frequent with age. The disor- and motor impersistence, with difficulty sustaining ongoing move-
der is genetically heterogeneous, with linkage to chromosome 9q13-21 ment. They may be unable to maintain forced eye closure, hold the
in some but not all families. Geniospasm has been suggested to be a mouth open, or protrude the tongue for long periods. With advanc-
form of hereditary essential myoclonus (EM). ing disease, there is progression of bradykinesia, and dystonic move-
ments appear. The chorea may become somewhat less prominent or
Fragile X Premutation may continue to worsen. The gait disorder of HD is complex, irregular,
Male carriers of the fragile X premutation have been found to have and dance-like, produced by a combination of chorea, parkinsonism,
a neurodegenerative syndrome characterized by the onset after age lapses in tone of antigravity muscles, and ataxia. The walking patient
50 years of kinetic tremor, gait ataxia, executive cognitive dysfunc- with HD resembles a marionette, lurching, swaying, dipping, and bob-
tion, parkinsonism, dysautonomia, erectile dysfunction, and periph- bing. Tandem walking becomes difficult, then impossible. Ultimately,
eral neuropathy (Hagerman and Hagerman, 2013). Daughters of the progressive bradykinesia and intractable falls lead to the wheelchair- or
patients often have ovarian failure. Bilateral cerebellar hyperintensi- bed-bound state. Dysarthria and dysphagia progressively impair com-
ties have been reported on T2-weighted MRI studies in some cases. munication and nutrition. Most patients spend the last several years of
Overexpression and CNS toxicity of the fragile X mental retarda- their lives in nursing home settings and die of complications such as
tion 1 gene (FMR1) messenger ribonucleic acid (mRNA) has been pneumonia and head injury. Mean survival is 17 years, but the natural
thought to cause this fragile X-associated tremor/ataxia syndrome history varies and is influenced by genetic and environmental factors.
(FXTAS). Generally, patients with onset at a younger age have the largest num-
There are other, more unusual tremors that physicians should be ber of CAG repeats and tend to progress more rapidly than patients
able to recognize but their discussion is beyond the scope of this chap- with onset at an older age. The juvenile HD differs from the adult phe-
ter (Ure et al., 2016). Functional (psychogenic) tremors are discussed notype, with prominent parkinsonism and dystonia, even early in the
below. course, and with myoclonus, seizures, and cognitive decline.
Behavioral changes contribute mightily to disability in HD; 98% of
CHOREA patients show one or more behavioral symptoms. The most common
changes in early disease are irritability, anxiety, and mood disturbance.
Huntington Disease Irritability may be accompanied by verbal or physical aggression.
The first complete description of HD is attributed to George Patients with HD often have a low threshold for anger and react to
Huntington in 1872. He accurately reported the salient clinical features minimal provocation with an explosive response. Depressed mood is
of the disease, its pattern of transmission from parent to child, and very common; 30% of patients meet criteria for major depressive dis-
its dismal prognosis. HD is a highly penetrant autosomal dominant order. Mania and hypomania are seen less commonly than depression.
disease characterized by a progressive movement disorder associated The risk of suicide is increased as much as sixfold over the general pop-
with psychiatric and cognitive decline, culminating in a terminal state ulation. Unmarried and childless persons living alone, those who are
of dementia and immobility (Testa and Jankovic, 2019). depressed, and those with a family history of suicide are particularly at
risk for suicide. Fear of the disease leads to an increased risk of suicide,
Epidemiology even in first-degree relatives of affected individuals who are at autopsy
Prevalence figures for HD vary depending on the geographical area, found not to have inherited the mutant gene. Psychosis is rare and may
but the best estimate is 10 per 100,000. The disorder is reported in all be difficult to treat. Obsessive-compulsive disorder has been reported
races, although it is much more common in Scotland and Venezuela but can be difficult to differentiate from frontal lobe personality with
and less common in Finland, China, Japan, and Black South Africans. perseveration. Apathy increases in concert with disease severity and is a
HD usually begins between the ages of 30 and 55 years, although nearly universal feature of advanced disease. Behavioral and psychiat-
it has been reported to begin as early as age 2 and as late as age 92. ric disorders may predate the onset of overt HD by as long as a decade,
Approximately 5% of cases begin in patients younger than 21 years; reflecting early pathological changes in the nonmotor areas of the stri-
the juvenile phenotype differs from the adult phenotype, and patients atum. Because some behavioral signs may be episodic and respond to
are often misdiagnosed. HD is a progressive degenerative disease that pharmacotherapy, their severity does not progress in a linear fashion
affects movement, behavior, and cognitive function. with cognitive and motor changes. Behavioral signs seem to improve
in the terminal stages of the illness, but ascertainment may be hindered

by the severe physical disability of such patients.
Cognitive changes are universal in HD. The dementia of HD fits the
description of subcortical dementia, with disordered attention, con-
centration, motivation, insight, judgment, and problem solving rather
than traditional cortical signs such as aphasia and apraxia. Executive
dysfunction renders affected persons unable to work, drive, and man-
age family finances relatively early in the disease course, but prominent
global dementia occurs later.
The diagnosis of HD in a patient with a typical clinical picture and
a confirmed family history is straightforward. Unfortunately, the fam-
ily history may be vague or it may be negative because of competitive
A
mortality, misdiagnosis, denial, inaccurate parental information, or
obfuscation. In addition, there is a small but definite new mutation
rate as expansion occurs with transmission of a premutation. Although
there is a broad differential diagnosis of chorea, there are few alterna-
tive causes of the fully developed syndrome. When the clinical sus-
picion of HD is high, the most cost-effective diagnostic procedure is
genetic testing.
The direct DNA test for the CAG repeat expansion in the hunting-
tin (HTT) gene, formerly called IT15, which codes for the huntingtin
(HTT) protein is highly sensitive and specific. A repeat CAG expansion
length of 37 and longer is considered pathogenic, resulting in motor,
cognitive, and neuropsychiatric manifestations of HD. CAG repeat
lengths between 27 and 36 are considered to be intermediate in range,
with some risk of expansion into the disease range during meiosis and B
manifested by typical HD in subsequent generations. Traditionally, Fig. 96.15 Pathology of Huntington Disease. A, Glial fibrillary acidic
these intermediate CAG repeat lengths have not been associated with protein immunostain of caudate nucleus of normal brain. B, Glial fibril-
clinical disease, but there has been a growing number of reports of lary acidic protein immunostain of caudate nucleus of patient with Hun-
patients with clinical (and neuropathological) evidence of HD who tington chorea. Note decreased neuronal density and marked reactive
possess CAG repeats in the intermediate range (Savitt and Jankovic, astrocytosis compared to normal brain. (Courtesy Elizabeth Cochran,
2019b). MD.)
The availability of the HD genetic test makes possible the identifi-
cation of mutant gene carriers long before they become symptomatic.
However, because of concerns about the potential for occupational, Neuroimaging studies can show generalized or preferential striatal
insurance, and social discrimination and the lack of neuroprotective atrophy, but these findings are not specific for the disorder. Although
treatment interventions, only a minority of eligible at-risk subjects volumetric analysis of the striatum shows declining volume even in
pursue testing. This, however, may change as potential disease-mod- presymptomatic gene carriers, many obviously symptomatic patients
ifying therapies are being developed (see below). Those who pursue do not have clinically apparent striatal atrophy. Somatosensory evoked
testing do so either to help with reproductive choices or because their potentials are abnormal in 94% of patients with HD, and abnormali-
uncertainty about the future is unbearable. Women are more likely ties correlate with clinical signs of the illness. However, the usefulness
to request presymptomatic testing than men at equal risk. Although of these and other electrophysiological studies for diagnosis or measur-
prenatal testing is also available, relatively few prenatal tests have been ing illness progression remains unproven.
performed. Interested researchers working in concert with lay orga-
nizations have outlined principles that guide clinicians in the prepa- Pathology
ration of potential gene carriers for predictive genetic testing. These The pathology of HD includes prominent neuronal loss and gliosis in
guidelines discourage genetic testing in asymptomatic minors and the caudate nucleus and putamen, along with regional and more dif-
recommend genetic and psychological counseling before and after fuse atrophy (Fig. 96.15). At autopsy, HD brains show about 20% loss
testing (Migliore et al., 2019). One obvious concern is the risk that of brain weight, suggesting that the degenerative process is not confined
once given a positive genetic test result, the patient may have a major to striatal tissues. Large cortical neurons in layer VI are also involved, as
depression or other psychopathology or may attempt suicide. When are neurons in the thalamus, SNr, superior olive, lateral tuberal nucleus
carefully managed, presymptomatic test programs are safe. In studies of the hypothalamus, and deep cerebellar nuclei. Within the striatum,
of life events after gene-carrier detection, less than 1% of patients have GABAergic medium spiny neurons bear the brunt of the degenerative
a potentially severe adverse outcome such as attempted or completed process. Early, there is preferential loss of GABAergic neurons that
suicide or hospitalization for psychiatric illness. Adverse outcomes co-localize enkephalin, dynorphin, and substance P. These neurons are
may be seen in patients whose predictive test suggests they are not gene thought to predominate in the indirect pathway, accounting for diffi-
carriers, the “survivor guilt” phenomenon. Depressive symptoms in culties suppressing adventitious movement early in the disease course.
such patients tend to become apparent several months after the test- With disease progression, all GABAergic medium spiny neurons are
ing process is completed. A premorbid history of depression increases affected, including those in the direct pathway, explaining the emer-
the risk of an adverse outcome of testing irrespective of test results, gence of parkinsonism in later disease. Juvenile-onset disease, more
confirming the need for careful screening and counseling in genetic severe from the beginning, resembles late-stage HD with degeneration
testing programs. of GABAergic neurons in both pathways.
A B C
Fig. 96.16 [11C]-Raclopride positron emission tomography scans of (A) normal control subject, (B) asymp-
tomatic carrier of Huntington disease (HD) gene, and (C) person with symptomatic HD, showing progressive
loss of D2-receptor-bearing striatal neurons.
Pathogenesis the NMDA receptor-associated ion channel, allowing ligand-associ-

HD is a dominantly inherited condition caused by an unstable ated depolarization of the postsynaptic receptor and excitotoxic-medi-
expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) ated damage. HTT may also interfere with the function of postsynaptic
gene on the tip of the short arm of chromosome 4, which codes for HTT density protein 95, a scaffolding protein associated with NMDA and
(Testa and Jankovic, 2019). Because repeat instability of this mutation kainate receptors, rendering these glutamate receptors hypersensi-
is much more common in spermatogenesis than in oogenesis, the off- tive. Mutant HTT also interferes with gene transcription, leading to
spring of men may have substantially greater CAG repeat lengths than an alteration in cell phenotype and disrupting many cell functions.
their fathers. This feature accounts for the phenomenon of anticipa- Mutant HTT may block the normal function of HTT to upregulate
tion in HD. There is a well-documented inverse correlation between brain-derived neurotrophic factor. Mutant HTT likely also triggers
the CAG repeat length and the age at disease onset. The extreme man- apoptotic cell death, but its full effect on cellular function, interaction
ifestation of this relationship is the association of juvenile-onset illness with other proteins, and how these actions lead to neurodegeneration
with repeat lengths of 60 or greater and onset within the first decade in HD have not yet been fully elucidated.
with repeat lengths of 80 or greater. Approximately 5% of patients
present before age 21 years; in nearly all cases of juvenile-onset dis- Treatment
ease, the mutant allele is inherited from the father. Likewise, very late As in all other neurodegenerative disorders, no treatment is yet proven
disease presentations often are associated with repeat lengths between to favorably influence disease progression (Schapira et al., 2014). As
36 and 41. The correlation between repeat length and age at onset is with other forms of neurodegeneration, many potential types of inter-
driven by a very tight relationship of these two factors at the two ends ventions might prove useful: blocking transcription of the mutant
of the mutation spectrum. The repeat length, however, accounts for gene, enhancing chaperone function, interfering with association and
only about 50%–70% of the variance in age at disease onset, suggesting aggregation of the protein, improving cell bioenergetics and mito-
that other genetic or environmental factors are important. For this rea- chondrial integrity, and interfering with the triggers and ultimate steps
son, the CAG repeat length is not a particularly useful tool for making in the process of apoptosis. Clinical trials of antioxidants designed to
predictions about disease onset, severity, or progression in individual slow down the progression of the disease have been disappointing.
patients. One large-scale study assessed the potential neuroprotective effects of
HD is a true dominant condition. Homozygotes do not have an the mitochondrial complex 1 booster coenzyme Q10 (600 mg/day), or
earlier onset or more severe form of the illness, suggesting the disorder the antiexcitotoxic agent remacemide (600 mg/day), on the decline of
results from a toxic effect of the mutant protein, a so-called gain of the total functional capacity score over 30 months. The study demon-
function (Cubo et al., 2019). The HD gene controls the synthesis of strated a trend toward slowing the decline in this measure of disability
HTT, a widely expressed protein of uncertain function. HTT is a cyto- in the coenzyme Q10 treatment arm, but this did not achieve statistical
plasmic protein, but ubiquitinated, mutant, proteolytic N-terminal significance. A number of other potential strategies have shown prom-
huntingtin fragments form protein aggregates in the cytoplasm and ise in transgenic disease models, although they have not been studied
nucleus of neurons. Mutant HTT interacts with a number of HTT- in human safety and efficacy trials. These include the caspase inhibitor
associated proteins and when it misfolds it can become more toxic. A minocycline, as well as creatine, lithium, ethyl eicosapentaenoic acid,
number of lines of evidence point to impaired mitochondrial function cystamine, bile acids, and inhibitors of transglutaminase. As with other
in HD, including abnormalities in complex I, II, III, and IV in caudate neurodegenerative diseases, there is no standard method for determin-
nuclei of affected brains. PET studies show reductions in striatal glu- ing disease severity or its rate of change over time. Studies relying on
cose metabolism and loss of dopamine D2 receptor-bearing neurons in clinical rating scales, such as the Unified HD Rating Scale, must be
the striatum (Fig. 96.16), and increased brain lactate levels. Systemic quite large and adequately powered to detect the disease-modifying
administration of the mitochondrial toxin 3-nitropropionic acid effect.
models the disease in animals. Intrastriatal administration of the exci- One intriguing discovery in HD is that, in transgenic models, turning
totoxins kainate and quinolinic acid also reproduces the striatal lesions off the HD gene not only stops progression of the experimental illness
of HD. One theory that ties these animal models together is that of but also reverses pathological findings, including aggregates, and is asso-
indirect excitotoxicity. Mitochondrial energy failure increases the vul- ciated with clinical improvement. Apparently, continued production of
nerability of the cell to excitotoxic injury because the resulting change the mutant protein is required for maintenance of cell dysfunction and
in cell membrane potential results in loss of the magnesium ion from ultimately for cell death. This argues for a period of cellular dysfunction
before death and raises the possibility that neuroprotection might have thorny projections, often with terminal bulbs. Acanthocytes are seen
the potential to at least partially reverse extant clinical features of the in peripheral blood smears in patients with three neurological syn-
disease. In this regard, an antisense oligonucleotide designed to inhibit dromes: abetalipoproteinemia, neuroacanthocytosis, and McLeod
HTT messenger RNA and thereby reduce concentrations of mutant syndrome (Walker et al., 2006). A broad spectrum of movement disor-
HTT has been tested in a randomized, double-blind, multiple-ascend- ders is seen in neuroacanthocytosis and McLeod syndrome.
ing-dose, phase 1-2a trial involving 46 patients with HD (Tabrizi et al., All forms of neuroacanthocytosis are rare disorders. Autosomal
2019). The intrathecal administration of 4 doses, 1 month apart, showed recessive neuroacanthocytosis is characterized by onset at around age
up to 38% reduction in the concentration of mutant HTT in CSF with- 35 years of a progressive syndrome that includes a movement disor-
out any serious adverse effects. A confirmatory phase 3 trial, involving der and behavioral and cognitive changes. The movement disorder
660 patients, followed for up to 2 years is currently under way. predominantly consists of chorea, dystonia, and tics; parkinsonism
Treatment of HD begins with an assessment of the nature of the patient’s may occur in more advanced stages. There is also prominent orofacial
complaints. Patients with chorea are often unaware of or untroubled by dystonia with dystonic tongue protrusion interfering with eating. In
their involuntary movements (Jankovic and Roos, 2014). Although typi- addition, many patients exhibit lip and tongue biting and prominent
cal neuroleptics represent the conventional approach to chorea, they have dysarthria and dysphagia. Behavioral changes resemble those seen in
been shown not to improve function in HD and are not used as much as HD: anxiety, depression, obsessive-compulsive disorder, and emo-
in the past (Frank and Jankovic, 2010). Preliminary study suggests that tional lability. Subcortical dementia is a late feature. Seizures develop
the glutamate antagonist, amantadine, may improve chorea in HD and is in approximately 50% of patients. There may be myopathy or axo-
well tolerated in doses up to 400 mg. Tetrabenazine and deutetrabenazine, nal neuropathy, and the creatine kinase level is elevated. In patients
inhibitors of the vesicular monoamine transporter 2 (VMAT2), that act with neuroacanthocytosis, acanthocytes usually make up 5%–20% of
by presynaptically depleting dopamine, have been approved by the US peripheral blood erythrocytes. Autopsy changes include atrophy of the
Food and Drug Administration (FDA) for the treatment of chorea asso- caudate, putamen, GP, and SN, with marked neuronal loss and gliosis.
ciated with HD. Although similar to typical neuroleptics, these drugs may The cerebral cortex is relatively spared. Mutations in the CHAC gene
cause drowsiness, parkinsonism, depression, and akathisia; in contrast to (recently renamed VPS13A) on chromosome 9 that lead to the pro-
the dopamine receptor blocking drugs, they do not cause TD (Bashir and duction of chorein, a truncated protein of unknown function, have
Jankovic, 2018a). Some patients with prominent bradykinesia improve been found in this syndrome. Homologous proteins in animals seem
with dopaminergic therapy. Selective serotonin reuptake inhibitors seem important in intracellular trafficking.
to improve irritability, aggression, depression, and obsessive-compulsive McLeod syndrome is an X-linked recessive disorder linked to a
symptoms. Irritability may respond to carbamazepine and some of the number of mutations in the XK gene, a gene for the Kell group of eryth-
newer antiepileptic drugs. Quetiapine, an atypical antipsychotic with rocyte membrane glycoprotein antigens on the X chromosome (Roulis
minimal risk for parkinsonism or TD, has been reported to be useful in et al., 2018). McLeod syndrome usually begins around age 50 and has a
patients with irritability and aggression. slowly progressive course. The most common clinical feature is an axo-
nal peripheral neuropathy. Some patients have evidence of myopathy
Dentatorubral-Pallidoluysian Atrophy as well, and all have elevations in serum creatine kinase level. The CNS
Dentatorubral-pallidoluysian atrophy is an inherited neurodegenerative illness is characterized by limb chorea. Oral movements and lip and
disease that appears to be rare outside Japan but has been found to be tongue biting are less common than in neuroacanthocytosis. Facial tics
relatively common in North Carolina: hence the alternative term Haw are common, and some patients have dystonia. Seizures may be seen.
River syndrome. Typical symptoms of DRPLA include chorea, ataxia, Subcortical dementia and behavioral changes occur later in the disease
myoclonic epilepsy, dystonia, parkinsonism, psychosis, and dementia. course in approximately 50% of patients. Cardiomyopathy and hemo-
Onset is usually in the 20s, with death about 20 years later. Anticipation lytic anemia are other common manifestations. Neuroimaging studies
occurs with paternal transmission of the gene. The pathology of DRPLA may show caudate atrophy with secondarily enlarged lateral ventricles.
includes degeneration of the dentate and red nuclei, the GP, and the Increased T2-weighted signals in the lateral putamen may be seen on
STN. Neurodegeneration may also be found in the cerebral white mat- MRI scans. Pathological changes include intense caudate atrophy, loss
ter, putamen, medulla oblongata, and spinal cord. Neuronal nuclear of small cells, and gliosis in the dorsolateral putamen, with less severe
inclusions stain for ubiquitin and atrophin-1. There is also evidence changes in the GP. Milder changes may be present in the thalamus, SN,
for aberrant phosphorylation of the DRPLA protein complex and the and anterior horns of the spinal cord. Neurons in the cerebral cortex,
nuclear membrane. DRPLA is associated with an expansion of CAG STN, and cerebellum are spared. The reported mutations in the XK
trinucleotide repeat in a gene on chromosome 12. In this region of the gene result in absence or truncation of the protein product. Kell is an
genome, the normal trinucleotide repeat length is 7–23. In DRPLA, endothelin processing enzyme. Endothelins are important in prolifer-
the CAG repeat length is between 49 and 75. Because of the polygluta- ation and development of neural crest–derived cells and are thought
mine stretch in the mutant protein, neurodegeneration likely relates to to be important in neurotransmitter release in dopaminergic neurons.
interactions between the protein, other cellular components, and cel- No information is available about treatment of neuroacanthocytosis,
lular proteins. The Haw River syndrome, described in a multigenera- but the physician should be guided by the clinical manifestations.
tional African American family, is caused by the same repeat expansion
as DRPLA. Clinical differences include lack of myoclonic epilepsy and Sydenham Chorea and Other Autoimmune Choreas
the presence of subcortical white-matter demyelination, basal ganglia Sydenham chorea (SC), one of the major manifestations of rheumatic
calcifications, and neuroaxonal dystrophy. No information is available fever, typically appears months after the initial streptococcal infection
about the treatment of DRPLA, but as in HD, the clinician should be (Baizabal-Carvallo and Jankovic, 2012). Because of the widespread avail-
guided by the nature and severity of symptoms. ability of antistreptococcal therapy, SC is now extremely rare in devel-
oped countries. It is a disorder of children, mainly girls, between ages 5
Neuroacanthocytosis and McLeod Syndrome and 15, with a mean age at onset of 8.4 years. The chorea begins insid-
The term acanthocyte is derived from the Greek word for “thorn.” iously, but progresses over a period of weeks, and it generally resolves
Acanthocytes are contracted erythrocytes with unevenly distributed within about 6 months. Choreic movements are usually generalized,
but asymmetric and hemichorea may also be seen. Behavioral accom-

BOX 96.4 Etiology of Hemiballism
paniments such as restlessness, irritability, and obsessive-compulsive
traits are common. It is a self-limited disorder, usually lasting up to 6 Structural Lesions
months. Approximately 20% of cases recur, but multiple recurrences Cerebrovascular Disease
are rare. Mild enlargement of the basal ganglia may be seen on MRI Infarction
brain scan. Pathologically, SC is characterized by inflammation of the Transient ischemic attack
cortex and basal ganglia. Anti–basal ganglia antibodies can be detected Hemorrhage
by enzyme-linked immunosorbent assay and Western immunoblot. The Arteriovenous malformation
mechanism of basal ganglia damage is likely molecular mimicry, with Subarachnoid hemorrhage
cross-reaction between antibodies directed against streptococcal and Subclavian steal syndrome
striatal antigens. Because it is often self-limited, the decision to treat SC
depends on the magnitude of each patient’s disability. A recent compar- Infection
ative trial suggested that valproic acid is the most effective treatment, fol- Syphilis
lowed by carbamazepine and haloperidol. The typical neuroleptics, such Tuberculoma
as haloperidol, however, are now rarely used in the treatment of chorea Toxoplasmosis
and instead VMAT2 inhibitors, such as tetrabenazine, deutetrabenazine, Acquired immunodeficiency syndrome
and valbenazine are now considered the drugs of choice (Bashir and Influenza A
Jankovic, 2018b). Because SC tends to be self-limited, periodic attempts
should be made to wean from therapy. Intravenous methylprednisolone Tumor
followed by oral prednisone may be useful in refractory cases. Later in Pituitary microadenoma
life, people who have survived SC may have a recrudescence of chorea in Metastasis
the presence of hormonal stresses like pregnancy (chorea gravidarum)
Immune-Mediated
or estrogen treatment.
Systemic lupus erythematosus
Besides SC, there are many other autoimmune choreas, including
Sydenham chorea
systemic lupus erythematosus and paraneoplastic choreas (Baizabal-
Behçet disease
Carvallo and Jankovic, 2012; Baizabal-Carvallo et al., 2013) and
Scleroderma
NMDAR encephalitis (Baizabal-Carvallo and Jankovic, 2018).
Other
Other Choreic Disorders
Static encephalopathy
There are many causes of chorea but here we will focus only on the Head injury
more common ones or those in which understanding of pathogene- Demyelinating disease
sis has improved. A condition previously referred to as benign heredi- Thalamotomy
tary chorea has been re-defined with the discovery of its genetic cause. Heredodegenerative disease
Inherited as an autosomal-dominant disorder, this disorder has been
linked to mutations in the NKX2-1 (previously called TITF1) gene cod- Metabolic
ing for a transcription essential for the organogenesis of the brain, lung, Nonketotic hyperosmolar hyperglycemia
and thyroid. Since all three of these sites are affected, the condition has
also been referred to as “BLT syndrome.” Initially defined as a non- Drug-Induced
progressive syndrome of inherited childhood-onset chorea with a good Phenytoin and other anticonvulsants
outcome in the absence of an underlying degenerative disease, the phe- Oral contraceptives
notype has been expanded markedly as new cases with mutations of the Neuroleptics (tardive)
NKX2-1 gene are being reported (Patel and Jankovic, 2014). Chorea is
present from early childhood, usually from the first decade of life, but a
variety of other movement disorders and nonmotor features have been on one side of the body (HB), but involvement in both legs (parab-
described. These include hypotonia in early infancy, delayed walking allism) or both sides of the body (biballism) is also possible. Ballism
ability, dystonia, myoclonus, and tics as well as a variety of behavioral overlaps with choreas, and both movements may coexist. Acute-onset
and cognitive features including attention-deficit/hyperactivity disor- ballism often evolves into and is replaced by chorea. Animal models
der. Because of the heterogeneity of clinical features, the term NKX2-1 with lesions in the STN result in a mixture of choreic and ballistic
disease has been suggested for this disorder. movements. The development of ballism varies with the underlying
Mutations in the adenylate cyclase 5 (ADCY5) gene have been asso- etiology. HB related to stroke appears suddenly or emerges more slowly
ciated with a variety of movement and behavioral disorders, includ- in a recovering plegic limb. Approximately 20% of cases relate to struc-
ing episodic and fluctuating chorea, dystonia, myoclonus, cognitive tural lesions within the contralateral STN and in 20% of cases no lesion
decline, delayed motor and speech milestones, hypotonia, ataxia, can be demonstrated by MRI. In other cases, the lesion is usually found
unexplained falls, and myopathy-like facial appearance (Carecchio in the afferent or efferent projections of the STN. Rarely, other etiolo-
et al., 2017). The disorder is frequently misdiagnosed as dyskinetic gies, even ipsilateral to the movement, have been described. Although
cerebral palsy (Monbaliu et al., 2017). A homozygous loss-of-func- the underlying lesion is usually cerebrovascular disease in the elderly
tion mutation in the PDE2A gene has been associated with early-onset and infectious or inflammatory disease in younger patients, any type of
hereditary chorea (Salpietro et al., 2018). structural lesion, appropriately placed, can produce the characteristic
movement. Metabolic disorders such as nonketotic hyperglycemia and
Ballism drug exposure may also cause HB (Box 96.4). The mechanism of bal-
Ballism is usually a high-amplitude proximal ballistic flinging move- lism is not well understood but loss of STN excitation of the GPi results
ment (see Chapter 24, Box 24.5) that most commonly affects the limbs in a loss of inhibitory drive to the thalamus, giving rise to excessive
motor activity which may be represented clinically by the ballistic reticular formation and periaqueductal gray matter of the PPN, cune-
movements. Low firing frequency of the STN has been confirmed in a iform nucleus, and griseum centrale mesencephali. These inclusions
few cases, using intraoperative recording. stained positive for ubiquitin, torsin A, and the nuclear envelope pro-
Long-term prognosis and outcome closely relate to the underly- tein lamin A/C. In addition, tau/ubiquitin-immunoreactive aggregates
ing etiology. Movements often regress or become more choreic over were found in the SNc and locus coeruleus. If confirmed by other stud-
several months, but they can be quite exhausting or disabling when ies, these findings support the notion that DYT1 dystonia is associated
present, and treatment is usually only indicated acutely and in patients with impaired protein handling, particularly in brainstem nuclei such
whose movements do not resolve spontaneously. Although the rarity as the PPN.
of the condition has precluded controlled clinical trials, there is ample
evidence from case series and reports that dopamine antagonists and Pathogenesis
dopamine depleters (VMAT2 inhibitors) effectively decrease choreic The low penetrance of DYT1 dystonia, combined with variable expres-
movements. Beneficial results have also been obtained using gabapen- sion that may range from an asymptomatic state to severe life-threat-
tin and valproic acid. ening dystonia (dystonic storm), may obscure its hereditary nature in
many families. The disorder is genetically homogeneous in Ashkenazi
DYSTONIA Jews, 90% of whom are found to have the DYT1 mutation (Inzelberg
et al., 2014). Non-Jewish patients are genetically more heterogeneous.
Childhood-Onset Generalized Primary Dystonia The DYT1 mutation is a GAG deletion in the TOR1A gene on chro-
Epidemiology and Clinical Features mosome 9, with an estimated frequency of 1 per 2000 to 1 per 6000 in
Dystonia is a disorder dominated by sustained muscle contractions, Ashkenazi Jews and about 1 per 20,000 to1 per 30,000 in non-Jewish
which often cause twisting and repetitive movements or abnormal populations. The high prevalence of DYT1 in Ashkenazi Jews is related
postures (Albanese et al., 2013; Balint et al., 2018) (see also Chapter to a founder mutation estimated to have originated about 350 years
24). Generalized dystonia is quite rare, with an estimated prevalence ago in Lithuania or Byelorussia and the subsequent large increase in
of approximately 1.4 per 100,000. Most cases of primary generalized the population from a limited number of ancestors.
dystonia that begin in childhood have DYT-TOR1A dystonia, caused The pathogenesis of generalized dystonia remains poorly under-
by a mutation in the torsin A gene (TOR1A) on chromosome 9q32-34 stood, but progress is being made in unraveling the cellular and molec-
(Dauer, 2014; Marras et al., 2016) (see also Chapter 24). Also referred ular mechanism of the genetic forms of dystonia (Dauer, 2014). Torsin
to as Oppenheim dystonia and previously called dystonia musculorum A is a protein of unknown function that is homologous to the ade-
deformans, DYT1 is an autosomal dominant disorder with relatively nosine triphosphatases and heat-shock proteins. Its structure suggests
low penetrance. DYT1 dystonia is one of several movement disor- a role in endoplasmic reticulum function, intracellular trafficking, or
ders particularly common in persons of Ashkenazi Jewish descent vesicular release. Mutant torsin A may interfere with these functions
(Inzelberg et al., 2014). The reported prevalence of DYT1 dystonia is or may contribute to misfolded protein stress. Besides DYT1 there
as high as 20–30 per 100,000. Half of patients are affected by age 9, are many other genetic and non-genetic causes of dystonia (see Table
and onset in patients older than 40 years of age is extremely rare. The 24.6A and 24.6B and Box 24.3).
earliest symptom is usually an action-induced dystonia in the leg or There is experimental, clinical, neuroimaging, and electrophys-
arm. Onset in the cervical, facial, laryngeal, or pharyngeal region is iological evidence of dysfunction at the cortical, subcortical, brain-
rare. In approximately 70% of patients, dystonic movements spread to stem, cerebellar, and spinal levels. Although sensation in patients
the trunk and other limbs, and the condition generalizes over about 5 with dystonia is normal, it has been suggested that there is disordered
years. Patients with earlier onset and onset in the leg are more likely to sensory function as suggested by the presence of alleviating maneu-
develop generalized dystonia than those presenting later or with arm vers (see Chapter 24), a characteristic feature of dystonia (Patel et al.,
dystonia. Generalized dystonia produces severe disability, and most 2014). Deep brain recordings support abnormally low firing rates in
patients with this severe form of the illness are nonambulatory. Even the GPi, with an abnormal pattern of firing as well. During sustained
in generalized disease, however, laryngeal and pharyngeal dystonia dystonia, metabolic activity in the midbrain, cerebellum, and thala-
remains rare. The diagnosis of childhood-onset primary generalized mus is increased. Functional neuroimaging of the dopamine system
dystonia is made clinically in a patient with onset before age 26 of limb suggests decreased dopamine neurotransmission in the striatum, but
dystonia, with subsequent spread; absence of other movement disor- decreased striatal dopamine has not been confirmed in postmortem
ders, with the exception of tremor; normal intellect and neurological tissue. Because dystonia may respond to pallidal lesions or stimulation,
examination; and absence of a pronounced response to LD (see also a central role of the GPi has been proposed. It is likely, however, that
Chapter 24). the pathophysiology of dystonia involves many factors that include
Routine laboratory and neuroimaging studies do not contribute changes in the rate and pattern of neuronal firing, the degree of syn-
to the diagnosis. Simultaneous recording of EMG activity from antag- chronization of firing, and aberrant focusing of sensory input. There is
onist muscles often reveals simultaneous contraction of antagonistic no diagnostic test for dystonia, although simultaneous EMG recording
muscles and spread or overflow of activity to muscles not involved in of agonist and antagonist muscles may show inappropriate co-contrac-
the intended action. Such studies are not required for the diagnosis. tion. But this is not required for diagnosis of dystonia.
DNA testing is available for DYT1 dystonia, but the low penetrance of
the disease limits the usefulness of this test for prenatal or presymp- Treatment
tomatic diagnosis. Rather limited information is available on the medical treatment of
childhood-onset primary generalized dystonia. Apart from an obvious
Pathology neurotransmitter deficiency or excess, there is no compelling ratio-
Pathological studies in childhood-onset primary generalized dystonia nale for the use of any particular pharmacotherapy, and no drug has
are limited. Although traditionally thought not to be associated with been found to be universally effective for symptom control (Balint
pathological changes, brains from genetically confirmed DYT1 dys- et al., 2018; Jankovic, 2009a; Thenganatt and Jankovic, 2014b). In
tonia patients showed perinuclear inclusion bodies in the midbrain the absence of genetic confirmation of the DYT1 mutation, a trial of
LD should be considered in all patients with childhood-onset dysto- involvement with adductor or abductor spasmodic dysphonia affects
nia because up to 10% will have dopa-responsive dystonia (DYT5a) phonation, resulting in a harsh and strangled or breathy voice, respec-
(Wijemanne and Jankovic, 2015). In patients younger than 20 years tively. Whispering and singing are often relatively unaffected in such
of age, some 50% will respond well to high-dose anticholinergic ther- patients. The occupational or task-specific dystonias are those that
apy. The response rate is better in patients treated within 5 years of arise in the context of repetitive or skilled use of a body part. The most
onset. Baclofen, clonazepam, benzodiazepines, and dopamine-de- common task-specific dystonia is writer’s cramp, in which action dys-
pleting medications may be useful in some patients. The treatment tonia of the arm and hand develop during writing. Musicians, hair styl-
of childhood-onset primary generalized dystonia is a trial-and-error ists, court reporters, and others who work repetitively with the hands
process. Treatment should be initiated with very small doses, and the may find these specific skills similarly affected. Players of wind instru-
dose should be increased slowly and gradually. Botulinum toxin injec- ments may develop embouchure dystonia, with difficulty maintain-
tions may be considered to treat one or a few particularly problematic ing the proper mouth and lip posture. Occasionally an adult patient
body areas in patients with generalized dystonia. Chronic intrathecal presents with a pure truncal dystonia with flexion, extension, or lateral
baclofen has been reported to help some patients with dystonia, espe- bending. As noted before, truncal dystonia is a typical manifestation of
cially those with concomitant spasticity. tardive dystonia. Isolated foot dystonia in an adult may be the initial
Thalamotomy has been replaced by GPi or STN DBS as the manifestation of isolated dystonia although it is more commonly the
treatment of choice for disabling medically intractable generalized initial presentation of an underlying neurodegenerative disorder, PD,
or segmental dystonia. Long-term studies have established the sus- or other form of parkinsonism, or SPS (see below). Some patients may
tained efficacy of DBS in patients with dystonia (Panov et al., 2013). become initially aware of their foot or leg dystonia while running, the
Advances in DBS techniques and in defining the appropriate targets so-called runner’s dystonia, another example of task-specific dystonia
have resulted in improved outcomes in patients with dystonia treated (Wu and Jankovic, 2006). The diagnosis of adult-onset primary focal
with DBS (Cheung et al., 2014; Meoni et al., 2017; Ostrem et al., 2017). or segmental dystonia is made clinically. Neuroimaging studies are
useful if an underlying cause is suspected but are generally normal.
Adult-Onset Primary Focal and Segmental Dystonia
Epidemiology and Clinical Features Pathogenesis
A community-based postal survey of primary dystonia suggested the Besides generalized dystonia, many studies have suggested that focal
prevalence of adult-onset primary focal or segmental dystonia was 12.9 and segmental dystonia might also have a genetic basis (Albanese
per 100,000. Cervical dystonia and blepharospasm were most com- et al., 2013; Balint et al., 2018; Dauer, 2014). Approximately 25% of
monly represented. The focal and segmental primary dystonias gener- adult-onset focal or segmental dystonia patients have a positive fam-
ally begin in adulthood with dystonic movements in the hand and arm, ily history of dystonia, which would be consistent with an autosomal
neck, or face. When spread occurs, the ultimate distribution tends to dominant condition with low penetrance (see also Chapter 24).
maintain a segmental pattern. Cervical dystonia is the most frequently The pathogenesis of adult-onset primary focal or segmental dys-
diagnosed form of focal dystonia, accounting for about half of focal tonia is unclear, but similar mechanisms to childhood-onset primary
dystonia cases. Patients with cervical dystonia present with neck pain, generalized dystonia are proposed. Studies suggest that there is reduced
difficulty maintaining a normal head position, and sometimes tremor. intracortical inhibition in dystonia, believed related to impaired cor-
Dystonic tremor, which may be present not only in patients with tical and striatal GABA levels. Several lines of evidence suggest that
cervical dystonia but also in those with limb dystonia, is usually an abnormal central somatosensory processing may lead to insufficient
irregular oscillatory movement that stops when the patient is allowed sensorimotor integration in dystonia. PET scans suggest an abnormal
to place the head or limb in the position of the dystonic pulling—the pattern of regional glucose metabolism with hypermetabolism of the
null point. There is a directional preponderance to dystonia move- basal ganglia, cerebellum, and SMA.
ments that is usually maintained throughout the course of the disease.
Alleviating maneuvers (also referred to as “sensory tricks”) are often Treatment
discovered and used by the patients to ameliorate the dystonia (see Medical treatment of adult-onset primary focal and segmental dystonia
Chapter 24) and include resting the head against a wall or high-backed is difficult and employs those agents typically used in generalized dysto-
chair or touching the chin or back of the head lightly with one hand. nia. Adults are less able to tolerate effective doses of these agents, so the
Spontaneous remissions may be seen in as many as 20% of patients, response to therapy is somewhat more disappointing than that seen in
although recurrence is common. children. Botulinum toxin injections, on the other hand, are very help-
Blepharospasm is one of the most common forms of focal dystonia. ful in the treatment of focal and segmental dystonia (Jankovic, 2017).
Symptoms of blepharospasm are often preceded by photosensitivity Botulinum toxin injections have been proven effective in the treatment
and a gritty or otherwise abnormal sensation in the eye. Increased of blepharospasm and other facial dystonias, as well as cervical dystonia
blinking may follow, or frank spasms of eyelid closure may begin. (Mittal et al., 2019b; Simpson et al., 2016). Clinical experience suggests
Symptoms of blepharospasm are typically worse with driving, reading, they are also useful in the treatment of oromandibular, laryngeal, trun-
or watching television and when exposed to bright light, wind, or stress. cal, and limb dystonia. Overall, more than 75% of treated patients report
Many patients notice improvement in their blepharospasm when they moderate to marked improvement in dystonic pain or posture. The pro-
talk or sing and when they place a finger on the eye orbit (alleviat- cedure is generally well tolerated, with weakness of injected muscles or
ing maneuver). Blepharospasm is often accompanied by oromandib- occasionally neighboring muscles the most often reported side effect.
ular dystonia (cranial dystonia), or the latter may occur in isolation. Botulinum toxin injections have a relatively brief duration of action,
Oromandibular dystonia typically causes involuntary jaw opening or requiring repeated injections every 3–6 months. Secondary resistance
closure (with trismus and bruxism), tongue protrusion, dysarthria, occurs in some chronically treated patients, especially those injected fre-
and dysphagia. Because the actions of eating and speaking activate the quently with higher doses of the toxin (Jankovic, 2018b).
dystonia, these tasks are particularly affected. Alleviating maneuvers Patients who fail to respond to botulinum toxin injections may be
used by patients with oromandibular dystonia include touching the offered surgical interventions. Blepharospasm can be treated by orbital
face or inserting an object such as a pencil into the mouth. Vocal cord myectomy, although this procedure is now rarely needed as botulinum
toxin provides adequate relief in most patients. Likewise, cervical rhi- Another childhood-onset dystonia related to deficient dopaminer-
zotomy or myectomy are rarely performed, even in patients with cer- gic neurotransmission is aromatic acid decarboxylase deficiency. This
vical dystonia who are resistant to botulinum toxin therapy. Pallidal or disorder is recessively inherited. Dystonia, parkinsonism, oculogyric
STN DBS has been tried with good results in some patients with refrac- crises, autonomic symptoms, and progressive neurological impair-
tory cranial-cervical dystonia, but this procedure is most frequently ment begin in childhood. There are deficiencies in central biogenic
used in patients with generalized dystonia (Meoni et al., 2017; Ostrem amines including dopamine, norepinephrine, epinephrine, and sero-
et al., 2017). tonin. Because the enzyme deficiency is distal to LD in the dopamine
synthetic pathway, the symptoms are not LD responsive. However,
X-linked Dystonia-Parkinsonism (Lubag) direct-acting DAs and MAOIs may be useful.
DYT/PARK-TAF1 (DYT3), or Lubag, is an X-linked condition with
progressive dystonia and parkinsonism affecting Filipino adult men Myoclonus Dystonia (DYT11)
descended from maternal lines from the Panay Island (Marras et al., In myoclonus dystonia (MD), dystonia is the predominant symptom,
2016). In addition to dystonia and parkinsonism, patients may man- but myoclonus in body parts not necessarily affected by dystonia is also
ifest tremor, chorea, and myoclonus. The phenotypical heterogeneity present. Some patients have pure myoclonus. Symptoms usually begin
is evident in colorful descriptions of the disorder in the local dialect. before the teenage years and predominantly affect the head, arms, and
Lubag means “intermittent,” and wa’eg “sustained twisting or postur- upper body. The involuntary movements may be exquisitely sensitive
ing,” suggesting the predominantly dystonic form of the illness. Sud- to ethanol. Psychiatric features including affective disorder, obses-
sud refers to shuffling gait, suggesting the parkinsonian form of the sive-compulsive disorder, substance abuse, anxiety, phobic or panic
illness. Lubag affects men in the fourth or fifth decades, although much disorders, and psychosis have been described. Cognitive decline has
earlier-onset cases have been described. Symptoms predominantly also been reported. No other neurological deficits are seen, and the
relate to dystonia, although parkinsonism is present in more than 30% course is usually benign. The pathology is unknown. A number of het-
of patients. A nearly pure parkinsonian phenotype is thought to pre- erozygous mutations in the ε-sarcoglycan gene on chromosome 7 have
dict a more benign prognosis. been reported in families with MD. Another dystonic disorder associ-
PET studies have shown both postsynaptic and presynaptic dopa- ated with myoclonus is DYT-KCTD17 (DYT26), an autosomal dom-
minergic changes. Some brains of patients with this dystonia-parkin- inant disorder of childhood or adult onset, manifested by myoclonus
sonism syndrome have been found to have a mosaic pattern of striatal and cranial-cervical dystonia. MD responds poorly to medical therapy,
gliosis. In some patients, parkinsonian symptoms are LD-responsive, but beneficial responses to clonazepam, valproic acid, and trihexyphe-
although there are reports that LD worsens symptoms in some pre- nidyl have been reported. Thalamic stimulation may also be beneficial.
dominantly dystonic patients.
Rapid-Onset Dystonia Parkinsonism (DYT12)
Dopa-Responsive Dystonia Rapid-onset dystonia parkinsonism (RDP), DYT/PARK-ATP1A3
Dopa-responsive dystonia (DRD) is an uncommon condition with a (DYT12), is a very rare disorder in which signs of parkinsonism and
prevalence of 0.5–1 per 1,000,000. Girls are preferentially affected. DRD upper-body dystonia develop subacutely (Heinzen et al., 2014). Onset
is a childhood-onset generalized dystonia with a dramatic, sustained, ranges from childhood to adulthood. Dystonia preferentially affects
and uncomplicated response to low doses of LD. The disorder begins in bulbar muscles and progresses over a period of days to weeks but then
the first decade of life, usually with an action leg dystonia. The condition remains stable. Although sporadic cases have been reported, most cases
then progresses to the fully formed illness that ranges in severity from belong to a small number of families showing dominant inheritance
mild focal to disabling generalized dystonia associated with marked gait with incomplete penetrance. A genetic locus on chromosome 19 has
difficulty and postural instability with a positive pull test. Early-onset been discovered. Low levels of homovanillic acid have been detected
cases may be mistakenly diagnosed as cerebral palsy. The most char- in the spinal fluid, but PET scans using presynaptic markers fail to
acteristic historical feature is prominent diurnal fluctuation, although demonstrate a loss of dopaminergic neurons. There is no evidence of
this is present in only 50% of the cases. Affected patients may be almost neurodegeneration, and symptoms do not improve with administra-
normal in the morning, becoming progressively more disabled over the tion of LD. Mutations in the Na+/K+-ATPase α3 gene, ATP1A3, on
course of the day, with peak disability due to generalized dystonia and chromosome 19q13 were found to be associated with RDP (see also
parkinsonism late in the evening. DRD is usually dominantly inher- Chapter 24).
ited with incomplete penetrance (DYT5a). DYT5 results from muta-
tions in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene on Wilson Disease (Hepatolenticular Degeneration)
chromosome 14 (Wijemanne and Jankovic, 2015). Over 100 different Clinical Features
mutations of the gene have been identified, and therefore commercially Wilson disease (WD) is a rare, autosomal recessive, heredodegenera-
available DNA testing identifies only the most common mutations. tive disorder thought to affect 1–2 per 100,000 persons (Dusek et al.,
Guanosine triphosphate cyclohydrolase 1 is an enzyme involved in 2015; Hedera, 2019). The WD gene, termed ATP7B, on the long arm
the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxy- of chromosome 13 encodes copper-transporting P-type ATPase. Over
lase, the rate-limiting enzyme in the synthesis of LD. Other mutations 600 mutations have been identified and most patients carry at least two
affecting enzymes involved in tetrahydrobiopterin synthesis, such as mutations. Because of the biallelic mutations in the ATP7B gene there
tyrosine hydroxylase (DYT5b), have also been implicated in DRD. The is a loss of function of copper transporter ATPase, which results in an
DYT5b form of DRD is recessively inherited. Patients with DRD have impaired excretion of copper into the bile and subsequent accumula-
low levels of tyrosine hydroxylase and therefore low levels of dopamine tion of copper in the liver and brain. Excessive copper not incorpo-
but F-dopa PET and postmortem studies confirm normal numbers of rated into copper-binding protein, ceruloplasmin, leads to cytotoxic
dopaminergic neurons. DRD responds very well to low doses of LD effects in hepatic and central nervous tissues. Many patients present
(100–300 mg daily). Patients with DRD do not typically develop the in childhood with symptoms and signs of liver disease ranging from
motor fluctuations and dyskinesias associated with chronic LD therapy cirrhosis to fulminant liver failure associated with progressive accu-
in PD. DAs and anticholinergic drugs may also be useful. mulation of copper. Once cirrhosis has developed, extrahepatic copper
deposits begin to form, especially in the brain, eyes, and kidneys. Some illness. Orthotopic liver transplantation is curative but has been used
patients present with hemolytic anemia, hypersplenism, or renal fail- largely in patients with fulminant hepatic failure who have not yet
ure. Nearly half of all patients with WD present with CNS symptoms developed significant neurological signs. The response of neurological
and signs. Neurological signs usually present during adolescence or symptoms to liver transplantation is not completely understood.
early adulthood, but presentations up to age 51 have been reported.
Neurological presentations include parkinsonism, postural and kinetic Neurodegeneration with Brain Iron Accumulation
tremor, ataxia, titubation, chorea, seizures, dysarthria, and dystonia Neurodegeneration with brain iron accumulation (NBIA), formerly
(see Video 96.22). A fixed stare with a smiling expression (risus sar- known as Hallervorden-Spatz disease, includes pantothenate kinase-as-
donicus) and drooling are classic features of the illness but are not seen sociated neurodegeneration (PKAN) and a variety of other genetic
in all cases. Dystonia is a common sign, present in about a third of neurodegenerative disorders associated with accumulation of iron in
patients at presentation. Dystonia may be focal, segmental, or gen- the brain, particularly the basal ganglia (Dusek et al., 2012; Hayflick
eralized. Dementia, if present, is mild, but psychiatric symptoms are et al., 2018). PKAN is an autosomal recessive neurodegenerative dis-
common and may be quite disabling. Mood and personality disorders, order presenting in childhood with the insidious onset of dystonia
behavioral changes, and psychosis are reported. In the presence of neu- and gait disorder. Rigidity, dysarthria, spasticity, dementia, retinitis
rological signs, ophthalmological examination that includes slit-lamp pigmentosa, and optic atrophy develop and progress relentlessly until
examination essentially always demonstrates copper deposition in death in early childhood. T2-weighted MRI brain scans show areas of
the Descemet membrane (Kayser-Fleischer rings; see Chapter 24, Fig. reduced attenuation in the GP surrounding an area of hyperintensity,
24.1). Many patients with WD also have sunflower cataracts (Waln and the eye of the tiger sign (McNeill et al., 2008).
Jankovic, 2018). Autopsy studies show a brown discoloration of the GPi and SNr,
Laboratory studies often show abnormalities in hepatic enzymes, reflecting pathological accumulation of iron. Microscopic changes
aminoaciduria, low uric acid, and demineralization of bone. MRI scan include neuronal loss, gliosis, loss of myelinated fibers, and axo-
usually shows decreased signal intensity (hypodensity) in the striatum nal swellings (spheroids). Families with typical PKAN have muta-
and superior colliculi and increased signal intensity in the midbrain tions in the pantothenate kinase gene (PANK2) on chromosome 20.
tegmentum (except for red nucleus) and in the lateral SNr, giving the Pantothenate kinase is an important regulatory enzyme in coenzyme
appearance of “face of the giant panda” on T2-weighted images. Low A synthesis. Aceruloplasminemia, characterized by anemia, iron over-
serum ceruloplasmin, elevated 24-hour copper excretion, and the load, diabetes, and neurodegeneration caused by homozygous muta-
presence of Kayser-Fleischer rings are useful in making the diagnosis, tion of the ceruloplasmin gene, may be associated with dystonia and
but confirmation by demonstrating elevated hepatic copper is occa- akinetic-rigid syndrome. The four subtypes of NBIA—PKAN, neu-
sionally required in ambiguous cases. roferritinopathy, infantile neuroaxonal dystrophy (INAD), and ace-
ruloplasminemia—can be differentiated by gradient echo (T2*) and
Pathology fast-spin echo (FSE) MRI (McNeill et al., 2008). Another subtype of
Gross inspection of the brain often reveals cerebral atrophy and NBIA, PLA2G6-associated neurodegeneration (PLAN), is manifested
shrunken discolored putamen and GP. Microscopically, WD brains by early childhood-onset axial hypotonia, spasticity, bulbar dysfunc-
show both preferential striatal and generalized neuronal loss. There tion, ataxia, and dystonia. Previously diagnosed as INAD, NBIA2, or
is diffuse gliosis with Alzheimer types I and II astrocytes, as well as Karak syndrome, PLAN may also present as adult-onset LD-responsive
Opalski cells, cells of microglial origin. dystonia-parkinsonism without iron on brain imaging. The PLA2G6
gene on chromosome 22q13.1 encodes a calcium-independent phos-
Pathogenesis pholipase A2 enzyme that catalyzes the hydrolysis of glycerophos-
The mutated ATP7B gene on chromosome 13 regulates a copper-trans- pholipids. Iron chelation with deferiprone and fosmetpantotenate, a
porting adenosine triphosphatase. Although the neurological disorder phosphopantothenic acid prodrug which aims to replenish phospho
clearly relates to harmful effects of intracellular copper, the precise pantothenic acid have been reported to result in regression of symp-
mechanisms of cell dysfunction and death are not well understood. toms after several months of treatment. Another form of NBIA,
mitochondrial membrane protein-associated neurodegeneration
Treatment (MPAN). may present as juvenile-onset LD-responsive parkinsonism
The goal of treatment of WD is to reduce the body burden of cop- as well as progressive dystonia-parkinsonism, optic atrophy, and axo-
per and to prevent its reaccumulation (Aggarwal and Bhatt, 2018). nal motor neuronopathy (Gregory et al., 2019).
Traditionally, acute chelation began with d-penicillamine, but more
recent treatment strategies stress somewhat less toxic therapies such Post-traumatic Dystonia and Peripherally Induced
as trientine and zinc or ammonium tetrathiomolybdate. The effective- Movement Disorders
ness of initial de-coppering is monitored by serially measuring urine Dystonia resulting from central trauma most often presents as hemidys-
copper excretion and plasma copper levels. Although there may be an tonia, but cervical, segmental, or axial dystonia can also be seen as
acute deterioration associated with the mobilization of copper stores, sequelae of brain or spinal cord trauma. Most cases of post-traumatic
most patients improve over time. Long-term therapy must be main- dystonia occurred in children or adolescents who have survived severe
tained, usually with trientine and zinc. d-Penicillamine is associated head injury. Often the dystonia emerges as a traumatic hemiparesis and
with a number of systemic toxicities including dermatopathy, neu- later improves or resolves. There may be a latent period between the
romuscular junction disorders, thrombocytopenia, and Goodpasture trauma and development of the dystonia from 1 day to 6 years, followed
syndrome. Ammonium tetrathiomolybdate (WTX101), which offers by slow progression of dystonic symptoms. Younger patients tend to have
potential advantages over zinc, penicillamine, and trientine in that it longer latencies than those who are older at the time of the head injury.
blocks copper absorption and forms complexes with copper in the Focal lesions in the caudate, putamen, or thalamus contralateral to the
blood, is emerging as the most effective and safest treatment of WD, affected side are usually found on neuroimaging studies. Lesions of the
but this drug is still considered experimental. Asymptomatic siblings mesencephalon or dentatothalamic pathways have also been found. The
should be tested for the disease because timely treatment prevents the prognosis of this form of post-traumatic dystonia is poor, with a low rate
of spontaneous improvement. Most cases are refractory to medical ther- TICS

apy, although some may respond to anticholinergic drugs. Botulinum
toxin injections may be helpful in the treatment of focal or segmental Tourette Syndrome
dystonia. DBS may also provide some benefit, although the magnitude Clinical Features
of response is much less than that seen in patients with primary dystonia. The most common cause of childhood-onset tics is Tourette syndrome
Although still somewhat controversial, there is growing evidence (TS), a complex neurological disorder, manifested not only by motor
that dystonia may also occur after peripheral injury (Jankovic, 2009b). and phonic tics but also by many behavioral comorbidities, particu-
For example, oromandibular dystonia may follow dental surgery or larly attention-deficit and obsessive-compulsive disorders (Robertson
facial and jaw trauma. Indeed edentulous dyskinesia, usually an oro- et al., 2017; Thenganatt and Jankovic, 2016). The diagnosis of TS rests
lingual stereotypy or dystonia occurring after loss of teeth, may be con- entirely on the history and physical examination. There is no diagnos-
sidered a classic example of peripherally induced movement disorder. tic test for TS, but according to the Diagnostic and Statistical Manual
Limb dystonia has also been reported to occur after peripheral trauma, of Mental Disorders, 5th Edition (DSM-5) (American Psychiatric
often in the context of a work- or sports-related injury, especially after Association, 2013) the following are criteria for the diagnosis of TS
immobilization as a result of casting (Pirio Richardson et al., 2017). (refer to Box 24.8 for full DSM-5 diagnostic criteria):
Peripherally induced dystonia tends to manifest with a fixed rather A. Both multiple motor and one or more vocal tics are present at some
than mobile dystonia and may be associated with complex regional time during the illness, although not necessarily concurrently.
pain syndrome, also known as causalgia or reflex sympathetic dystro- B. The tics may wax or wane in frequency but have persisted for more
phy (Jankovic, 2009b; van Rooijen et al., 2011). The response of this
than 1 year since first tic onset.
condition to medical or other therapies is disappointing.
C. Onset is before age 18 years.
Paroxysmal Movement Disorders D. The disturbance is not attributable to the physiological effects of a
Paroxysmal movement disorders consist of intermittent movements substance (e.g., cocaine) or a general medical condition (e.g., HD,
that are now classified both clinically and genetically (Erro and Bhatia, postviral encephalitis).
2019; Waln and Jankovic, 2015) (see also Chapter 24). Prevalence estimates for TS vary from 10 to 700 per 100,000,
Paroxysmal kinesigenic dyskinesia (PKD) is a disorder of childhood depending on the population studied and the study methods used.
onset characterized by attacks of involuntary movements that include Meta-analysis of 21 studies yielded a prevalence of TS at 0.52% (Scharf
prominent dystonia, chorea, and other hyperkinesias. Because the et al., 2015). Although the prevalence of tics is greater among children
attacks are often not witnessed and therefore appropriate phenomeno- in special schools and those with disorders in the autism spectrum, the
logical categorization is not possible, the less specific term, paroxysmal vast majority of patients with TS have normal intelligence.
dyskinesia, is preferred. Boys make up 80% of cases. There is often a Typical early signs of TS are motor tics, including eye blinks, facial
family history. Patients typically recount that episodes are triggered by grimacing, head jerks, shoulder shrugs, and a variety of limb and trunk
rapid movement, often in response to an unexpected stimulus such movements (see Chapter 24). Phonic tics include sniffing, throat
as the telephone ringing. There may be a premonitory sensation in an clearing, grunting, whistling, chirping, and words—including verbal
affected limb, such as limb paresthesia before the onset of the abnormal obscenities (coprolalia) and obscene gestures (copropraxia). Over time,
involuntary movement. The movements may be unilateral or bilateral. the tics wax and wane, and new tics emerge as other tics resolve. Tics
The spells last less than 1 minute and occur up to 100 times daily. There may be simple or complex and can resemble any voluntary or invol-
is a tendency for spells to decrease in adulthood. Diagnosis depends on untary movement. Tics are often preceded by regional or generalized
careful history taking; because the examination usually shows no abnor- premonitory feelings, such as an urge to move, increased tension, a
malities, typical spells may not be elicited in the examination setting, compulsive need to move or make sound, and other sensations. These
and neuroimaging and electrophysiological studies are usually normal. premonitory phenomena differentiate tics from other jerk-like move-
Paroxysmal nonkinesigenic dyskinesia (PNKD) usually begins in ments such as myoclonus and chorea and highlight the sensory aspects
infancy and affects boys more than girls. The spells of PNKD occur of movement disorders (Patel et al., 2014). Symptoms tend to increase
less often but are more prolonged than those in PKD. Their frequency throughout childhood, typically peaking just prior to puberty and
ranges from several episodes a month to several episodes a day, and spontaneously subsiding after the age of 18 years.
their duration is generally between 10 minutes and several hours. They Behavioral changes are very common in TS, especially attention-defi-
are not precipitated by action but may be triggered by ethanol, caf- cit/hyperactivity disorder, obsessive-compulsive disorder, impulse con-
feine, fatigue, or stress. Unlike PKD, PNKD does not show a dramatic trol disorders, and a variety of conduct disorders. In one study involving
response to anticonvulsants. Some patients respond to clonazepam, 1374 patients with TS, 72.1% met the criteria for attention-deficit/hyper-
other benzodiazepines, carbamazepine, gabapentin, anticholinergics, activity disorder, obsessive-compulsive disorder (Hirschtritt et al., 2015).
LD, acetazolamide, and neuroleptics. Mutations in many genes, such as
PRRT2, MR-1, SCL2A1, SLC16A2, GLUT1, KNCMA1, SCN8, ECHS1,
CACNA1A, ADCY5, and ATP1A3 have been identified to cause parox- Pathogenesis
ysmal dyskinesia (Erro and Bhatia, 2019). Although TS is clearly a biological genetic disorder, no causative
Secondary paroxysmal dyskinesia has been thought to be quite rare gene or genes have been identified, although several susceptibility
(Waln and Jankovic, 2015). However, in one series, 26% of paroxys- genes have been found through various genetic techniques, including
mal dyskinesia cases occurred in the context of another nervous system genome-wide association studies (Deng et al., 2012; Yu et al., 2015).
disease. Underlying etiologies include cerebrovascular disease, trauma, Possible reasons for the absence of reported causative genes include
infection, and metabolic encephalopathy. The clinical manifestations lack of specific diagnostic criteria, clinical and genetic heterogeneity,
of secondary paroxysmal dyskinesia are heterogeneous. Some are kine- and bilineal transmission (inherited from both parents).
sigenic and some are not. Some are associated with premonitory sensa- Because there is a robust response to dopamine receptor–block-
tions; others have no warning signs. Treatment of the underlying cause ing medications, altered central neurotransmission has been pro-
may improve the dyskinesia. posed to underlie TS. PET studies, however, have failed to provide
evidence of dopaminergic hyperactivity in TS. One PET study, using Disabling tics are most effectively suppressed by dopamine-receptor
[11C]-flumazenil, and structural MRI provided evidence of decreased blocking drugs such as fluphenazine (Wijemanne et al., 2014), and
binding of GABAa receptors in TS patients bilaterally in the ventral dopamine-depleting drugs such as tetrabenazine, deutetrabenazine,
striatum, GP, thalamus, amygdala, and right insula and increased and valbenazine (Jankovic, 2016b, 2020). But many other drugs have
binding in the bilateral SN, left periaqueductal gray, right posterior been reported to be effective in treating tics, such as cannabinoids, nic-
cingulate cortex, and bilateral cerebellum (Lerner et al., 2012). This otine, ondansetron, and ecopipam, a D1 receptor antagonist (Gilbert
suggests that the GABAergic system plays an important role in TS and and Jankovic, 2014; Jankovic, 2015c). Obsessive-compulsive disor-
provides evidence that TS represents a “disinhibition” disorder. der responds to selective serotonin reuptake inhibitors. Comorbid
Adult-onset tics usually represent recurrences of childhood tics ADHD can be safely treated with clonidine, methylphenidate, and
or may be present in the setting of cocaine use or with exposure to other CNS stimulants. Guanfacine and clonidine have been found use-
other CNS stimulants, dopamine receptor blockers (tardive tics), and ful in patients with TS and impulse-control problems. Patients with
in association with neuroacanthocytosis. Rarely, movement disorders disabling tics (with or without obsessive-compulsive disorder) may
resembling tics may be of psychogenic (functional) origin (Baizabal- benefit from DBS of the thalamus or GPi (Martinez-Ramirez et al.,
Carvallo and Jankovic, 2014). 2018; Viswanathan et al., 2012). The American Academy of Neurology
Practice Guideline made 46 recommendations regarding the assess-
Treatment ment and management of TS, including treatment options such as
Treatment of TS must be individualized and should be reserved for Comprehensive Behavioral Intervention for Tics, antidopaminergic
patients who are experiencing interference from tics in the educational, and other medications, botulinum toxin injections for focal motor and
social, or family spheres (Billnitzer and Jankovic, 2020) (Fig. 96.17). phonic tics, and DBS (Pringsheim et al., 2019).
Treatment algorithm for Tourette syndrome
Motor and phonic tics
Assess for behavioral

comorbidities (ADHD, OCD, etc.) 1. Characterize motor and phonic tics (clonic, dystonic, tonic,
stereotypic, compulsive, blocking; premonitory urges,
variability, suggestibility, suppressibility, persist during sleep)
2. Explore behavioral comorbidities (ADHD, OCD, etc.)
3. Explain neurobiological, neurophysiological, genetic basis
Educate the patient, family, 4. Discuss waxing and waning course, prognosis
teachers, classmates, etc. 5. Discuss treatment options and strategies
(behavioral vs. pharmacological/surgical)
Are symptoms troublesome? Yes Prioritize and customize

Treat tics before ADHD
No Tics Comorbidities
CNS stimulants,
Periodic follow-up 1. Behavioral treatment (e.g. CBIT, HRT) SSRI,SNRI
2. Pharmacotherapy
i. Alpha2A agonists (guanfacine)
ii. Dopamine depleters/blockers
iii. Topiramate Experimental therapeutics
iv. Aripiprazole, fluphenazine, risperidone
Ecopipam – D1 antagonist
3. BoNT
AZD5312 – H3 antagonist
4. DBS in medically refractory cases
SNC-102 – GABA-glutamate
Cannabis products – dronabinol,
nabiximols, ABX-1431, etc.
Serine hydrolase, D-cycloserine,
amantadine, pimavanserin
Fig. 96.17 Treatment Algorithm for Tourette Syndrome. ADHD. attention deficit hyperactivity disorder;
CBIT, comprehensive behavioral intervention for tics; CNS, Central nervous system; DBS, deep brain stim-
ulation; GABA, γ-aminobutyric acid; HRT, habit reversal training; OCD, obsessive compulsive disorder; SNc,
substantia nigra pars compacta; SNRI, selective noradrenergic reuptake inhibitor; SSRI, selective serotonin
reuptake inhibitor.
MYOCLONUS and recessive inheritance have been described. Two forms of startle
have been described. The major form of the illness is characterized by
Essential Myoclonus continuous stiffness beginning in infancy and exaggerated startle cul-
EM is diagnosed when myoclonus is present as an isolated neurological minating in falls. Some patients have seizures and low intelligence. In
sign or is accompanied only by tremor or dystonia. EM can be spo- the minor form, there is only excessive startle with hypnic myoclonic
radic or inherited. Dominantly inherited EM usually presents before jerks. The hereditary form is typically caused by mutations in the gene
age 20. EM is usually multifocal with upper body predominance. coding for the α1 subunit of the inhibitory glycine receptor (GLRA1)
Although spontaneous jerks are seen, they are exacerbated by action. on chromosome 5. The disorder is also caused by mutations in the
Alcohol may dramatically suppress the myoclonus. Sporadic forms of β subunit of the inhibitory glycine receptor (GLRB), by mutations
this illness are also described. Myoclonus-dystonia and EM are allelic in the gephyrin gene (GPHN), and by mutations in SLC6A5, which
disorders linked to the ε-sarcoglycan gene on chromosome 7. Besides encodes the presynaptic glycine transporter 2. The SLC6A5 mutations
DYT-SGCE (DYT11), other genetic forms of myoclonus-dystonia are predominately associated with recessive hyperekplexia, symptoms
include GCH1 (DYT5a), DYT/PARK-TH (DYT5b), DYT-KCTD17 of which include life-threatening neonatal apnea and breath-holding
(DYT26) (see Chapter 24). spells.
Startle in patients with hyperekplexia differs from normal startle
Posthypoxic Myoclonus (Lance-Adams Syndrome) because it has a lower threshold, is more generalized, and fails to nor-
The first cases of posthypoxic myoclonus (PHM) were described in mally habituate with repeated stimuli. Electrophysiological studies in
1963 by Lance and Adams (Jankovic, 2015c). PHM is a generalized well-characterized cases suggest the origin of the pathological startle in
myoclonus that occurs with recovery from the acute effects of severe the lower brainstem, possibly the medial bulbopontine reticular forma-
brain hypoxia. The most common etiologies of the hypoxia are respi- tion. The disorder is genetically heterogeneous, with most mutations
ratory arrest (especially asthmatic), anesthetic and surgical accidents, occurring in patients with the major form of the illness. Symptomatic
cardiac disease, and drug overdose. The typical patient is in coma hyperekplexia has been reported to result from infarct, hemorrhage, or
for several days to 2 weeks. Myoclonus and seizures may be present encephalitis. Clonazepam is the treatment of choice, although it may
during the comatose phase. After recovery from coma, myoclonic jerks be only partially effective.
become apparent, especially with voluntary movements, which trigger
volleys of high-amplitude jerks and intermittent pauses in the activated Palatal Myoclonus
body part. The myoclonic movements typically flow to body parts not Palatal myoclonus, sometimes also referred to as palatal tremor, is
directly involved in the voluntary movements. The amplitude of the characterized by rhythmic movements of the soft palate. Since the
myoclonus is directly proportional to the delicacy of the attempted movement consists of repetitive rather than oscillatory contractions of
task, producing extreme disability in the performance of activities of agonists only, it is also classified as segmental myoclonus rather than
daily living. Gait is disturbed not only by positive myoclonic jerks but tremor. There are two types of PM, depending on the presence or
also by negative myoclonus, resulting in falls. Other neurological signs absence of a structural lesion of the brainstem or cerebellum. Patients
are always present and include seizures, dysarthria, dysmetria, ataxia, without an underlying structural lesion are considered to have essen-
and cognitive impairment. tial PM, and those with underlying structural lesions are considered to
CSF studies have shown low levels of 5-hydroxyindoleacetic acid have symptomatic PM. Essential and symptomatic PM can be distin-
(5-HIAA), the main metabolite of serotonin. A role for GABA in this guished by clinical features and neuroimaging.
disorder is suggested by the production of myoclonus by injecting Essential PM is very rare. It affects men and women equally.
GABA antagonists into the rat thalamus. Autopsies in patients with Patients with essential PM complain of audible ear clicks. The move-
PHM show changes related to hypoxic brain damage but do not reveal ments usually disappear during sleep. In essential PM, the palatal
any specific structural changes in brainstem raphe nuclei. Myoclonus movements are produced by rhythmic movement of the tensor veli
in posthypoxic rats responds to serotonin agonists that stimulate par- palatini muscle. Symptomatic PM is more common than essential PM
ticular subtypes of serotonin receptors (5-HT1B, 5-HT2A/2B, and pos- and affects men more often than women. Symptomatic or secondary
sibly 5-HT1D). Other studies in rat models have suggested that basal PM is not associated with ear clicks because the levator veli palatini
serotonin levels are normal, but there is an abnormality in release of rather than the tensor veli palatini is involved. Simultaneous tremor of
serotonin by potassium chloride and NMDA. There is some tendency other regional structures with cranial nerve innervation may be seen.
for improvement in myoclonus over time, but most patients have sig- Some patients have oscillopsia from pendular nystagmus. Laryngeal
nificant disability related to the movements. involvement may interrupt speech or cause rhythmic involuntary
GABAergic drugs such as valproic acid and clonazepam are usu- vocalizations. Rhythmic limb tremor may be seen. In patients with
ally used in the treatment of PHM. Each is associated with improve- symptomatic PM, hypertrophy of the superior olive is demonstrable
ment in approximately 50% of treated patients. Levetiracetam has on MRI brain scans. Symptomatic PM may be associated with slow
been reported to be effective in some patients, but other GABAergic rhythmic movement in the face and limbs, called myorhythmia, and
drugs such as vigabatrin and gabapentin are usually not helpful is often associated with structural lesions found in the brainstem or
(Jankovic, 2015c). Piracetam, available in Europe and Canada but not cerebellum within the Guillain-Mollaret triangle, which connects the
in the United States, may also improve myoclonus by an imperfectly dentate nucleus with the contralateral red nucleus and inferior olive
understood mechanism that does not involve serotonin or GABA. L-5 (Baizabal-Carvallo et al., 2015). Many underlying etiologies have been
hydroxytryptophan (L-5HTP) administered with carbidopa may be reported: neurodegenerative, infectious, inflammatory, demyelinating,
useful, but this investigational agent is no longer available, and gastro- traumatic, ischemic, and even psychogenic. Characteristic pathological
intestinal side effects limit its tolerability. changes include enlargement of olivary neurons with vacuolation of
the cytoplasm. Astrocytic proliferation with aggregates of argyrophilic
Startle and Hyperekplexia fibers may also be seen.
Hyperekplexia is a startle syndrome characterized by muscle jerks in The pathophysiology of PM is incompletely understood, but it is
response to unexpected stimuli. Families with autosomal dominant believed that in symptomatic PM, damage to the dentato-olivary tract
Treatment requires withdrawal of the causative drug and symptomatic

BOX 96.5 Drugs Associated with
treatment, if required, with clonazepam or levetiracetam.
Myoclonus There are many other causes of myoclonus, but autoimmune disor-
Anesthetics: etomidate, chloralose ders, such as opsoclonus-myoclonus, NMDAR encephalitis, progres-
Antibiotics, anthelmintics, antiviral drugs: penicillin, imipenem, quinolones, sive encephalomyelitis with rigidity and myoclonus, and Hashimoto
piperazine, acyclovir encephalopathy should be considered, particularly when the onset is
Anticonvulsants: phenytoin, phenobarbital, primidone, valproic acid, carba- subacute (Baizabal-Carvallo and Jankovic, 2018).
mazepine, gabapentin, lamotrigine, vigabatrin
Amantadine TARDIVE DYSKINESIA
Antihistamines
Sodium bicarbonate (baking soda) Classic Tardive Stereotypy
Benzodiazepine withdrawal TD is a movement disorder that develops in the context of chronic
Psychotropic medications: tricyclic antidepressants, selective serotonin dopamine receptor blockade, usually in patients who are chronically
reuptake inhibitors, monoamine oxidase inhibitors, lithium, buspirone, neu- treated with antipsychotics or antiemetics (Savitt and Jankovic, 2018).
roleptics With the decline in the use of typical antipsychotics and metoclopra-
Antineoplastic drugs: chlorambucil, prednimustine, ifosfamide mide and introduction of atypical antipsychotics there has been a slight
Narcotics: morphine, meperidine, hydromorphone, fentanyl, sufentanil, dia- decline in the incidence of TD. TD usually requires a minimum of 6
morphine weeks or more of dopamine receptor blockade, but onset as soon as
after the first dose has been reported. Reported risk factors include old
age, female gender, affective disorder, edentulousness, diabetes melli-
tus, and prior CNS injury. Although orofacial stereotypy is the most
induces synchronization of cells in the inferior olive. The firing rhythm common hyperkinetic movement disorder associated with TD, other
appears to be determined by membrane properties of the olivary neu- hyperkinetic disorders such as chorea, akathisia, dystonia, tics, and
rons. This rhythm is then propagated through the inferior cerebellar myoclonus may be seen. Tardive parkinsonism has also been reported,
peduncle to the contralateral cerebellar hemisphere, where it interferes but some patients with parkinsonism persisting years after withdrawal
with oculomotor, cerebelloreticular, and cerebellospinal systems. of the offending neuroleptic have been found to have pathological evi-
Treatment of PM is difficult. Because of the rarity of the condi- dence of PD. The classic appearance of TD is repetitive stereotypic (e.g.,
tion, there have been no randomized controlled clinical trials of ther- chewing) movements of the mouth, tongue, and lower face (oral-buc-
apeutic agents. Phenytoin, carbamazepine, clonazepam, diazepam, colingual dyskinesias) (Savitt and Jankovic, 2018). In contrast to HD,
trihexyphenidyl, and baclofen are considered first-line agents in the the upper face tends to be spared (see Chapter 24) (Jankovic and Roos,
treatment of PM. Second-line drugs include 5-HTP and presynaptic 2014). Choreic movements may also affect the trunk and pelvis, caus-
antidopaminergic drugs such as tetrabenazine. Sumatriptan has been ing pelvic thrusting movement and respiratory dyskinesia (Mehanna
reported to aid a single patient. Injections of botulinum toxin into the and Jankovic, 2010). Limb chorea and restlessness (akathisia) may also
tensor veli palatini muscle have been reported beneficial in essential be seen.
PM. The pathophysiology of TD is incompletely understood, but the
drugs that cause this syndrome appear to exhibit potent binding to
Spinal Myoclonus postsynaptic D2 receptors (Savitt and Jankovic, 2018). Denervation
Spinal myoclonus is a syndrome of involuntary rhythmic or semirhyth- supersensitivity of the postsynaptic dopamine receptor has been pro-
mic myoclonic jerks in a muscle or group of muscles. The myoclonic posed as a possible mechanism. There are other theories, including oxi-
jerks may be unilateral or bilateral. In some cases, they are stimulus dative stress and insufficiency of GABA. Evidence is accumulating that
sensitive. The jerks relate to spontaneous motoneuron discharge in a suggests that neuroleptics are toxic to the striatum, and apoptotic cell
limited area, often a single segment of the spinal cord. Propriospinal death has been described in animals chronically exposed to neurolep-
myoclonus is a more widespread disorder in which myoclonic jerks tics. Genetic susceptibility factors that might be involved in increased
are propagated up and down the spinal cord from a central generator. risk of TD include polymorphisms of the dopamine D3 receptor gene
Most patients with propriospinal myoclonus have had minor spinal and the 5-HT2C serotonin receptor gene.
cord trauma with normal MRI findings, but the disorder has been The most important intervention in TD is to prevent its occur-
reported in severe spinal cord injury, multiple sclerosis, human immu- rence. In prospective studies, high-risk individuals treated with
nodeficiency virus, Lyme infection, syringomyelia, spinal cord tumors, atypical rather than typical antipsychotics appear to have a reduced
and spinal cord infarction. Propriospinal myoclonus has been reported risk of TD compared with historical controls. Because patients may
to affect particularly the transition from wake to sleep. An increasing not complain about early or mild movements, the clinician must
number of cases of propriospinal myoclonus have been documented to carefully examine neuroleptic-treated patients for early signs of
be of psychogenic origin. TD. Neuroleptics should be discontinued if possible. Mild TD may
improve with benzodiazepines or baclofen. Deutetrabenazine and
Toxin- and Drug-Induced Myoclonus valbenazine, dopamine-depleting drugs (VMAT2 inhibitors), have
A number of drugs and environmental agents with CNS toxicity been approved by the US FDA for the treatment of TD (Bashir and
have been shown to cause myoclonus (Box 96.5). Criteria for drug- Jankovic, 2020; Savitt and Jankovic, 2018).
or toxin-induced myoclonus include verified exposure, temporal
association, and exclusion of genetic or other causes. The myoclo- Tardive Dystonia
nus produced by drugs and toxins is often multifocal or generalized, Tardive dystonia should be differentiated from transient acute dys-
stimulus- and action- or stimulus-sensitive, and accompanied by tonic reaction and from the more typical TD. In contrast to TD,
other suggestive nervous system signs, particularly by encephalopathic which tends to affect more elderly women, young men are more
signs. Metrizamide and diclofenac may cause segmental myoclonus. likely to develop tardive dystonia. All of the typical antipsychotics,
as well as antiemetics with dopamine receptor-blocking proper- et al., 2014). Also, in contrast to leg stereotypy syndrome, RLS often
ties, have been associated with the development of tardive dystonia requires treatment with medications such as gabapentin, DAs, or even
(Savitt and Jankovic, 2018). Symptoms begin insidiously after days opiates (Wijemanne and Jankovic, 2015).
to decades of neuroleptic therapy. Although rare cases have been
reported after a short duration of therapy, the median duration of MISCELLANEOUS MOVEMENT DISORDERS
exposure to neuroleptics at the time of onset is 5.1 years. Tardive
dystonia usually presents as focal or segmental dystonia (e.g., bleph- Hemifacial Spasm
arospasm) or oromandibular or cervical dystonia, but the most The prevalence of HFS is 14.5 per 100,000 in women and 7.4 per
typical presentation is a truncal dystonia with opisthotonic postur- 100,000 in men, but the prevalence seems to be much higher in Asian
ing in a young man associated with pronating movements of arms populations (Wu et al., 2010; Yaltho and Jankovic, 2011). HFS is char-
and extension of the elbows. There is a relationship between age at acterized by twitching of the muscles supplied by the facial nerve. The
onset and distribution of the dystonic movements, with trunk and disorder usually begins in adulthood, with an average age at onset of
leg symptoms in younger persons and face, jaw, and neck involve- 45–52 years. Although there are some familial cases, most are spo-
ment in older persons. In comparison with primary focal or seg- radic. In typical cases, twitching first affects the periorbital muscles
mental dystonia, there is more retrocollis and anterocollis. Dystonic but spreads to other ipsilateral facial muscles over a period of months
symptoms may improve over a period of 5 years if the offending to years. The spasms are synchronous in all affected muscles. In
neuroleptic agent is withdrawn, although recovery is less common approximately 5% of patients, the opposite side of the face becomes
than in patients with choreic or stereotypic TD. Young patients with affected, but when bilateral, the spasms are never synchronous on the
a shorter duration of neuroleptic exposure have the greatest likeli- two sides. The spasms of HFS may be clonic or tonic, and often a
hood of remission. paroxysm of clonic movements culminates in a sustained tonic con-
As with TD, the primary treatment of tardive dystonia is preven- traction. Although the spasms occur spontaneously, they may be pre-
tion, but once it has developed, every attempt should be made to rid the cipitated or exacerbated by facial movements or by anxiety, stress, or
patient of the offending neuroleptic. Neuroleptic-dependent patients fatigue. The affected muscles may be weaker than their contralateral
should be managed with atypical antipsychotics if possible. VMAT2 counterparts. Some patients have evidence of regional cranial neurop-
inhibitors, anticholinergics, benzodiazepines, and baclofen have all athy, such as altered hearing or trigeminal function. Detailed neurora-
been reported to help patients with tardive dystonia. Botulinum toxin diological work-ups using routine and specialized MRI techniques
injections can be particularly helpful in patients with disabling focal may demonstrate compressing vascular structures in the facial nerve
or segmental dystonia such as blepharospasm or cervical and truncal root entry zone in most patients with HFS. More advanced scanning
dystonic movements (Jankovic, 2018b). Oral and intrathecal baclofen techniques such as high-resolution T1- and T2-weighted spin echo
infusions may also be helpful. or gradient echo imaging with gadolinium provide maximum visual-
ization of the root entry zone. Yet, serious underlying causes are rare,
and many clinicians do not routinely image patients with typical HFS
STEREOTYPIES unless the clinical picture is atypical or the patient is being considered
Stereotypies are involuntary or unvoluntary (in response to or induced for surgery.
by inner sensory stimulus or unwanted feeling), coordinated, patterned, HFS is an example of peripherallyinduced movement disorder,
repetitive, rhythmic, seemingly purposeless movements or utterances. thought to result from compression of the facial nerve at the root exit
Stereotypies can be seen in a variety of conditions, such as TD, but when zone, usually by vascular structures (Yaltho and Jankovic, 2011). The
they occur in children they are often seen in the setting of autism or facial nerve root entry zone generally shows axonal demyelination
intellectual impairment (Oakley et al., 2015). In this situation typical or nerve degeneration. Vessels commonly implicated are the poste-
motor stereotypies include body rocking, head nodding, head banging, rior inferior cerebellar artery, the anterior inferior cerebellar artery,
hand waving, fluttering of fingers in front of the face, repetitive and and the vertebral artery. Tumors or other space-occupying lesions
sequential finger movements, lip smacking, pacing, skin picking, and are found in approximately 5% of patients. Epidermoid tumors,
various self-injurious behaviors such as biting, scratching, and hitting. neuroma, meningioma, astrocytoma, and parotid tumors are most
Although TD is one the most common causes of adult-onset common.
stereotypies, there are many other causes of coordinated, repetitive There are two main theories of pathogenesis. The first proposes that
movements. One of the most common causes of repetitive move- in the area of compression-induced demyelination, an ephapse, or false
ments is the “leg stereotypy syndrome” (Lotia et al., 2018), This is synapse, forms. Mechanical irritation or other regional changes induce
defined as a repetitive, continuous movement present almost exclu- ectopic activity in the region, which is then conducted antidromically
sively in the legs while the patient is seated. The characteristic features within the nerve fiber. The main competing theory proposes that the
of leg stereotypy disorder include continuous or intermittent flexion– aberrant signals arise from the facial nerve nucleus, which is reorga-
extension, abduction–adduction, movement of proximal legs when nized as a result of deranged afferent information.
seated with feet resting on the floor or flexion–extension of the knees Traditionally, patients with HFS were treated with anticonvul-
or ankles when legs are crossed in a sitting position. When standing sants, baclofen, anticholinergics, and clonazepam, but the introduc-
there is often swaying movement of the trunk and shifting of weights tion of botulinum toxin injections revolutionized treatment of the
from one to the other. Leg stereotypy syndrome must be differenti- disorder. Botulinum toxin injected into the periorbital subcutaneous
ated from other sensorymotor disorders, such as RLS. Although both tissue produces clinically meaningful improvement in almost 100%
conditions are familial the latter is characterized by diurnal pattern, of patients, and side effects are mild and transient. Botulinum toxin
is worse at night, and is associated with unpleasant sensations such injections must be administered every 3–6 months. Follow-up of
as “crawling,” “tingling,” “creeping,” “pulling,” “electric,” “itch- chronically treated patients shows the injections retain efficacy for at
ing,” “burning,” “prickly,” and other sensory phenomenon (Patel least 15 years.
A number of surgical techniques have been used in HFS. These Untreated, SPS progresses to extreme disability. Diazepam at
include removal of the orbicularis oris or other affected muscles, selec- doses of 20–400 mg/day is the most effective symptomatic treatment.
tive destruction of parts of the facial nerve, decompression of the facial Clonazepam, baclofen, valproic acid, clonidine, vigabatrin, and tiaga-
canal, and radiofrequency thermocoagulation of the nerve. Intracranial bine have also been reported to be effective. Intrathecal baclofen and
microvascular decompression of the nerve is successful in relieving local intramuscular injections of botulinum toxin have been helpful
spasms in up to 90% of patients, but complications such as facial nerve in some cases. Plasmapheresis, intravenous immunoglobulin (IVIG),
injury and hearing loss occur in as many as 15% of patients. and immunosuppression have been reported to have variable effects
on the condition. In a recent placebo-controlled crossover study of
Painful Legs–Moving Toes Syndrome IVIG, active treatment was associated with clinical improvement and
PLMTS is a very rare condition characterized by pain in the legs and decreases in anti-GAD antibody titers. Newer agents such as rituximab
spontaneous movements of the foot and toes. The pain usually pre- are currently under study for the treatment of SPS.
cedes the onset of involuntary movements and varies in constancy
and intensity. In some cases, the condition is painless. The toe and Functional (Psychogenic) Movement Disorders
foot movements are complex, combining flexion, extension, abduc- Functional movement disorders (FMDs), previously referred to as
tion, and adduction in various sequences at frequencies of 1–2 Hz. “psychogenic movement disorders,” represent about 5% of patients in
The movements may be precipitated or aborted by moving or repo- a movement disorders clinic, but the relative frequency is increasing as
sitioning the foot or toes, but they cannot be simulated voluntarily. patients with atypical movement disorders, many of whom have FMD,
Similar movements have been described in the arms, with or with- are referred to specialized centers (see Chapter 113). In many cases,
out accompanying pain. In most cases, there is an underlying cause, the symptoms are abrupt in onset and associated with a specific trig-
although there is little consistency from case to case. PLMTS has been ger. Clinically, distractibility is common, as are stimulus sensitivity and
associated with injuries to the spinal cord and cauda equina, spinal entrainment with voluntary activities. Other functional (psychogenic)
nerve roots, peripheral neuropathy, and soft-tissue or bony limb symptoms are often present. Approximately 25% of patients have a
trauma. EMG studies show that the movements are produced by long comorbid organic movement disorder. About half have an Axis 1 psy-
bursts of normal motor unit firing with normal recruitment patterns. chiatric disorder, most often depression. The predominant movement
PLMTS doubtless has a central origin. Central reorganization con- disorders diagnosed as psychogenic (functional) include tremor, often
sequent to altered afferent information from the periphery has been manifested by irregular, distractible shaking of variable amplitude and
proposed, but a precise location and mechanism of these changes frequency, dystonia, typically manifested by fixed abnormal posture,
remain unknown. myoclonus, parkinsonism (Jankovic, 2011), tics (Baizabal-Carvallo
Treatment of PLMTS is very difficult. Many medications have been and Jankovic, 2014), and a variety of other movement disorders (Stone
tried—baclofen, benzodiazepines, anticonvulsants, and antidepres- et al., 2016; Thenganatt and Jankovic, 2019).
sants—but none has emerged as effective. Lumbar sympathetic block The pathophysiology of FMDs is poorly understood (Baizabal-
or epidural stimulation may give transient relief. Spontaneous resolu- Carvallo et al., 2019). Although stressful events on a background of
tion is very unusual. depression and anxiety are common precipitants of FMDs, this link is
not always possible to establish in all patients. While usually attributed
Stiff Person Syndrome to some psychiatric causes, several neurobiological abnormalities dif-
SPS is a rare autoimmune movement disorder, characterized by pro- ferentiate patients with FMD from normal controls. These include
gressive rigidity of axial and proximal appendicular muscles, exagger- evidence of strengthened connectivity between the limbic and motor
ated lumbar lordosis, and a stiff gait (Baizabal-Carvallo and Jankovic, networks, increased activation of areas implicated in self-awareness,
2012, 2018). Intense spasms are superimposed on a background of self-monitoring, and active motor inhibition such as the cingulate
continuous muscle contraction. Spasms and stiffness improve with and insular cortex, coupled with decreased activation of the SMA and
sleep and are eliminated by general anesthesia and neuromuscular pre-SMA. Furthermore, the sense of agency defined as the feeling of
blocking agents. Clinical criteria for diagnosis include insidious devel- controlling external events through one’s own action also seems to be
opment of limb and axial (thoracolumbar and abdominal) stiffness, impaired in individuals with FMDs.
clinical and electrophysiological confirmation of co-contraction of Some studies have correlated a recall of real-life events with abnor-
agonist and antagonist muscles, episodic spasms superimposed on malities on functional imaging studies suggesting that the chief mech-
chronic stiffness, and no other underlying illness that would explain anism of functional (psychogenic) disorders involves repression of
the symptoms. Some authors divide SPS into three syndromes: stiff memories and conversion to somatic symptoms (Aybek et al., 2014).
trunk syndrome, stiff limb syndrome, and rapidly progressive enceph- Treatment of patients with functional (psychogenic movement
alomyelitis with rigidity. EMG examination shows continuous firing of disorders) is very challenging and requires tactful disclosure of the
normal motor units. diagnosis, followed by insight-oriented and physical therapy, supple-
SPS is associated with autoimmune disorders such as type 1 dia- mented by treatment of underlying anxiety, depression, and other psy-
betes, thyroiditis, myasthenia gravis, pernicious anemia, and vitiligo. chological and psychiatric issues (Thenganatt and Jankovic, 2019; see
High titers of antibodies to the 65-kD fraction of GAD and to other Chapter 113).
antigens are present. It is thought that SPS results from dysfunc-
tion of descending suprasegmental pathways possibly secondary to The complete reference list is available online at https://expertconsult.
immune-mediated inhibition of GABA synthesis. Paraneoplastic SPS inkling.com/.
has been reported with breast and other cancers.
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Video 96.1 Parkinson Disease; Patient with Young-Onset Parkinson Dis- Video 96.12 Multiple System Atrophy; Patient Describes Symptoms of
ease and Gait Difficulty Due to Freezing (Motor Blocks) Dysautonomia, Demonstrates Flexion of the Neck and Apraxia of Eyelid
Video 96.2 Patient with Parkinson Disease and Anterocollis and Camp- Opening, Typical of Multiple System Atrophy
tocormia Video 96.13 Corticobasal Degeneration; Patient Describes Apraxia of
Video 96.3 Patient with Parkinsonism and Striatal Hand Deformities Left Leg, Demonstrates Ideomotor Apraxia in Left More than Right
Video 96.4 Parkinson Disease; Patient with Young-Onset Parkinson Dis- Hand and Marked Left Leg and Foot Apraxia
ease and Gait Difficulty Due to Freezing (Motor Blocks) Video 96.14 Corticobasal Degeneration; Patient Describes Alien Hand
Video 96.5 Parkinson Disease; Patient Describes Levodopa-Induced Phenomenon in the Right Arm, Demonstrates Marked Apraxia in the
Visual Hallucinations (e.g., Seeing and Picking Worms) Right More than Left Hand, Spontaneous and Evoked Myoclonus in the
Video 96.6 Parkinson Disease; Levodopa-Induced Dyskinesia Right Hand, Markedly Impaired Graphesthesia
Video 96.7 Progressive Supranuclear Palsy; Typical Worried, Frowning Video 96.15 Corticobasal Degeneration; Evoked Hand and Arm Myoc-
Facial Expression (Procerus Sign), Apraxia of Eyelid Opening, Although lonus
Vertical (Downward) Gaze is Preserved, Vertical Optokinetic Nystag- Video 96.16 Corticobasal Degeneration; Patient Describes Right Alien
mus is Absent, When Walking Patient Pivots on Turning (in Contrast to Hand Phenomenon, Right Hand Myoclonus, Marked Ideomotor Apraxia
Patients with Parkinson Disease Who Turn En Bloc) in the Right More than Left Hand
Video 96.8 Progressive Supranuclear Palsy; Marked Vertical Ophthal- Video 96.17 Vascular Parkinsonism; Broad-Based Gait, Freezing on Turn-
moparesis, Perseveration of Gaze to Left even though the Body Faces ing (Lower Body Parkinsonism) Associated with Binswanger’s Disease
Forward Video 96.18 Vascular Parkinsonism; Gait Initiation Failure (Pure Freezing)
Video 96.9 Progressive Supranuclear Palsy; Typical Facial Expression Video 96.19 Essential Tremor; Marked Improvement in Right Hand
with Deep Facial Folds, Square Wave Jerks on Primary Gaze, Slow Sac- Tremor with Contralateral Deep Brain Stimulation of the VIM Thalamus
cades, Inappropriate Laughter (Pseudobulbar Palsy), Right Arm Levita- Video 96.20 Cerebellar Outflow Tremor Because of Multiple Sclerosis;
tion Markedly Improved with Deep Brain Stimulation of the ventral interme-
Video 96.10 Progressive Supranuclear Palsy; Deep Facial Folds, Vertical diate nucleus (VIM) Thalamus
Ophthalmoplegia, Marked Postural Instability, Slumps into a Chair Video 96.21 Orthostatic Tremor; Patient Describes Problems with
Video 96.11 Progressive Supranuclear Palsy; Deep Facial Folds, Apraxia Standing, Demonstrates High Frequency (16 Hz) Tremor in Legs Pres-
of Eyelid Opening, in Addition to Vertical Ophthalmopareses, Patient ent Only Upon Standing, Leg Tremor Disappears When Leaning Against
Demonstrates Evidence of Internuclear Ophthalmoplegia, the Presence Table
of Right Arm Tremor (Atypical for Progressive Supranuclear Palsy) Sug- Video 96.22 Wilson Disease; Slow Tremor (Myorhythmia) in the Left
gests the Co-Existence of Parkinson Disease Hand
97
Disorders of Upper and Lower Motor Neurons
Conor Fearon, Brian Murray, Hiroshi Mitsumoto
OUTLINE
Disorders of Upper Motor Neurons, 1535 Benign Focal Amyotrophy, 1548
Neuroanatomy of Upper Motor Neurons, 1535 Spinal Muscular Atrophy, 1549
Signs and Symptoms of Upper Motor Neuron Involvement, 1536 Kennedy Disease (X-Linked Recessive Bulbospinal Neuronopa-
Laboratory Evidence of Upper Motor Neuron I nvolvement, 1537 thy), 1553
Primary Lateral Sclerosis, 1537 Progressive Muscular Atrophy, 1554
Hereditary Spastic Paraplegia, 1538 Subacute Motor Neuronopathy in Lymphoproliferative
Human T-Lymphotropic Virus Type 1-Associated Myelopathy, Disorders, 1555
or Tropical Spastic Paraparesis, 1543 Postirradiation Lower Motor Neuron Syndrome, 1556
Human T-Lymphotropic Virus Type 2-Associated Disorders of Both Upper and Lower Motor Neurons, 1556
Myelopathy, 1543 Amyotrophic Lateral Sclerosis, 1556
Adrenomyeloneuropathy, 1543 Familial Amyotrophic Lateral Sclerosis, 1564
Plant Excitotoxins, 1544 Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex
Disorders of Lower Motor Neurons, 1544 (Western Pacific Amyotrophic Lateral Sclerosis), 1566
Neuroanatomy of Lower Motor Neurons, 1544 Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease), 1566
Clinical Features of Lower Motor Neuron Involvement, 1544 Adult Hexosaminidase-A Deficiency, 1566
Laboratory Evidence of Lower Motor Neuron Involvement, 1545 Allgrove Syndrome (Four-A Syndrome), 1567
Acute Poliomyelitis and Other Viral Acute Flaccid P
aralyses, 1545 Adult Polyglucosan Body Disease, 1567
Postpolio Syndrome/Progressive Postpoliomyelitis Muscular Paraneoplastic Motor Neuron Disease, 1567
Atrophy, 1547 Human Immunodeficiency Virus Type 1-Associated Motor
Multifocal Motor Neuropathy, 1548 Neuron Disorder, 1567

It is important for the practicing clinician to make the distinction innervate skeletal muscles. The UMNs are rostral to the LMNs and
between the term motor neuron disease (MND) and motor neuron exert direct or indirect supranuclear control over the LMNs (Box 97.1).
diseases (MNDs). The intention of the first term, coined by Brain in
1969, is to refer to a specific disorder of both upper and lower motor Motor Cortex
neurons, otherwise known as amyotrophic lateral sclerosis (ALS). The In the cerebral cortex, UMNs are located in the primary motor cortex
second term refers to the broader family of disorders that may affect (Brodmann area 4) and the premotor areas (Brodmann area 6), which
the upper and/or lower motor neuron system as well as nonmotor are subdivided into the supplementary motor area (sometimes called
systems. Within this heterogeneous family are included familial and the secondary motor cortex) and the premotor cortex, respectively. Betz
sporadic disorders, inflammatory and immune disorders, and oth- cells (giant pyramidal neurons) are a distinct group of large motor
ers of undetermined cause. Many are distinct entities, but some (e.g., neurons in layer 5 of the primary motor cortex and represent only a
primary lateral sclerosis [PLS], progressive muscular atrophy [PMA]) small portion of all primary motor neurons with axons in the cortico-
may be variations of a single multisystem disorder that predominantly spinal tracts. Individual motor neurons in the primary motor cortex
involves motor neurons. This chapter reviews the causes, diagnosis, initiate and control the contraction of small groups of skeletal muscles
and treatment of the motor neuron diseases according to whether the subserving individual movements. The entire motor area of the cere-
disorder affects upper motor neurons (UMNs), lower motor neurons bral cortex controls the highest levels of voluntary muscle movement,
(LMNs), or both UMNs and LMNs. including motor planning and programming of muscle movement.
Corticospinal and corticobulbar tracts. Axons from the motor
DISORDERS OF UPPER MOTOR NEURONS areas form the corticospinal and corticobulbar tracts. Axons arising
from neurons in the primary motor cortex constitute only one-third
Neuroanatomy of Upper Motor Neurons of all the corticospinal and corticobulbar tracts. Among these, Betz cell
The UMN is a motor neuron, the cell body of which lies within the axons make up 3%–5% of the tract, and the remaining fibers from the
motor cortex of the cerebrum, and the axon of which forms the cor- primary motor cortex arise from other neurons in layer 5 of the primary
ticobulbar and corticospinal tracts. The LMNs, lying in the brain- motor cortex. Another one-third of the axons in these tracts derive
stem motor nuclei and the anterior horns of the spinal cord, directly from Brodmann area 6, which includes the supplementary motor and
1535
the lateral premotor cortex. The remaining third derives from the (at least in animal studies). Furthermore, the generation of signs of
somatic sensory cortex (areas 1, 2, and 3) and the adjacent temporal pseudobulbar hyperemotionality (pseudobulbar affect, emotional
lobe region. The corticobulbar tract projects bilaterally to the motor incontinence) in ALS is closely related to an abnormal limbic
neurons of cranial nerves V, VII, IX, X, and XII. Most corticospinal motor control, particularly in the periaqueductal gray and nucleus
fibers (75%–90%) decussate in the lower medulla (pyramidal retroambiguus. The latter nuclei project to the somatic motor neurons
decussation) and form the lateral corticospinal tract in the spinal cord that innervate pharyngeal, soft palatal, intercostal, diaphragmatic,
(the pyramidal tracts). The remaining fibers descend in the ipsilateral abdominal, and probably laryngeal muscles. Pseudobulbar
ventral corticospinal tract. The lateral corticospinal tract projects to hyperemotionality symptoms may appear when UMN control over
ipsilateral spinal motor neurons and their interneurons that control these motor nuclei is impaired, and thus limbic motor control is
extremity muscle contraction, whereas the anterior corticospinal tract disinhibited. There appears to be some degree of emotional regulation
ends bilaterally on ventromedial motor neurons and interneurons by the cerebellum. The “cerebellar cognitive affective syndrome” can
that control the axial and postural muscles. These corticospinal axons arise when stroke, tumor, or infection interrupts connections between
provide direct glutamatergic excitatory input to alpha motoneurons. the cerebellum and cerebral association and paralimbic regions
Brainstem control. Several brainstem nuclei exert supranuclear (Schmahmann and Sherman, 1998).
influence on the LMN population in the spinal cord through highly
complex projections. The fibers originating in the medial and inferior Signs and Symptoms of Upper Motor Neuron
vestibular nuclei in the medulla descend in the medial vestibulospinal Involvement
tract and terminate both on medial cervical and thoracic motor Loss of Dexterity
neurons and on interneurons. They excite ipsilateral motor neurons Loss of dexterity is one of the most characteristic signs of UMN impair-
but inhibit contralateral neurons. The lateral vestibulospinal tracts ment. Voluntary skillful movements require the integrated activation
originating in the lateral vestibular nucleus (Deiters nucleus) activate of many interneuron circuits in the spinal cord; such integration is ulti-
the extensor motor neurons and inhibit the flexor motor neurons in mately controlled by the corticospinal tract and thus by UMNs. Loss
all limbs. of dexterity may express itself as stiffness, slowness, and clumsiness in
The brainstem reticular formation also strongly influences the spi- performing any skillful motor actions. Asking the patient to perform
nal motor neurons, exerting widespread polysynaptic inhibitory input rapid repetitive motions such as foot or finger tapping assesses loss of
on extensor motor neurons and excitatory input on flexor motor neu- dexterity at the bedside. It is useful to assess both sides of the body, as
rons. The reticulospinal tracts modulate various reflex actions during many motor neuron disorders are asymmetrical (Box 97.2).
ongoing movements. The brainstem reticular formation receives
supranuclear control from the motor cortex via the cortical reticulo- Loss of Muscle Strength (Weakness)
spinal pathway to act as a major inhibitor of spinal reflexes and activity. The degree of muscle weakness resulting from UMN dysfunction is
Therefore, a lesion of the corticoreticular pathway can disinhibit retic- generally mild. Extensor muscles of the upper extremities and flexor
ulospinal control of the LMNs. The tectospinal tract originates in the muscles of lower extremities may become weaker than their antagonist
superior colliculus and controls eye and head movement. Variations in muscles because the UMN lesion disinhibits brainstem control of the
the balance between inhibitory input (mediated by the dorsal reticulo- vestibulospinal and reticulospinal tracts.
spinal tract) and facilitatory input (mediated by the medial reticulospi-
nal tract) alter muscle tone. To some extent, the vestibulospinal tract Spasticity
alters tone by input to muscle stretch receptors. Spasticity is the hallmark of UMN disease, but its pathophysiology is
Limbic motor control. The limbic system is involved in emotional complex and controversial. It seems to reflect altered firing of alpha
experience and expression and associated with a variety of autonomic, motoneurons and interneurons within the spinal cord, together
visceral, and endocrine functions. It strongly influences the somatic with increased activity of group II nerve fibers derived from muscle
motor neurons. The emotional status and experience of an individual spindles. An excess level of excitatory input to gamma motoneurons
determines overall spinal cord activity, and the limbic motor system exists via excess synaptic levels of excitatory neurotransmitters such
also influences respiration, vomiting, swallowing, chewing, and licking as serotonin, norepinephrine, and glutamate. In addition, there is
reduced inhibitory glycinergic and γ-aminobutyric acid (GABA)ergic
neurotransmission. The result is a state of sustained increase in mus-
BOX 97.1 Upper Motor Neurons and Their
cle tension when the muscle lengthens. Clinically, muscles exhibit a
Descending Tracts sudden resistive “catch” midway during passive movement of the
The motor areas limb. However, when a sustained passive stretch is continued, spastic
The primary motor neurons (Betz giant pyramidal cells and surrounding motor muscles quickly release the tension and relax, an event often described
neurons)
The premotor areas (the supplementary motor area and BOX 97.2 Signs and Symptoms of Upper
premotor cortex) Motor Neuron Involvement
Corticospinal and corticobulbar tracts
Lateral pyramidal tracts Loss of dexterity
Ventral (uncrossed) pyramidal tracts Loss of muscle strength (mild weakness)
Spasticity
Brainstem control Pathological hyperreflexia
Vestibulospinal tracts Pathological reflexes (Babinski, Hoffmann sign, loss of abdominal reflexes)
Reticulospinal tracts Increased reflexes in an atrophic limb (probable upper motor neuron sign)
Tectospinal tracts Pseudobulbar (spastic bulbar) palsy (emotional lability, brisk jaw jerk, hyperac-
tive gag, forced yawning, snout reflex, suck reflex, slow tongue movements,
Limbic motor control spastic dysarthria)
CHAPTER 97 Disorders of Upper and Lower Motor Neurons 1537
as the “clasp-knife phenomenon.” In muscles that are severely spas- Transcranial Magnetic Stimulation
tic, passive movement becomes more difficult and even impossible. Transcranial magnetic stimulation (TMS) is an electrophysiological
Sustained increases in muscle tone lead to a slowing in motor activities. technique that has detected cortical hyperexcitability/impaired inhibi-
tion as well as cortical motor neuron and long-tract degeneration in
Pathological Hyperreflexia and Pathological Reflexes
ALS. The stimulus is a brief, high-intensity electromagnetic pulse gen-
Pathological hyperreflexia is another crucial manifestation of UMN erated from a series of capacitors and discharged through wire coils
disease. The Babinski sign (extensor plantar response) is perhaps the applied at the scalp over the motor cortex and the evoked response
most important sign in the clinical neurological examination and is measured at skeletal muscle. Several different techniques are under
characterized by extension of the great toe (often, but not univer- investigation, including single-pulse TMS, cortical silent period mea-
sally, accompanied by fanning of the other toes) in response to strok- surement, paired pulse TMS, and repetitive TMS (Geevasinga et al.
ing the outer edge of the ipsilateral sole upward from the heel with a 2019). Overall, this promising, noninvasive tool requires further evalu-
blunt object. This sign may only evolve at a later stage of disease and ation as a marker of UMN dysfunction. Recent evidence suggests that it
may be absent in the setting of marked atrophy of the toe extensor may be useful in combination with other tools such as DTI.
muscles.
Pseudobulbar (Spastic Bulbar) Palsy Primary Lateral Sclerosis

Pseudobulbar palsy (or spastic bulbar palsy) develops when there is PLS, first described by Erb in 1875, is a rare UMN disease variant
disease involvement of the corticobulbar tracts that exert supranuclear that accounts for 2%–4% of all cases of ALS and is traditionally dis-
control over those motor nuclei that control speech, mastication, and tinguished by a lack of LMN involvement. In fact, the latter feature
deglutition. The prefix pseudo distinguishes this condition from true would lead some to argue that PLS is an entity that is distinct from
bulbar palsy that results from pure LMN involvement in brainstem ALS (Kolind et al., 2013). The Pringle criteria for PLS stipulated that
motor nuclei. Articulation, mastication, and deglutition are impaired disease be restricted to the UMN system for at least 3 years from the
in both pseudobulbar and bulbar palsies, but the degree of impairment time of clinical onset (Pringle et al., 1992), but a figure of 4 years is
in pseudobulbar palsy is generally milder. Spontaneous or unmoti- now proposed during which there is neither clinical nor neurophys-
vated crying and laughter uniquely characterize pseudobulbar palsy. iological evidence of LMN involvement. In a recent study compar-
This is also termed emotional lability, hyperemotionality, labile affect, ing the evolution of disease in PLS versus UMN-predominant ALS
or emotional incontinence and is often a source of great embarrassment and typical ALS, the median time to development of electromyo-
to the patient. graphic (EMG). LMN features after onset in those with an evolving
ALS was 3.17 years; in those patients, clinical signs of LMN disease
Laboratory Evidence of Upper Motor Neuron occurred on average about 6 months later. Nonetheless, later devel-
Involvement opment of LMN signs may occur and require reclassification as ALS
Several promising imaging and electrophysiological techniques are in some cases, which therefore necessitates constant longitudinal
under investigation as potential markers of UMN involvement in neu- review of each case (Gordon et al., 2009). Indeed, it is possible to
rological disease. However, a thorough bedside examination is the eas- divide PLS patients into subgroups based on clinical and molecular
iest and most effective means to detect UMN disease. characteristics. A recent study identified two broad clinical groups
presenting with PLS; those with bulbar/dysphagia and those with
Neuroimaging urinary urgency. Furthermore, there were PLS-like presentations
The use of brain magnetic resonance imaging (MRI) in ALS is largely due to mutations in C9Orf72 but also in PARK2, SPG7, and DCTN1
to exclude other conditions but sometimes shows abnormal signal (Mitsumoto et al., 2015).
intensity in the corticospinal and corticobulbar tracts as they descend PLS typically presents in patients in their early 50s (about a decade
from the motor strip via the internal capsules to the cerebral pedun- younger than typical MND/ALS patients) as a very slowly evolving
cles. In ALS, signal changes, best appreciated on proton density images spastic paraparesis that spreads to the upper limbs and eventually
of the internal capsules, probably represent Wallerian degeneration; causes pseudobulbar palsy. In rare instances, onset is in the bulbar sys-
similar changes also appear on conventional T2-weighted and fluid- tem or follows a slowly ascending or descending hemiplegic pattern
attenuated inversion recovery (FLAIR) sequences. However, these (Mills hemiplegic variant), but a bulbar-onset presentation should
changes do not appear to be sufficiently sensitive, and efforts continue make the clinician wary of later LMN signs elsewhere. Other features
to evaluate other potential MRI techniques such as diffusion tensor include cramps and fasciculations, but such complaints are neither
imaging (DTI) and high-field volumetric MRI, which may serve as prominent nor universal. Bladder dysfunction is rare and, if it occurs
markers of UMN disease (Foerster et al., 2013). at all, tends to be a late feature. Although muscle weakness is present,
the main deficits are due to spasticity in dexterity and gait. The rate
Magnetic Resonance Spectroscopy Imaging of progression can be exceedingly slow, often progressing over many
Proton density magnetic resonance spectroscopy (1H-MRS) is a non- years to the point where the patient manifests a robotic gait, debilitat-
invasive nuclear magnetic resonance technique that combines the ing generalized spasticity, and prominent pseudobulbar palsy. Muscle
advantages of MRI with in vivo biochemical information. A signif- atrophy, if it occurs at all, is a very late feature. No clinically detect-
icant reduction of N-acetylaspartate, a neuronal marker, relative to able sensory changes occur. Neuropsychological test batteries may
creatine or choline (used as internal standards) exists in the sensorim- define subtle cognitive deficits due to frontal cortical involvement,
otor cortices of patients with ALS who have UMN signs. Alterations but dementia is not a prominent feature. A few patients may exhibit
in the measured levels of these metabolites using 1H-MRS are use- abnormal saccadic voluntary eye movements. Corticobasal syndrome
ful in the detection of UMN dysfunction early in the evolution of can develop rarely in patients who initially present with a pure upper
ALS and are useful for monitoring progression over time. MRS still motor neuron syndrome (Johnson et al., 2015). Breathing is usually
requires further technological improvements before it comes into unimpaired in PLS, and as a consequence, forced vital capacity (FVC)
widespread use. is not affected (Gordon et al., 2009).
The prognosis is significantly better than for MND/ALS: one pump. Tricyclic antidepressants, selective serotonin reuptake inhibi-
series had a median disease duration of 19 years and another series tors, or dextromethorphan/quinidine may control pseudobulbar affect
exhibited a range of survival from 72 to 491 months (Murray, 2006). lability (Brooks et al., 2005).
The underlying pathogenesis of PLS remains undefined. Pathological
changes include a striking loss of Betz cells in layer 5 of the fron- Hereditary Spastic Paraplegia
tal and prefrontal motor cortex (and other smaller pyramidal cells)
HSP (or familial spastic paraparesis) is a genetically and clinically het-
together with laminar gliosis of layers 3 and 5 and degeneration of the
erogeneous group of disorders rather than a single entity. The clinical
corticospinal tracts. Spinal anterior horn cells are characteristically
feature common to all cases is progressively worsening spasticity of the
unaffected.
lower extremities, often with variable degrees of weakness. The charac-
teristic pathology is retrograde degeneration of the longest nerve fibers
Diagnosis in the corticospinal tracts and posterior columns due to mutations
The diagnosis of PLS is essentially one of exclusion (Table 97.1). Rare affecting vesicular trafficking, axonal transport, lipid metabolism,
reports of UMN-onset ALS exist where the interval between onset of mitochondrial dynamics, and myelination. Its estimated prevalence is
UMN signs and subsequent LMN signs has been up to 27 years. As 3–10 per 100,000, but its worldwide prevalence may actually be under-
such, it is vital to reassess patients diagnosed with PLS, as late signs of estimated because of the benign nature of the disease in many families
LMN involvement may occur that would reclassify their disorder as (Blackstone, 2012). It may be inherited in an autosomal dominant,
UMN-onset ALS. autosomal recessive, or X-linked fashion, but it should be borne in
Appropriate testing must exclude all definable causes for gener- mind that a number of cases will lack a family history, as stated below
alized UMN involvement. These include structural abnormalities (Depienne et al., 2006, Lan et al., 2015).
(Chiari malformation and intrinsic and extrinsic spinal cord lesions) Although most cases present in the second to fourth decades,
and myelopathies such as multiple sclerosis (MS) spondylotic cervi- onset is from infancy into the eighth decade. The clinical syndrome is
cal myelopathy, human immunodeficiency virus (HIV) myelopathy, broadly divisible into the pure form and the complicated form. In the
human T-lymphotropic virus type 1 (HTLV-1) myelopathy, Lyme pure form, patients develop only lower-extremity spasticity, but some
disease, syphilis, or adrenomyeloneuropathy. Spondylotic cervical of these cases eventually become complicated. However, the compli-
myelopathy and MS are probably the most common causes among cated form may also include optic neuropathy, pigmentary retinopa-
these disorders. The family history must be negative to rule out hered- thy, deafness, ataxia, ichthyosis, amyotrophy, peripheral neuropathy,
itary spastic paraplegia (HSP)/familial spastic paraparesis, spinocer- dementia, autoimmune hemolytic anemia/thrombocytopenia (Evans
ebellar ataxia (SCA), hexosaminidase-A (Hex-A) deficiency, familial syndrome), extrapyramidal dysfunction, cerebellar dysfunction, pto-
ALS (FALS), or adrenomyeloneuropathy. It is now apparent that some sis, ophthalmoparesis, intellectual disability, and bladder dysfunction
forms of HSP, including spastin and paraplegin mutation-associated (Video 97.1).
HSP, may lack a family history; it is worthwhile to carry out genetic There is an ever-expanding list of genes and genetic loci in the HSP
testing for HSP in patients presenting with symptoms and signs family. Over 70 genetic subtypes have been described (de Souza et al.,
that are restricted to the lower extremities (Brugman et al., 2009). 2017; Table 97.2). Novel techniques such as exome sequencing are
Paraneoplastic syndromes (especially in association with breast can- valuable in discovering new genes. Inheritance of most pure HSP is
cer) and Sjögren syndrome may clinically resemble PLS. Thus, it is autosomal dominant, whereas complicated forms are more often auto-
important to consider paraneoplastic diseases, particularly in an older somal recessive. For example, approximately 40% of autosomal dom-
woman presenting with a pure upper motor syndrome and other inant pure HSP worldwide is due to mutations of the SPAST gene on
genetic mimics. chromosome 2p22–21, which encodes spastin, a 616-amino acid pro-
tein. Mutations of various types (missense, nonsense, frameshift, splice
Treatment site) may affect this gene (McDermott, 2006). Spastin is a highly con-
No specific pharmacotherapy is available, and treatment therefore served member of the AAA family of proteins (adenosine triphospha-
focuses on symptom control and supportive care. However, antis- tase [ATPase] associated with various cellular activities). The exact role
pasticity drugs such as the GABA-B agonist baclofen and the central of mutant spastin in the pathogenesis of HSP is not known, although a
α2-agonist tizanidine may be tried for symptomatic treatment. Severe disturbance in maintenance of the microtubule cytoskeleton may exist,
spasticity sometimes requires the insertion of an intrathecal baclofen thus disrupting axonal transport. More than half of all cases do not
TABLE 97.1 Disorders of Upper Motor Neurons and Their Key Characteristics
Disorders Key Characteristics
Primary lateral sclerosis A diagnosis of exclusion
Hereditary spastic paraplegia Heredity, usually autosomal dominant, spastin gene mutation, other mutations
(see text), “sporadic”
HTLV-1-associated myelopathy Slowly progressive myelopathy, endemic, and positive HTLV-1
HTLV-2-associated myelopathy Amerindian, IV drug abuser, concomitant HIV
Adrenomyeloneuropathy X-linked recessive inheritance, adrenal dysfunction, myelopathy, very long-chain
fatty acid assay
Lathyrism History of consumption of chickling peas
Konzo Eastern African, cassava root consumption
HIV, Human immunodeficiency virus; HTLV, human T-lymphotropic virus; IV, intravenous.
TABLE 97.2 Hereditary Spastic Paraplegia Known Phenotype-Genotype Disorders

Phenotype
(OMIM Proposed Mode of Key Clinical/Radiographic Gene OMIM
Reference) Gene Location Mechanism Inheritance Features Reference
Spastic paraple- L1CAM Xq28 Neuronal migration, X-linked Mental retardation, aphasia, shuffling *308840
gia 1/MASA myelination gait, short stature, and adducted
syndrome/ production thumbs, corpus callosum hypoplasia,
CRASH syndrome hydrocephalus
(#303350)
Spastic paraplegia PLP1 Xq22.2 Myelin production X-linked Onset in childhood, highly variable *300401
2 (#312920) phenotype including cerebellar signs/
optic atrophy/contractures/mental
retardation
Spastic paraplegia ATL1 14q22.1 Membrane traf- AD Early-onset (often before age 5–10), *606439
3A (#182600) ficking slowly progressive, pes cavus, sphinc-
ter disturbance.
Spastic paraplegia SPAST 2p22.3 Microtubule AD Variable age at onset, symptom severity *604277
4 (#182601) dynamics and rate of symptom progression. Pes
cavus, sphincter disturbance, mild
dysarthria
Spastic paraplegia CYP7B1 8q12.3 Lipid metabolism AR Variable age at onset, mostly pure but *603711
5A (#270800) variable cerebellar involvement, optic
atrophy, reduced vibration/proprio-
ception
Spastic paraplegia NIPA1 (SPG6) 15q11.2 Membrane trans- AD Insidious onset in 2nd–3rd decade, *608145
6/Familial spastic port/lysosomal variable severity, seizures, tremor
paraparesis degradation
(#600363)
Spastic paraplegia SPG7, (PGN 16q24.3 Mitochondrial AR, some Onset in 3rd–5th decade, variable *602783
7 (#607259) CMAR, CAR) dysfunction heterozygous cerebellar signs/optic atrophy/eye
mutations movement abnormalities/attention
deficits, cortical/cerebellar atrophy
Spastic paraplegia KIAA0196 8q24.13 Protein aggregation AD Onset 18–60 years, upper limb spasticity, *610657
8 (#603563) amyotrophy, severe phenotype
Spastic paraplegia ALDH18A1 10q24.1 Amino acid metab- AD Juvenile or adult, ALS-like, short stature, *138250
9A (#601162) olism cataracts, pes cavus.
Spastic paraplegia KIF5A 12q13.3 Membrane transport AD Onset 3rd–4th decade, with or without *602821
10 (#604187) axonal sensorimotor neuropathy.
Can be associated with amyotrophy,
parkinsonism, cerebellar ataxia
Spastic paraplegia SPG11 15q21.1 Unknown, presumed AR Onset in adolescence, mental *610844
11 (#604360) membrane impairment, cerebellar ataxia,
transport parkinsonism, amyotrophy, thin corpus
callosum, “ears-of-the-lynx sign”
Spastic paraplegia RTN2 19q13.32 Tubular endoplas- AD Onset 1st–2nd decade, pure phenotype, *603183
12 (#604805) mic reticulum net- rapidly progressive
work dysfunction
Spastic paraplegia HSPD1 (SPG13, 2q33.1 Mitochondrial pro- AD Variable age at onset, pure phenotype, *118190
13 (#605280) HSP60, HLD4) tein instability severe spasticity
Spastic paraplegia ZFYVE26 14q24.1 Unknown, presumed AR Onset in 1st–2nd decade, variable *612012
15/Spastic para- membrane intellectual disability/dysarthria/reti-
plegia and retinal transport nal degeneration, distal amyotrophy,
degeneration/ parkinsonism, seizures, axonal neurop-
Kjellin syndrome athy, thin corpus callosum, cerebral
(#270700) atrophy, white matter hyperintensities
Spastic paraple- BSCL2 11q12.3 Tubular endoplas- AD Variable age at onset, distal amyotrophy *606158
gia 17/Silver mic reticulum net-
spastic paraplegia work dysfunction
(#270685)
Continued
TABLE 97.2 Hereditary Spastic Paraplegia Known Phenotype-Genotype Disorders—cont’d

Phenotype
Spastic paraplegia ERLIN2 8p11.23 Endoplasmic AR Onset in infancy, severe psychomotor *611605
18 (#611225) reticulum-associ- retardation, joint contractures, global
ated degradation muscle weakness and atrophy, high
pathway arched palate, kyphosis/scoliosis,
speech absent or limited, occasional
seizures
Spastic paraplegia SPG20 13q13.3 Microtubule AR Onset in early childhood, distal amyot- *607111
20/Troyer syn- dynamics rophy and contractures, short stature,
drome (#275900) hypertelorism, maxillary overgrowth,
tongue dyspraxia
Spastic paraplegia SPG21 15q22.31 Dysregulation of AR Onset 2nd–3rd decade, presenile demen- *608181
21/Mast syn- CD4 activity tia, parkinsonism, cerebellar signs,
drome (#248900) thin corpus callosum and white matter
abnormalities
Spastic paraplegia DSTYK 1q32.1 Unknown AR Vitiligo, hyperpigmentation, lentigines, *612666
23 facial features, mental retardation,
mild neuropathy
Spastic paraplegia B4GALNT1 12q13.3 Sphingolipid metab- AR Onset in 1st -2nd decades of life, slowly *601873
26 (#609195) olism progressive, distal amyotrophy, intel-
lectual disability, axonal sensorimotor
neuropathy, dysarthria, variable
cerebellar signs, extrapyramidal signs,
cortical atrophy, and white matter
hyperintensities
Spastic paraplegia DDHD1 14q22.1 Lipid metabolism AR Onset in childhood or adolescence, *614603
28 (#609340) slowly progressive pure phenotype
Spastic paraplegia KIF1A 2q37.3 Microtubule AR Onset 1st–2nd decade, variable cerebel- *601255
30 (#610357) dynamics lar involvement/peripheral neuropathy
Spastic paraplegia REEP1 2p11.2 Tubular endoplas- AD Bimodal age of onset (usually 1st–2nd *609139
31 (#610250) mic reticulum net- decade), variable severity, mostly pure
work dysfunction HSP, occasionally complicated (e.g.,
bulbar dysfunction, distal amyotrophy)
Spastic paraplegia ZFYVE27 10q24.2 Dysfunction of AD Adult onset, pure phenotype *610243
33 (#610244) membrane traf-
ficking
Spastic paraplegia FA2H 16q23.1 Lipid metabolism AR Onset in 1st decade, dysarthria, mild *611026
35/Fatty acid cognitive decline, variable dystonia/
hydroxylase- optic atrophy/seizures, leukodystrophy
associated neu- and occasional evidence of neuro
rodegeneration degeneration with brain iron accumula-
(#612319) tion, atrophy of cerebellum/brainstem/
corpus callosum
Spastic paraplegia PNPLA6 19p13.2 Unknown, presumed AR Childhood onset, distal upper and lower *603197
39/NTE-related lipid/myelination extremity wasting, cerebellar signs,
motor neu- related spinal cord atrophy
ron disorder
(#612020)
Spastic paraplegia SLC33A1 3q25.31 Glycoprotein and AD Variable age at onset, pure phenotype *603690
42 (#612539) ganglioside
metabolism in
Golgi apparatus
Spastic paraplegia C19orf12 19q12 Mitochondrial AR Onset in 1st decade, decreased vibration, *614297
43 (#615043) transmembrane distal muscle atrophy, reduced
protein, function reflexes, contractures
unknown

Phenotype
Spastic paraplegia GJC2 1q42.13 Disruption of AR Onset of mild symptoms in 1st–2nd *608803
44 (#613206) oligodendrocyte decade with progression in adulthood,
homeostasis cerebellar signs, hearing loss, seizures,
hypomyelinating leukodystrophy and
thin corpus callosum
Spastic paraplegia NT5C2 10q24.32-q24.33 Purine/pyrimidine AR Onset before age 2, intellectual *600417
45 (#613162) (10q24.3-q25.1) nucleotides disability, contractures, optic atrophy,
metabolism dysplastic corpus callosum
Spastic paraplegia GBA2 9p13.3 Sphingolipid metab- AR Onset in childhood cerebellar involve- *609471
46 (#614409) olism ment, variable cognitive impairment/
cataracts/kyphoscoliosis/testicular
atrophy, variable cerebral, cerebellar,
and corpus callosum atrophy
Spastic paraplegia AP4B1 1p13.2 Membrane transport AR Onset at birth, severe mental retardation *607245
47 (#614066) with poor or absent speech develop-
ment, stereotyped laughing, spastic
tongue protrusion, variable dysmorphic
features
Spastic paraplegia AP5Z1 7p22.1 Membrane trans- AR Adult onset, pure phenotype, mild cervi- *613653
48 (#613647) port/DNA repair cal spine hyperintensities
Spastic paraplegia TECPR2 14q32.31 Interruption of intra- AR Onset in the first 2 years of life, mod- *615000
49 (#615031) cellular autophagy erate to severe intellectual disability,
pathway dysmorphic features, episodes of
central apnea, thin corpus callosum,
cerebral and cerebellar atrophy
Spastic paraplegia AP4M1 7q22.1 Membrane transport AR Neonatal hypotonia, severe mental retar- *602296
50 (#612936) dation, dysmorphism, speech absent or
limited, pseudobulbar signs, ventricu-
lomegaly, white-matter abnormalities,
and variable cerebellar atrophy
Spastic paraplegia AP4E1 15q21.2 Membrane transport AR Presents with neonatal hypotonia, severe *607244
51 (#613744) intellectual disability, speech absent or
limited, dysmorphic features, seizures,
stereotypic laughing, contractures,
ventriculomegaly, cerebral/cerebellar
atrophy, and leukodystrophy
Spastic paraplegia AP4S1 14q12 Membrane transport AR Presents at birth with neonatal hypo- *607243
52 (#614067) tonia, severe intellectual disability,
speech absent or limited, talipes
equinovarus, decreased shank muscle
mass, short stature, dysmorphic
features and microcephaly, stereotypic
laughing
Spastic paraplegia VPS37A 8p22 Endosomal sorting AR Onset in infancy, mild-moderate *609927
53 (#614898) cognitive impairment, dystonia, pectus
carinatum, marked kyphosis
Spastic paraplegia DDHD2 8p11.23 Lipid metabolism AR Onset of spasticity by age 2 years, intel- *615003
54 (#615033) lectual disability, short stature, foot
contractures, dysarthria, dysphagia,
variable optic hypoplasia, strabismus,
telecanthus, thin corpus callosum and
periventricular white-matter lesions,
MR spectroscopy shows an abnormal
lipid peak
Continued

Phenotype
Spastic paraplegia C12orf65 12q24.31 Mitochondrial AR Onset in 1st decade, axonal peripheral *613541
55 (#615035) dysfunction neuropathy, optic atrophy, strabismus,
mental retardation, arthrogryposis of
small joints, thin corpus callosum
Spastic paraplegia CYP2U1 4q25 Unknown, gene AR Onset birth to 8 years, upper limb *610670
56 (#615030) may play a role in involvement, dystonia, thin corpus
immune functions callosum, basal ganglia calcification
Spastic paraplegia TFG 3q12.2 Endoplasmic AR Early onset, optic atrophy, wasting of *602498
57 (#615658) reticulum and hand and leg muscles and contrac-
microtubule tures, axonal demyelinating sensorimo-
function tor neuropathy
Spastic paraplegia ARL6IP1 16p12.3 Protein transport AR Present in first 2 years of life, senso- *607669
61 (#615685) rimotor neuropathy, severe mutilating
acropathy
Spastic paraplegia ERLIN1 10q24.31 Endoplasmic reticu- AR Cerebellar ataxia, distal amyotrophy *611604
62 (#615685) lum function
Spastic paraplegia AMPD2 1p13.3 Purine nucleotide AR Present in first 2 years of life, short *102771
63 (#615686) metabolism stature, white-matter changes, thin
corpus callosum
Spastic paraplegia ENTPD1 10q24.1 Purine nucleotide AR Onset in childhood, intellectual disability, *601752
64 (#615683) metabolism microcephaly, delayed puberty,
dysarthria
Spastic paraplegia REEP2 5q31.2 Shaping of endo- AD or AR Onset in early childhood, slowly progres- *609347
72 (#615625) (SGC32445, plasmic reticulum, sive, postural tremor
C5orf19) membrane inter-
actions
Spastic paraplegia CPT1C 19q13.33 Altered lipid metab- AD Onset in early adulthood, slowly progres- *608846
73 (#616282) olism sive, mild amyotrophy
Spastic paraplegia IBA57 1q42.13 Mitochondrial AR Onset in first decade, slowly progressive, *615316
74 (#616451) dynamics optic atrophy, distal amyotrophy
AD, Autosomal dominant; AR, autosomal recessive.
manifest symptoms and signs until after age 30 years. Although this is paraplegin; this disorder can be either pure or complicated (cerebellar
normally a pure HSP, complicated forms occur, and some cases can signs, pale optic discs, and peripheral neuropathy). The genes for two
develop a late-onset cognitive decline. Pathologically, degeneration of different X-linked complicated HSP have been identified. In the first,
the longest corticospinal tracts and, to a lesser degree, the posterior mutant L1 (neural) cell adhesion molecule (L1CAM) may disrupt neu-
columns of the spinal cord is seen. ronal migration or differentiation; in the second mutant proteolipid
Mutations in the SPG3A gene on 14q11–q21 encoding the novel protein (PLP1) is found in association with changes in white matter
protein, atlastin, give rise to another autosomal dominant, often ear- (duplication mutations in this same gene can also cause Pelizaeus-
ly-onset (<10 years of age) pure HSP, which accounts for about 10% Merzbacher disease). Spastic paraplegia 17 (SPG17) is caused by muta-
of autosomal dominant cases. This protein shares structural homology tions in the seipin gene on chromosome 11q12–q14. Also known as
with guanylate-binding protein 1, which is a member of the dynamin Silver syndrome, this disorder is an autosomal dominant complicated
family. Dynamins are important in intracellular trafficking of various form of HSP with distal hand and foot amyotrophy beginning in the
kinds of vesicles. Mutations in KIF5A (SPG10, Chr 12q), a kinesin late teens to early 30s. Mutations in this gene are also the cause of a
motor domain that is critical in intracellular transport, can cause both form of distal hereditary neuropathy (Charcot-Marie-Tooth [CMT]
early- and late-onset spastic paraparesis with distal amyotrophy (Blair disease type 5).
et al., 2006). Spastic paraplegia 11 (SPG11) is an autosomal reces- Using novel techniques such as exome sequencing, it is evi-
sive complicated HSP (thin corpus callosum, neuropathy, cognitive dent that there are multiple genes, some likely yet to be discovered,
impairment) due to mutations in the spatacsin gene on chromosome mutations of which can lead to a HSP phenotype. The terms “the
15q. This protein is of unknown function and does not appear to inter- HSPome” and “the HSP interactome” have been coined to highlight
act with the Golgi apparatus or microtubules. The cause of autosomal the ways in which known and candidate genes are connected. For
dominant pure HSP, linked to 2q24–34, is a mutation in the SPG13 example, known mutations are associated with various pathogenic
gene, which encodes a mitochondrial heat shock protein. Recessively mechanisms which affect cellular transport or the metabolism and
inherited complicated HSP links to chromosome 16q and is caused development of axons and synapses (Novarino et al., 2014) (see
by a mutation in a gene encoding a mitochondrial protein known as Video 97.1 and Table 97.2).
Diagnosis Examination reveals UMN signs in the legs (weakness, spasticity, patho-
The basis for diagnosis of HSP is evidence of a family history in the logical reflexes, hyperreflexia), although reflexes may also be brisk in the
setting of progressive gait disturbance, evidence of lower-extremity arms. Overall, evidence of LMN involvement may be scant, and objective
spasticity, and sparing of craniobulbar function. However, difficulties sensory findings may be difficult to detect. MRI may reveal increased
arise when there is no clear family history in recessive or X-linked dis- signal on T2-weighted sequences in periventricular white matter and
ease and in cases of apparently sporadic HSP. Furthermore, consid- atrophy of the thoracic cord, but these findings may not be specific to
erable variation in disease expression exists between and within HSP HTLV-1. The definitive diagnosis of HAM/TSP requires HTLV-1–posi-
families. In the absence of a family history or a demonstration of a tive serology in blood and cerebrospinal fluid (CSF). To be sensitive and
known mutation, it is important to consider alternative causes for the specific, CSF should reveal a combination of a polymerase chain reaction
clinical presentation, including structural disease (e.g., cerebral palsy, (PCR) amplification of HTLV-1 deoxyribonucleic acid (DNA), together
hydrocephalus, myelopathy), degenerative/infiltrative/inflammatory with evidence of an increased HTLV-1–specific antibody index and oli-
disease (e.g., MS, ALS, SCA, leukodystrophy), infections (syphilis, goclonal bands (Puccioni-Sohler et al., 2012). At present, no antiviral
HIV, HTLV), levodopa-responsive dystonia, metabolic/toxic damage agents effectively treat HAM/TSP, but a case report showed partial ben-
(vitamin B12 deficiency [subacute combined degeneration of the spinal efit of plasmapheresis (Narakawa et al., 2001). As more is learned about
cord (SCDC)], vitamin E deficiency, copper deficiency, lathyrism), and the molecular etiology of HAM/TSP, future therapies will likely target
paraneoplastic disorders. MRI may reveal that cervical and thoracic the pathogenic effect of HTLV-1–reactive T cells.
spinal cord diameters are significantly smaller in both pure and com- Human T-Lymphotropic Virus Type 2-Associated
plicated HSP than in controls (Sperfeld et al., 2005). Perhaps the most
important differential diagnosis is that between apparently sporadic
Myelopathy
pure HSP and PLS, especially as the later may present with a slowly Though phylogenetically similar in many respects, HTLV-1 and HTLV-2
evolving spastic paraparesis for many years prior to the development are still antigenically distinct. Nonetheless, using enzyme-linked immu-
of upper limb or bulbar features. The only reliable way to distinguish nosorbent assay (ELISA) and Western blot techniques, many labo-
such disorders is through genetic testing; age at onset, urgency of mic- ratories worldwide often report the presence of sero- indeterminate
turition, and signs of dorsal column involvement (clinical or abnormal HTLV-1/2. It has long been thought that myelopathy in such sero-
somatosensory evoked potentials [SSEPs]) are not accurate indicators indeterminate cases is due to HTLV-1 rather than HTLV-2, but rare
of HSP versus PLS (Brugman et al., 2009). cases are now being described of a syndrome characterized by spastic
paraparesis, diffuse hyperreflexia, spastic bladder, and periventricular
Treatment white-matter changes on MRI in patients infected with HTLV-2 but
At present, treatment of spastic paraplegia is limited to symptomatic not HTLV-1. This retrovirus is endemic in some Native American tribes
interventions, supportive care to reduce spasticity, and appliances and and is now often encountered worldwide among intravenous (IV) drug
orthotics such as canes, walkers, and wheelchairs. Antispasticity drugs abusers. It is worthwhile to test CSF and serum for the presence of this
such as baclofen, tizanidine, diazepam, and dantrolene are often sub- virus in known IV drug abusers who present with a spastic paraparesis
optimal, and patients with very disabling spasticity may require intra- (Silva et al., 2002). However, coinfection with HIV-1 is a confounding
thecal baclofen administered through an implanted pump. factor in many cases of presumed HTLV-2–associated neurological dis-
ease. It has been suggested that such coinfection, rather than infection
Human T-Lymphotropic Virus Type 1-Associated with HTLV-2 alone, increases the likelihood of neurological manifesta-
Myelopathy, or Tropical Spastic Paraparesis tions (Araujo and Hall, 2004; Posada-Vergara et al., 2006).
HTLV-1 causes a chronic progressive myelopathy that is referred to as
tropical spastic paraparesis (TSP) in the Caribbean or HTLV-1–associated Adrenomyeloneuropathy
myelopathy (HAM) in Japan. This retrovirus is endemic in the Caribbean Adrenomyeloneuropathy is a variant of adrenoleukodystrophy, an
area, southwestern Japan, equatorial Africa, South Africa, parts of Asia, X-linked recessive disorder caused by mutations in the ABCD1 gene
Central America, and South America, where it infects between 10 and 20 on chromosome Xq28 that encodes a ubiquitously expressed integral
million people. The true incidence and prevalence figures are likely an membrane peroxisomal ATPase-binding cassette transporter protein.
underestimate (Gessain and Cassar, 2012). While between 2% and 3% Mutations in this gene lead to abnormal peroxisomal β-oxidation,
of those infected can develop adult-onset T-cell leukemia, an estimated which results in the harmful accumulation of very long-chain fatty
2.5%–3.8% can develop a chronic inflammatory myelopathy, with up to acids (VLCFAs) in affected cells. Excessive levels of VLCFAs may inter-
20/100,000 affected in the Caribbean population and 3/100,000 in Japan. fere with the membrane components of both neurons and axons. The
Recent evidence implicates high levels of activated HTLV-1–specific most common phenotype, adrenoleukodystrophy, is an inflammatory
helper T cells and cytotoxic T cells in the pathogenesis of this syndrome; disorder of brain and spinal cord that affects young boys 4–8 years of
these immune cells appear to activate in response to interactions with age, who develop severe adrenal insufficiency, progressive cognitive
retroviral env and tax proteins with greatest activity within the thoracic deterioration, seizures, blindness, deafness, and spastic quadriparesis.
cord. Increased susceptibility for neurological disease appears to depend Adrenomyeloneuropathy is a noninflammatory axonopathy of the spi-
on both viral and host factors, with differences in certain HTLV-1 sub- nal cord that involves descending corticospinal tracts in the thoracic
groups, proviral load, and HLA background being important. This may and lumbosacral regions and the ascending posterior columns in the
also explain differences in susceptibility between ethnic populations (Bassi cervical region. The characteristic clinical picture is a slowly progressive
et al., 2014; Saito, 2010). Mode of transmission is through contaminated spastic paraparesis and mild polyneuropathy in adult men (in their late
blood, sexual activity, breastfeeding, and very rarely in utero. 20s), with or without sensory symptoms and sphincter disturbances.
HAM/TSP is a chronic, insidiously progressive myelopathy that typi- Adrenal insufficiency may be present and may predate onset of neuro-
cally begins after age 30 years (but can occur as early as the first decade). logical symptoms by several years. Adult female carriers may present
In addition to slowly progressive spastic paraparesis, patients complain with an age-related slowly progressive spastic paraparesis (Habekost
of lower-extremity paresthesias, a painful sensory neuropathy, and blad- et al., 2014). Approximately 20% of men with adrenomyeloneurop-
der dysfunction, and some patients may also develop optic neuropathy. athy also develop cerebral changes on MRI that may accompany
cognitive/language/behavioral deterioration. Rare cases may present stimulate the AMPA glutamate receptor subtype, causing excitotoxic
as a spinocerebellar degeneration. Considerable phenotypic variation neuronal injury. As with lathyrism, there appears to be a selective
exists even within individual families. Female carriers may manifest effect on Betz cells of the cerebral cortex and the longest correspond-
more subtle symptoms such as cramps, back pain, or arthralgias. The ing corticospinal tracts. Patients typically present with spastic parapa-
diagnosis should be suspected in male cases with progressive sen- resis (although some may exhibit only lower-extremity hyperreflexia).
sorimotor deficits in the legs and a family history of a myelopathy Occasionally one may detect weakness of the upper extremities, but
(including supposed MS). Progressive sensorimotor deficits in the not to the same degree as that of the lower extremities.
lower extremities with a history of memory loss or “attention deficit
disorder” should also prompt testing for adrenomyeloneuropathy, DISORDERS OF LOWER MOTOR NEURONS
as should a history of idiopathic childhood epilepsy or primary adre-
nal failure (Mukherjee et al., 2006). Sural nerve biopsies show loss of Neuroanatomy of Lower Motor Neurons
both myelinated and unmyelinated axons, with some degree of onion Interneurons
bulb formation. Ultrastructural examination may show characteris- The interneurons constitute most of the anterior horn cells of the spi-
tic inclusions (empty lipid clefts) in Schwann cell cytoplasm. Nerve nal cord and determine the final output of the LMNs. The interneuron
conduction studies and needle electrode examination may reveal a system receives supranuclear excitatory and inhibitory motor control
predominantly axon-loss type of sensorimotor polyneuropathy with a from the brainstem descending tracts, corticospinal tracts, and lim-
lesser component of demyelination, and SSEPs may show reduced or bic system; this system also receives afferent information, directly and
absent responses. There may be signal abnormalities seen in the corti- indirectly, from the afferent peripheral nerves. The interneuron system
cospinal tracts and parieto-occipital white matter on MRI (Teriitehau forms intricate neuronal circuits involving automatic and stereotyped
et al., 2007). The diagnostic test of choice is to demonstrate increased spinal reflexes to coordinate and integrate the activation of synergist
VLCFA levels in plasma, red blood cells, or cultured skin fibroblasts. muscles while inhibiting antagonist muscles, contralateral muscles,
No specific therapy exists for adult-onset adrenomyeloneuropathy. and sometimes even a distant motor pool. The same interneuron net-
work that mediates such automatic and stereotyped reflex behavior
Plant Excitotoxins also acts as the basic functional unit involved in highly skillful volun-
Lathyrism tary movements. Ultimately, all of the interneuronal paths converge on
Lathyrism is a chronic toxic nutritional neurological disease caused by the LMNs that innervate skeletal muscles, which Sherrington called the
long-term (or subacute) ingestion of flour made from the drought-re- final common path.
sistant chickling pea (Lathyrus sativus). It is an important example of
a disease in which a natural excitotoxin causes selective UMN impair- Lower Motor Neurons
ment. The responsible neurotoxin is β-N-oxalylamino-l-alanine LMNs are located in the brainstem and spinal cord and send out motor
(BOAA), an α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic axons that directly innervate skeletal muscle fibers. Spinal cord LMNs,
acid (AMPA) glutamate receptor agonist. Ingestion of this neurotoxin also known as anterior horn cells, cluster in nuclei forming longitudi-
results in increased intracellular levels of reactive oxygen species and nal columns; those innervating the distal muscles of the extremities
subsequent impairment of the mitochondrial oxidative phosphoryla- are located in the dorsal anterior horn, whereas those innervating
tion chain. Degeneration is most prominent in those Betz cells of the proximal muscles of the extremities are in the ventral anterior horn.
motor cortex (and the longest corresponding pyramidal tracts) that Those LMNs that innervate the axial and truncal muscles are the most
subserve lower-extremity function. Lathyrism occurs in the indige- medially located. The normal cervical and lumbar enlargements of the
nous populations of Bangladesh, China, Ethiopia, India, Romania, and spinal cord are the result of markedly enlarged lateral anterior horns
Spain. It also occurred in regional concentration camps during World containing the LMNs for the upper and lower limb muscles.
War II. The condition may occur in epidemic form when malnour- Large spinal cord LMNs called alpha motoneurons are the principal
ished populations increase consumption of flour made from L. sativus motor neurons innervating muscle fibers. Medium-sized motor neu-
chickling peas during times of food shortage due to droughts. An anal- rons (beta motoneurons) innervate both extrafusal and intrafusal (mus-
ysis of an epidemic of neurolathyrism in Ethiopia showed a higher inci- cle spindle) fibers, and intermediate and small motor neurons (gamma
dence in boys aged 10–14 years. The increased risk was associated with motoneurons or fusimotor neurons) innervate only spindle muscle
cooking grass pea foods in traditional clay pots (Ngudi et al., 2012). fibers. The rest of the small anterior horn cells are interneurons.
The onset of clinical toxicity is either acute or chronic, manifesting as Alpha motoneurons are among the largest neurons of the nervous
muscle spasms, cramps, and leg weakness. In addition to spastic para- system. Each has a single axon that branches to its target muscles and
paresis, sensory (including leg formications) and bladder dysfunction a number of large dendrites that provide an extensive receptive field.
may occur. Occasionally there is a coarse tremor of the upper extremi- The motor unit is the smallest unit of the motor system and consists
ties. Although irreversible, the disorder is not progressive (unless there of one alpha motoneuron, its axon, and all of its target muscle fibers.
is continuing intoxication), and lifespan is not affected.
Clinical Features of Lower Motor Neuron Involvement
Konzo Loss of Muscle Strength (Weakness)
Konzo (“tied legs”) is another toxic nutritional disorder of cortical The loss of an LMN results in denervation of its motor unit, whereas
motor neurons caused by chronic dietary ingestion of a neurotoxin an impaired LMN may lead to abnormal or impaired activation of its
derived from flour made from cassava roots that have not been soaked motor unit. In either case, the number of fully functional motor units
for a sufficient time. The disorder is endemic in protein-deficient decreases, which reduces overall muscle twitch tension.
communities in Tanzania, Zaire, and Eastern Africa and in times of In a disease causing chronic motor unit depletion, neighboring
famine can occur in epidemic form. The neurotoxic effect of chronic axons belonging to healthy motor neurons may reinnervate dener-
cassava root ingestion likely is derived from the liberation of cyano- vated muscle fibers belonging to a diseased motor unit by collateral
hydrins (cyanoglucoside linamarin) from the flour, which may be sprouting. In this way, existing motor units continually modify in the
further metabolized to thiocyanate. The latter in turn may excessively face of persistent losses of motor axons to maintain muscle strength.
For example, in patients who have recovered from acute poliomyelitis, loss of motor units reflects in the loss of the amplitude of the maximal
depletion of more than 50% of LMNs occurs before residual muscle compound muscle action potential (CMAP). In a primarily demyelin-
weakness is clinically detectable. Healthy individuals have sufficient ating process, conduction velocity slows, and, in severe cases, conduc-
motor units available to offset an unexpected loss of motor neurons tion block occurs. In a primarily axon loss process, there is usually only
(Box 97.3). a modest degree of conduction velocity slowing commensurate with
Muscle atrophy and hyporeflexia. Muscle fiber denervation dropout of large myelinated axons. Sensory nerve conduction studies
causes muscle fiber atrophy, and progressive LMN involvement are normal in pure LMN disorders.
results in reduced overall muscle bulk. Hyporeflexia occurs with LMN The needle electrode examination EMG is crucial in obtaining
involvement because the loss of active motor units reduces the overall electrophysiological evidence of abnormal motor units in LMN
muscle twitch tension; thus, muscle stretch reflexes elicit less tension disorders. Actively denervated muscle fibers discharge spon-
(diminished reflexes) or no visible twitch (absent reflexes). taneously, producing fibrillation potentials and positive sharp
Muscle hypotonicity or flaccidity. Hypotonicity, or flaccidity, refers waves. Fasciculation potentials may also be detectable, but as an
to the decrease or complete loss of normal muscle resistance to passive isolated EDX finding, they are not sufficient evidence to diagnose
manipulation. In contrast to spasticity, the muscle tone is flaccid. an axon-loss disorder. The recruitment pattern during voluntary
muscle activation is also altered in neurogenic disease, with a
Fasciculations reduced number of motor units that have an increased firing rate;
Fasciculations are spontaneous contractions of muscle fibers belong- this reflects a compensatory effort on the part of surviving motor
ing to a single (or part of a) motor unit (Video 97.2). Clinically, units to maintain a particular force. Because denervation of muscle
fasciculations appear on the muscle surface as fine, rapid, flicker- fibers triggers a reinnervation process, motor units continuously
ing, and sometimes vermicular contractions that occur irregularly remodel. Early in the reinnervating process, newly formed neuro-
in time and location. The impulse for the fasciculation appears to muscular junctions are electrically unstable, and thus an individual
arise from hyperexcitable motor axons anywhere in their course. motor unit action potential will vary in amplitude during repeated
Fasciculations can occur both in healthy individuals and in patients firing. Furthermore, newly regenerated axons that reinnervate
with LMN involvement, so fasciculations themselves do not indicate denervated muscle fibers tend to have slow conduction velocities,
LMN disease. causing a prolonged conduction time within one motor unit. All
In general, larger muscles have larger motor units and therefore these changes alter the configuration of the motor unit potential
larger fasciculations. In tongue muscles, fasciculations produce small so that it becomes irregular and polyphasic. In a chronic reinner-
vermicular movements on the tongue surface. Fasciculations usually vating process, surviving motor units may reinnervate a greater
do not cause any joint displacement but when they occur in muscles number of muscle fibers, resulting in a potential that is broader in
moving the fingers, joint movements can occur (mini-polymyoclonus) duration and higher in amplitude. Therefore, the shape of a typical
(see Video 97.2). Large fasciculations may occur in muscles undergo- chronic neurogenic motor unit potential is polyphasic, broad, and
ing extensive chronic reinnervation, such as chronic spinal muscular high in amplitude.
atrophy (SMA), Kennedy disease, and the postpoliomyelitis syndrome. Motor unit number estimation (MUNE) and similar techniques
are specialized neurophysiological tools that can estimate the number
Muscle Cramps of functioning motor units that remain in a progressive neurogenic
Muscle cramps are common in the general population and are a com- process.
mon symptom of LMN involvement and many chronic neuromuscular
diseases. The pathogenesis of cramps in all these diseases, as in normal Muscle Biopsy
individuals, is poorly understood. Cramps and fasciculations are likely Although EDX usually provides sufficient evidence of LMN involve-
to share a common pathogenic mechanism such as hyperexcitability ment, muscle biopsy may also reveal early evidence of muscle fiber
of the motor neurons. Muscle cramps are an abrupt, involuntary, and denervation and rule out other causes of muscle weakness. Denervated
painful shortening of the muscle, accompanied by visible or palpable muscle fibers are small, angular, and stain darkly by oxidative enzyme
knotting, often with abnormal posture of the affected joint. Relief of and nonspecific esterase stains. As the denervation process progresses,
cramps is by stretching or massaging. small groups of atrophied muscle fibers (group atrophy) may appear.
In normal human muscle, the different muscle fiber types that are
Laboratory Evidence of Lower Motor Neuron distinguished using myosin ATPase stain appear in a random distri-
Involvement bution, sometimes mistakenly termed a “checkerboard pattern.” In
Electrodiagnostic Examination chronic denervating disease, repeated denervation and reinnervation
The electrodiagnostic examination (EDX) consists of nerve conduc- eventually results in loss of this random pattern, and in very chronic
tion studies and needle electrode examination (see Chapter 36). The neurogenic disease (such as SMA), large areas of the biopsy con-
sist of just one muscle fiber type, a process called fiber-type grouping.
However, in a relatively rapid disorder of motor unit loss such as ALS,
there is insufficient time to develop marked fiber-type grouping.
BOX 97.3 Signs and Symptoms of Lower
Motor Neuron Involvement Acute Poliomyelitis and Other Viral Acute Flaccid
Paralyses
Loss of muscle strength (moderate to severe weakness)
Muscle atrophy Poliomyelitis has long been considered the most important cause of
Hyporeflexia virus-associated acute flaccid paralysis. However, due to the wide-
Muscle hypotonicity or flaccidity spread use of polio vaccine, it is evident now that other enteroviruses
Fasciculations and, indeed, arboviruses are more likely causes of these presentations.
Muscle cramps Poliovirus, a single-stranded ribonucleic acid (RNA) enterovirus
belonging to the picornavirus family has three subtypes, with type
I being responsible for most cases of the epidemic paralytic disease. then improves. Within 5 days, weakness, develops along with fever,
Wild-type polioviruses spread via the fecal-oral route. Before the intro- headache, and pain (in other words, a biphasic mode of presentation
duction of poliovirus vaccine in the late 1950s, epidemics of acute par- similar to childhood poliomyelitis). The patterns of weakness are sim-
alytic poliomyelitis were relatively common in temperate zones and ilar to poliomyelitis.
primarily affected children and young adults (infantile paralysis). In The EV-A71 initial presentation may be with herpangina or HFMD,
1988, the World Health Organization resolved to eradicate poliomy- with paralysis beginning between 2 and 6 days later. In addition to
elitis worldwide, but this remains unachieved as outbreaks still occur acute flaccid paralysis, there can be elements of meningitis, encephalo-
(e.g., in Nigeria, Pakistan, Afghanistan, Syria). The live oral polio myelitis, and transverse myelitis.
vaccine can itself cause poliomyelitis and there are occasions when a WNV can present dramatically with an acute asymmetrical flaccid
parent will decline polio vaccination for their child. Thus, even in the paralysis in a febrile patient with or without meningitis, encephalitis,
developed world, it is still important that physicians be acquainted and cranial neuropathies (including hearing loss). Aching pains in
with this syndrome. affected limbs often accompany the paralysis, but actual sensory loss is
Acute paralytic disease caused by other viruses such as West Nile not a feature. Respiratory failure and death may occur, and up to one-
flavivirus, Japanese encephalitis flavivirus, enterovirus D68 (EV-D68), third of cases suffer bladder and bowel dysfunction. Recovery is very
enterovirus A71 (EV-A71), and various coxsackievirus species is very slow, and, from the available evidence, incomplete.
similar to acute poliomyelitis. Awareness of EV-D68 as a major cause of Physical examination in acute flaccid paralysis reveals severe LMN-
acute flaccid paralysis increased on the back of an outbreak in 2014 in type muscle weakness with hypoactive or absent deep tendon reflexes,
North America, Europe, and Asia. Small outbreaks continue to occur decreased muscle tone, and fasciculations. With time, muscle atrophy
in clusters. This re-emergence has been postulated to be due to genetic occurs (usually beginning about 3 weeks after onset). Objective signs of
evolution of the virus over time. EV-A71 was first isolated in California sensory loss are not characteristic. In polio, the risk of paralytic disease
in the 1960s but the largest outbreaks have been in Asia in associa- seems to increase with patient age and with the level of virulence of the
tion with hand, foot, and mouth disease (HFMD) or herpangina. This virus. Most patients with paralytic polio recover significant strength.
is largely transmitted by the fecal-oral route but transmission can be Improvement may begin as early as the first week after the onset of
respiratory. Severe disease occurs in up to 30% of children hospitalized paralysis, and estimates are that 80% of recovery occurs by 6 months.
and in addition to acute flaccid paralysis, patients can develop auto- Further improvement may be modest, but it may continue over the
nomic dysregulation and brainstem encephalitis. ensuing 18–24 months. Up to two-thirds of patients have some degree
A number of arboviruses have been implicated in similar acute of functional impairment. Long-term outcome in EV-D68 is still
paralysis presentations, including West Nile virus, Japanese enceph- being evaluated but full recovery appears to be rare. There is signifi-
alitis virus, and European tick-borne encephalitis virus. Of these, the cant variability in recovery from EV-A71 but in one study only 12.5%
most important is West Nile virus (WNV), an arthropod-borne flavi- of patients had muscle weakness at 6-month follow-up, suggesting a
virus that causes epidemics of meningitis, encephalitis, and in some more favorable outcome (Hu et al., 2015). In WNV, respiratory failure
instances an acute polio-like flaccid paralysis. Approximately 80% of and death may occur, and up to one-third of cases suffer bladder and
those who are infected are asymptomatic, and 20% develop a flu-like bowel dysfunction. Recovery is very slow, and, from the available evi-
illness (termed West Nile fever). Less than 1% present with neuroin- dence, incomplete.
vasive disease. There is a predilection for adults rather than c hildren,
with a mean age of presentation of 56 years (Sejvar et al., 2005). Laboratory Features
Following the 1999 outbreak in New York, an epidemic spread across Motor nerve conduction studies performed 21 or more days after
the North American continent and peaked in 2002/2003. Epidemics the onset may reveal low-amplitude maximum CMAPs. No evidence
also occurred in multiple countries. WNV is now endemic in North of significant demyelination-related motor conduction slowing or
America and is a leading cause of arboviral encephalitis in the United block exists. Sensory nerve action potentials (SNAPs) are normal.
States. WNV is a zoonotic pathogen that has crossed over from birds EMG examination in the acute phase shows profuse axon loss in the
to humans, the latter serving as incidental hosts. The prime bridge vec- form of positive sharp waves and fibrillation potentials. In addition,
tor is the Culex mosquito, and the spread of disease appears to have fasciculations may be prominent. As motor axon loss progresses, evi-
followed the migration patterns of bird populations (Kilpatrick et al., dence of neurogenic MUP changes may be detected. The CSF typ-
2006). Human-to-human transmission can occur via blood transfu- ically shows increased protein content with normal glucose and a
sion, organ transplant, intrauterine exposure, and breastfeeding: hence pleocytosis, with polymorphonuclear cells predominating during the
the need to screen for the virus among blood donors. acute stages and lymphocytes predominating later in the disease in all
of the above infections. Poliovirus-, EV-D68-, and EV-A71-specific
Clinical Features antibodies are only rarely detected in CSF. Microbiological diagnosis
Most cases of poliomyelitis are abortive and present as a mild flu-like is most frequently made from respiratory tract and stool samples. If
illness lasting up to 3 days. An aseptic meningitis can occur but this is EV-A71 encephalitis has occurred, detection rates in CSF are higher.
also self-limiting in most patients. The paralytic polio (which affects Acute West Nile virus is most accurately detected in blood samples.
less than 1% of infected patients) typically develops 2–5 days after the In light of the knowledge that most new cases of poliomyelitis
prodromal flu-like illness and commences with myalgias, meningism, are vaccine-derived, PCR is important to distinguish wild-type from
paresthesiae, and fasciculations. Muscle weakness then develops over vaccine–induced disease.
the following 1–2 days. Any skeletal muscle can weaken, including bul-
bar muscles and muscles of respiration, but the leg muscles are the Treatment
most commonly affected and often this occurs in a monomelic fashion The treatment of acute flaccid paralysis consists of aggressive general
(Bitnun and Yeh, 2018). Acute flaccid paralysis in children can be par- supportive care. Most patients will require hospitalization in an inten-
ticularly grave. sive care unit to optimize close monitoring of ventilatory and cardio-
EV-D68 is clinically similar to poliomyelitis but spread is largely vascular function. After the acute illness, aggressive rehabilitation is the
respiratory. Often the prodrome features respiratory symptoms and mainstay of continued treatment. All healthcare staff treating patients
with acute paralytic poliomyelitis require prior immunization. There is Etiology

no proven specific treatment for EV-D68. The WHO Guide to Clinical The etiology of postpolio syndrome/PPMA is not established.
Management recommends use of intravenous immunoglobulin (IVIG) Numerous studies have failed to identify chronic persistent poliovi-
therapy for EV-A71 in patients who develop autonomic dysfunction or rus in PPMA, and solid evidence is lacking to implicate a persistent
central nervous system (CNS) disease (Cardosa et al., 2011). immune-mediated mechanism, although CSF and muscle biopsy sam-
ples show some chronic inflammation. The “peripheral disintegration
Vaccination
model” is the most widely held theory. This theory proposes that an
The best treatment for polio is prevention. Two vaccines are available, oversprouting of new axon terminals from surviving LMNs occur in
the Sabin (live-attenuated) and the Salk (inactivated). The Sabin tri- the immediate aftermath of the acute paralytic poliomyelitis. This
valent oral poliovirus vaccine, in widespread use since the early 1960s, compensatory distal reinnervation expands the size of motor units and
contains all three live attenuated serotypes of poliovirus. It is almost provides effective motor function; this stabilizes muscle strength for
100% effective in preventing acute paralytic poliomyelitis. Adults who many years. However, this extensive nerve sprouting also increases the
plan to travel to areas where poliomyelitis is prevalent should receive metabolic burden of surviving LMNs; so, after many years, an uniden-
an extra dose of this vaccine. However, the oral poliovirus vaccine itself tified process first causes nerve terminal dysfunction, presenting as
(specifically the type 2 serotype) is responsible for very rare cases of fatigue, and then nerve terminal disintegration, presenting as muscle
acute paralytic poliomyelitis in the developed world. For this reason, weakness and atrophy. It is possible that normal age-related neuronal
there is a move toward a bivalent vaccine containing only serotypes 1 loss may be the process causing this late degeneration.
and 3 (Bitnun and Yeh, 2018, Diop et al., 2014). A vaccine has been
developed for EV-A71 and has gained use in China. There is evidence
Clinical Features
that the vaccine has prevented 600,000 cases of HFMD/herpangina and
435 deaths. Although a vaccine for WNV is available for horses and Patients who develop postpolio syndrome/PPMA previously had a
also for birds in zoos, no vaccine for humans exists. The best way to stable course for many years (on average >15 years) after the acute
prevent this condition is to avoid mosquito bites through judicious poliomyelitis infection. These patients then experience progressive
use of appropriate clothing and insect repellants (Petersen et al., 2013). symptoms of new muscle weakness and new atrophy in previously
A recent trend toward parents declining to vaccinate their children affected muscles or sometimes in muscles apparently not affected by
remains a potential cause of future outbreaks. the original poliomyelitis; this deterioration occurs over a protracted
timeframe of at least 1 year. EMG examination reveals that muscles
Postpolio Syndrome/Progressive Postpoliomyelitis thought to be clinically unaffected by acute poliomyelitis often have
Muscular Atrophy evidence of previous disease (characterized by chronic neurogenic
In the United States alone, it is estimated that over 570,000 people motor unit potential (MUP) changes with or without some acute
have had poliomyelitis, of which between 15% and 80% may develop denervation). Weakness can involve limbs and/or bulbar muscula-
postpolio syndrome (PPS) (Lo and Robinson, 2018). Many years after ture. Muscle cramps and fasciculations may accompany new weak-
recovery from acute poliomyelitis, these patients experience progres- ness, but they are often present in stable muscles also. Generalized
sive functional impairment, with muscle fatigue, pain, sleep distur- fatigue is characteristic and can be the most disabling accompani-
bances, cold intolerance, depression, dysphagia, and dysarthria. If ment, often called the polio wall. Other common symptoms include
progressive muscle weakness and wasting occurs in this setting, the pain, sleep disturbances, cold intolerance, depression, hypoventila-
term progressive postpoliomyelitis muscular atrophy (PPMA) is used. By tion (manifesting as dyspnea), dysphagia, and dysarthria. The pro-
definition, patients with postpolio syndrome/PPMA have recovered posal is that these new symptoms should have persisted for a full year
from acute poliomyelitis, and the disease course has been stable for at if one is to consider the diagnosis of postpolio syndrome. The neu-
least 10 years after the recovery (Box 97.4). rological examination reveals focal and asymmetrical muscle weak-
ness and atrophy, but it may be difficult to determine whether the
weakness and atrophy is new and progressive or remote and static.
Fasciculations can be unusually coarse and large in keeping with the
giant motor units detectable during EMG examination.
BOX 97.4 Characteristic Features
of Postpolio Syndrome/Progressive Laboratory Features
Postpoliomyelitis Muscular Atrophy Because EMG provides definitive evidence of remote poliomyelitis
and can help exclude diseases mimicking PPMA, it is an indispensable
Medical history:
test when suspecting PPMA, though it cannot confirm the diagnosis.
Recovery from acute poliomyelitis
In patients with PPMA, the motor nerve conduction studies may be
A long, stable course—at least 10 years
abnormal (low maximum CMAP amplitudes) when recorded from
Signs and symptoms:
affected muscles. The needle electrode examination of affected weak
Progressive weakness, usually in previously affected muscles
muscles typically shows a reduced number of motor units and chronic
Accompanying overstressed muscle pains and arthralgia
neurogenic MUPs. Giant motor units may be present, indicative of
Laboratory studies:
chronic denervation and reinnervation. Modest numbers of fibril-
EMG is helpful to identify evidence of previous polio infection
lation potentials and occasional fasciculations may occur in affected
No test is specific for PPMA
muscles, but such electrophysiological evidence of acute muscle fiber
Diagnosis:
injury is not necessary to make the diagnosis. Sensory nerve conduc-
Exclusion of other treatable diseases
tion studies are normal. The muscle biopsy specimen usually shows
Treatment:
acute and chronic neurogenic atrophy and often marked group muscle
Symptomatic and supportive care
fiber atrophy and fiber-type grouping; however, these biopsy findings
EMG, Electromyography; PPMA, postpoliomyelitis muscular atrophy. are not diagnostic of PPMA.
Diagnosis clinically restricted to one limb. The etiology is unknown. Autopsy

A history of clinical stability for at least 10 years after recovery from studies have shown the affected region of spinal cord flattened, the
acute poliomyelitis is a prerequisite for considering the diagnosis of anterior horn markedly atrophied and gliotic, and a reduction in the
PPMA. When this requirement is satisfied, PPMA is then a diagnosis of numbers of both large and small motor neurons. Based upon neu-
exclusion. Exclude all potential diseases causing progressive, focal, and roradiological studies, Hirayama, who established the disease entity,
asymmetrical weakness. Myelopathy, radiculopathy, electrolyte abnor- has proposed a mechanically induced limited form of ischemic cervi-
malities, endocrine diseases, diabetic amyotrophy, connective tissue cal myelopathy, being the result of local compression of the dura and
disorders, entrapment neuropathies, inflammatory myositis, inflam- spinal cord against vertebrae during repeated neck flexion/extension,
matory neuropathy, and vasculitis are among the diseases to exclude in turn due to disproportionate growth between the contents of the
by appropriate laboratory studies. The symptoms of progressive focal dural sac and the vertebral column (Hirayama, 2008; Hirayama and
muscle weakness in PPMA may raise the possibility of the PMA variant Tokamaru, 2000). However, surgical decompression has not altered
of ALS. Approach this diagnosis with great caution in the setting of a the course of the disease, and this theory is no longer widely held.
history of prior paralytic polio. Another school of thought is that this is a segmental, perhaps geneti-
cally determined, SMA, but the actual cause is still unknown.
Treatment The disease usually begins in the late teens, but many cases can pres-
ent in the fourth decade. More than 60% of patients are men. Although
No specific pharmacotherapy for postpolio syndrome exists. Care
originally described in Indian and Japanese patients, the disorder is
focuses on symptom relief (Gonzalez et al., 2010). A randomized
now recognizable around the world. The most common presentation
controlled trial of IVIG (2 courses of IVIG at a dose of 90 g per
is one of an idiopathic, slowly progressive, painless weakness and atro-
course over 3 days, with a 3-month interval) reported a signifi-
phy in one hand or forearm. The distribution of muscle weakness var-
cant improvement in muscle strength but not quality of life in 135
ies markedly from case to case, but a characteristic feature is that the
patients (Gonzalez et al., 2006). Other agents have also been studied
condition remains limited to only a few myotomes in the affected limb.
but at present there is insufficient evidence to support use of any
The most common pattern is unilateral atrophy of C7–T1 innervated
of these (IVIG included) in postpolio syndrome (Koopman, 2015;
muscles, with sparing of the brachioradialis (the “oblique atrophy”
Patwa et al., 2012).
pattern). Muscle stretch reflexes are invariably hypoactive or absent in
The care plan should focus on avoiding fatiguing activities that
the muscles innervated by the involved cord segment but are normal
aggravate symptoms, modifying activities to conserve energy, weight
elsewhere. UMN signs are not present, and if they are, one should con-
reduction for those who are overweight, and treating underlying
sider the onset of ALS instead. Approximately 20% have hyperesthesia
medical disorders that reduce overall well-being. Careful screening
to pinprick and touch, usually located on the dorsum of the hand. The
and treatment for possible sleep apnea and depression are important.
cranial nerves, pyramidal tracts, and the autonomic nervous system
Those patients who have worsening of preexisting ventilatory muscles
are normal. Weakness and atrophy may progress steadily for the initial
may require noninvasive positive-pressure ventilation (NIPPV) or
2–3 years, but most patients have stabilized within 5 years. The arm is
noninvasive bilevel positive airway pressure (BiPAP) ventilation.
the affected limb in approximately 75% of the patients and the leg in
Physical therapy should focus on nonfatiguing aerobic exercise,
the remaining 25% (benign calf amyotrophy). Spread may occur to
modest isometric/isokinetic exercise, and range-of-motion stretching
the contralateral limb in about 20% of cases (Gourie-Devi and Nalini,
maneuvers. The goal should be to maintain exercise in affected mus-
2003), and rare patients later develop an ALS-like picture.
cles but not to the point of overuse, while also limiting the disuse of
No pathognomonic laboratory or electrodiagnostic tests exist for
unaffected muscles. Low-impact exercise in warm water can be par-
this condition; their main purpose is to exclude alternative diagno-
ticularly helpful and also appears to help control fatigue and pain. In
ses. Motor nerve conduction studies are either normal or reveal only
patients with more serious functional decline, prescribe appropriate
reduction in the maximum CMAPs; a modest reduction in SNAPs
assistive devices to maintain activities of daily living. Pulmonologists
occurs in up to one-third of patients. The EMG examination may show
must evaluate those who develop respiratory insufficiency to rule
some fibrillation and fasciculation potentials, and chronic neurogenic
out primary pulmonary disease and to prevent/treat chest infections.
motor unit changes are prominent. The C5–T1 myotomes are most
Patients whose employment or lifestyle involves significant physical
commonly involved when the arms are affected. Careful EMG exam-
exertion need to modify their work duties and other activities.
ination may reveal mild neurogenic changes on the asymptomatic con-
tralateral side. The serum creatine kinase (CK) concentration may be
Multifocal Motor Neuropathy modestly elevated, but other routine laboratory test results are normal.
A complete description of multifocal motor neuropathy is in Chapter Cervical MRI may reveal segmental spinal cord atrophy or occasionally
106. The condition is believed to be autoimmune in nature, and most an area of increased signal on T2-weighted scans of the cervical spinal
cases have evidence of focal demyelination in the peripheral nerves cord enlargement. “Incidental” spondylosis and cervical spinal canal
(multifocal motor neuropathy with conduction block [MMNCB]) stenosis detected by MRI require careful evaluation before the diagno-
similar to that in chronic inflammatory demyelinating peripheral sis of benign focal amyotrophy is established.
neuropathy. The clinical presentation, however, is with pure LMN
involvement. The condition enters into the differential diagnosis of Differential Diagnosis
benign focal amyotrophy and the PMA variant of ALS. It is important Two diseases require distinction from benign focal amyotrophy: ALS,
to search for this condition since it is treatable by high-dose immuno- which is almost always a relentlessly progressive terminal disease, and
globulin infusions or other immunotherapy. MMNCB, which is a treatable peripheral motor neuropathy. A small
proportion of ALS presents as an LMN monomelic disease, albeit in an
Benign Focal Amyotrophy older patient population. It is only with follow-up examination that
The terms benign focal amyotrophy, brachial monomelic amyotrophy, the more widespread anterior horn cell disorder becomes apparent and
benign calf amyotrophy, Hirayama disease, or juvenile segmental muscu- UMN signs appear. Deep tendon reflexes are almost always hyperac-
lar atrophy are used to describe disorders characterized by LMN disease tive early in the evolution of ALS. Furthermore, the electrodiagnostic
finding of generalized widespread acute and chronic motor neuron forms of the disease, there can be periods where the child will improve
loss distinguishes ALS from the segmental motor neuron involvement or plateau, but long-term studies have demonstrated a net deteriora-
of benign focal amyotrophy. The slowly progressive focal weakness tion (Russman, 2007) (Table 97.3). The estimated incidence of infan-
that is distinctive of benign focal amyotrophy may also be the present- tile and juvenile recessive SMA is 1 in 6000 to 10,000 live births, with
ing picture of MMNCB, but detailed motor nerve conduction studies an approximate carrier frequency of 1 in 35 of the general popula-
and serum tests for elevated titers of anti-GM1 antibodies can differ- tion, making it a leading genetic cause of infant mortality, although
entiate these two conditions. the carrier frequency is lower in people of sub-Saharan African origin
Cervical or lumbosacral radiculopathy may also appear in a manner (Sangaré et al., 2014). True adult-onset disease accounts for probably
somewhat akin to benign focal amyotrophy. However, radicular pains and less than 10% of all cases of SMA, with an estimated prevalence of 0.32
sensory impairment are typical of radiculopathies. Neuralgic amyotrophy/ in 100,000. The mean age at onset is the mid-30s but ranges from 20 to
Parsonage-Turner syndrome typically begins with severe pain before the the late 40s. Up to 95% of all childhood cases are due to deletion of the
onset of weakness and wasting in the distribution of predominantly motor survival motor neuron (SMN1, telomeric SMN, SMNT) gene located
nerves derived from the brachial plexus. It may also involve selected sen- on chromosome 5q11.2–13.3. The remaining cases are due to small
sory nerves. Most cases are monophasic and do not progress over years, as SMN mutations (rather than full deletions). SMN1 is located within
does benign focal amyotrophy, although hereditary neuralgic amyotrophy an inverted gene duplication, the other half of which is occupied by the
can present as recurrent bouts of brachial plexopathy. Cervical syringomy- almost identical SMN2 (centromeric SMN, SMNC) gene. The SMN1
elia or a benign tumor involving nerve roots or the spinal cord may also protein product is functionally absent in the vast majority (95%–98%)
cause progressive weakness in a monomelic fashion. Careful EMG studies of cases of SMN-mutated SMA, and small amounts are present in the
and neuroimaging should differentiate these diseases. remaining few percent. The SMN2 protein is present in all patients,
but the copy number can vary considerably. Only 1%–2% of child-
Treatment hood-onset SMA is unrelated to the SMN locus on chromosome 5.
The term benign in benign focal amyotrophy distinguishes it from malig- SMN1 protein is a 38-kDa polypeptide important in the process-
nant motor neuron disease, as seen in ALS. This condition is not life ing of the primary transcripts of other genes. Although a ubiquitous
threatening, but it nevertheless severely impairs motor function in the protein, expression is great within spinal motor neurons, and this
involved extremity (although most patients adapt very well to their dis- may be why the disorder manifests as a motor neuron disease. It is
ability). Supportive care consists of physical and occupational therapy associated with both nuclear and cytoplasmic complexes involved in
and effective use of assistive devices (splinting and braces). Tendon trans- messenger RNA (mRNA) splicing and interacts with other proteins
fers are a consideration in selected patients with focal weakness in a mus- that are important in the regulation of ribosomal RNA processing
cle group whose function is crucial for certain activities of daily living. and modification. Within the nucleus, SMN1 forms macromolecular
complexes with other nuclear proteins important in the assembly of
Spinal Muscular Atrophy spliceosomal small nuclear ribonucleoproteins (snRNPs). It is thus
SMA is a group of disorders caused by degeneration of anterior horn possible that SMA develops because of disruption in mRNA transport
cells and, in some subtypes, of bulbar motor neurons. Almost all cases and/or SMN-dependent snRNP biogenesis. SMN2 protein is almost
are genetically determined, with most being autosomal recessive due identical to SMN1 protein but only has about 10% of the activity of
to homozygous deletions of the survival motor neuron (SMN) gene on SMN1 protein because of a C-to-T transition within exon 7 that alters
chromosome 5. Traditionally, SMA is classified as one of the four types splicing. The full-length SMN1 transcript has all 9 exons, whereas
based on the age at onset: SMA type 1 (infantile SMA or Werdnig- 90% of the transcripts from SMN2 lack exon 7. Thus, only 10% of the
Hoffmann syndrome), SMA type 2 (intermediate SMA), SMA type SMN2 output is the full-length SMN transcript, the remainder being
3 (juvenile SMA or Kugelberg-Welander disease), and SMA type 4 unstable and rapidly degraded. Therefore, despite the near-identical
(adult-onset SMA, pseudomyopathic SMA). A very severe prena- nature of the two proteins, SMN 2 cannot compensate fully for loss
tal form of SMA (type 0 SMA) can manifest prenatally with reduced of SMN1. Motor neuron health requires at least 23% full-length SMN
fetal movements and respiratory distress at birth. It is also important protein. The SMN genome is rather unstable and, as a consequence,
to consider the maximum function that a child achieves in terms of increased copy numbers of SMN2 are possible through a process of
sitting and walking; this is of prognostic significance. In the less severe gene conversion from SMN1 to SMN2. This has major implications for
TABLE 97.3 Childhood and Adult Spinal Muscular Atrophies

Maximum Function
SMA Type Age at Onset Achieved Survival/Prognosis Inheritance Defective Gene
0. Prenatal Prenatal Needs respirator support Fatal at birth without AR SMN gene
at birth respirator support
1. Infantile SMA (Werd- Birth to 6 months Sits with support Death by age 2 years AR SMN gene
nig-Hoffmann)
2. Intermediate SMA Before 18 months Sits independently No walking, adulthood AR SMN gene
3. Juvenile (Kugel- After 18 months Walks independently: Adulthood AR SMN gene
berg-Welander) approx. 25 steps
4. Adult-onset SMA After 5 years Walks normally Slow progression AR, AD “Sporadic” SMN gene VAPB, dyn-
(pseudomyopathic (most >30 years) Proximal or distal actin unknown, distal
SMA) overlap with HMN-V
AD, Autosomal dominant; AR, autosomal recessive; HMN-V, hereditary motor neuropathy type V; SMA, spinal muscular atrophy; SMN, survival
motor neuron; VAPB, vesicle-associated membrane protein B.
.
the clinical phenotype: the infantile form is very severe because most of may reveal fine, small-amplitude involuntary movements called
these children have no SMN1 and only two copies of SMN2, thus pro- minipolymyoclonus that are due to dense fasciculations. Contractures
ducing about 9% of full-length functional transcript, whereas multiple usually do not develop in the early phases but may develop after
copies of SMN2 (3–5) are associated with mild SMA (Hirth et al., 2005; several months of immobilization. Bulbar muscle weakness makes
Kostova et al., 2007; Monani, 2005). A study from Japan showed that feeding laborious, causes a continuous gurgling, and eventually leads
the type of SMA mutation itself is also an independent determinant of to aspiration pneumonia. Fasciculations of the tongue occur in about
severity (Yamamoto et al., 2014). 50% of affected infants. In contrast to bulbar and extremity muscles,
Most (about 70%) adult-onset type 4 SMA is autosomal recessive, the facial muscles are only mildly weak, giving these children an alert
is allelic with SMA types 1, 2, and 3, and is due to mutations or dele- expression. Extraocular movements are always normal. Intercostal
tions in the SMN1 gene. Gene conversion events occur in some cases muscles are severely weak, but diaphragmatic strength preserves
with SMA type 4 whereby SMN1 is “converted” to SMN2. The remain- until late in the disease. This dysequilibrium of ventilatory muscle
ing adult-onset SMA cases are autosomal dominant, autosomal reces- function causes outward flaring of the lower ribcage and gives rise
sive (but not linked to chromosome 5), or are apparently sporadic. to a bell-shaped chest deformity. Death from respiratory failure,
One rare form of adult-onset SMA described in a large Brazilian family pneumonia, and malnutrition usually occurs before age 2 years. A
was caused by a missense mutation in the vesicle trafficking protein, rare form of atypical infantile SMA, spinal muscular atrophy with
vesicle-associated membrane protein (VAPB). This can present with respiratory distress (SMARD) (Viguier et al., 2019), is associated with
typical ALS or with a late-onset SMA (Nishimura et al., 2004). respiratory distress, cardiomyopathy, and lactic acidosis. This disorder
is not due to SMN1 deletion but caused by mutations in the gene for
Clinical Features immunoglobulin mu-binding protein 2 (IGHMBP2). It is interesting
Spinal muscular atrophy type 1, infantile form (Werdnig- that this gene has homology to SETX, the gene responsible for ALS4,
Hoffmann disease). SMA type 1 begins within the first few months which can cause a familial form of distal amyotrophy, oculomotor
of life. By definition, children with this disease are never able to sit apraxia–cerebellar ataxia, or juvenile ALS.
without support. Symptoms include severe hypotonia, a weak cry, and Spinal muscular atrophy type 2, intermediate form (chronic
respiratory distress. These children are unable to lift their heads when spinal muscular atrophy). The signs and symptoms of SMA type 2
placed prone and demonstrate severe head lag when pulled from a usually begin between the ages of 6 and 18 months. Delayed motor
supine to a seated position (Fig. 97.1). The baby’s posture at rest also milestones are often the first clue to neurological impairment, with
takes a characteristic “frog-leg” position, with the thighs externally more prominent leg weakness then arm weakness. A fine hand tremor
rotated and abducted and the knees flexed (a “floppy” baby). Limb due to minipolymyoclonus suggests the diagnosis. The distribution,
weakness is severe, generalized, and worse proximally. The infant pattern, and progression of weakness is similar to that found in
is unable to sit and raise its arms or legs from the examining table, SMA type 1, but type 2 disease is quantitatively much milder, and
but there may be antigravity movements of the hands and flickering progression is slower. Most children eventually are able to roll over
movements of the feet. Muscle stretch reflexes are usually absent, and sit unsupported, but they rarely achieve independent walking.
and the sensory examination is normal. Observation of the fingers Weakness of trunk muscles produces a characteristic rounded kyphosis
A B D
Fig. 97.1 A 6-Month-Old Baby with Werdnig-Hoffmann Disease. A, The baby has a typical “frog leg”
posture; mouth is triangular, and facial expression suggests facial weakness. B, On sitting, the baby cannot
sustain his head upright. C, When the baby is pulled by the arms, the head falls back. D, When the body is
held supine, the head and extremities drop by force of gravity, and there is no active body motion. (Courtesy
Neil Friedman, Cleveland Clinic.)
in the seated position, and, as the shoulders weaken, the child becomes a scapuloperoneal-type presentation (Biasini et al., 2016). CHCHD10
less mobile and eventually wheelchair confined. Contractures of the autosomal dominant disorders are also highly variable and can be
hips and knees, clubfoot deformities, severe scoliosis, and dislocation ALS-like, frontotemporal-type dementia (FTD)-like, myopathy-like,
of the hips may eventually develop. The long-term prognosis varies or SMA-like (Penttila et al., 2015).
markedly; some die in childhood because of respiratory failure, but A relatively new class of adult-onset SMA has recently emerged and
many others survive into the third or fourth decade of adulthood. is sometimes referred to as SMA-5 to help distinguish a distal rather
Another rare childhood-onset form of SMA that is distinct from SMA than proximal pattern of slowly PMA. The classification of these rare
type 2 is Fazio-Londe disease. This is a form of sporadic autosomal dom- disorders is rather vague, and considerable overlap with distal CMT (see
inant or autosomal recessive progressive facial and bulbar palsy of late later discussion) exists. Several patterns of inheritance occur, includ-
childhood. Affected children are normal at birth but develop progressive ing autosomal dominant, autosomal recessive, and X-linked recessive.
bulbar palsy (PBP) and eventual respiratory failure in the second decade Some lack any apparent pattern of inheritance. Distal-predominant
of life, with little or no evidence of involvement of other motor neurons adult-onset SMA and some of the neuronal forms of CMT disease
and with usually normal extraocular motility. The differential diagnosis appear to overlap both clinically and genetically: indeed, the difference
includes a structural brainstem lesion, myasthenia gravis, and the Miller may be purely semantic. Motor-predominant CMT variants such as
Fisher variant of Guillain-Barré syndrome (GBS). hereditary motor neuronopathy type 5 (HMN-5), itself a heteroge-
Spinal muscular atrophy type 3, juvenile form (Kugelberg- neous group of conditions, present with a slowly progressive LMN-
Welander disease). The onset of the juvenile form of SMA is typically predominant disorder affecting distal limb muscles. Mutations in the
after 18 months of age (usually between 5 and 15 years) and presents glycyl-tRNA synthetase (GARS) gene, for example, were identifiable in
with difficulty in walking. Patients with onset before the age of 3 years multiple families around the world. Patients usually present with very
are subclassified as SMA type 3a and those after age 3 years as SMA indolent symmetrical or asymmetrical weakness, clumsiness, and wast-
type 3b. The disorder has an appearance not unlike a limb-girdle ing of intrinsic hand muscles (with a particular predilection for thenar
muscular dystrophy. As weakness in hip-girdle muscles increases, the muscles) in the absence of any proximal weakness or sensory findings.
child develops a waddling (Trendelenburg) gait, with a protuberant There is little functional disability (Del Bo et al., 2006; Dubourg et al.,
abdomen due to an exaggerated lumbar lordosis, and trouble climbing 2006). Mutations in the p150Glued subunit of the dynactin gene, a
stairs. As weakness progresses, the Gowers maneuver is used to arise microtubule protein important in axonal transport, cause another
from lying supine on the floor. Pseudohypertrophy of the calf muscles distal-predominant atrophic disorder that also has a predilection for
sometimes occurs, but this may be an illusion resulting from relative thenar muscles. Unlike the GARS-associated disorder, involvement of
preservation of calf muscles as compared to thigh muscles. Eventually, the face and vocal cords may occur (Puls et al., 2005).
wasting and weakness of the neck, shoulders, and arms develop,
but, as with SMA type 2, weakness in the lower extremities is nearly Laboratory Studies
always more severe than in the upper extremities. Fasciculations are The first-line investigation in autosomal recessive proximal SMA (types
more prominent than in SMA types 1 and 2, and a fine action tremor 0–4) is molecular genetic analysis to identify homozygous deletions
is common. Tendon reflexes uniformly reduce and are lost, and the in the SMN gene on chromosome 5q and, if confirmed, no further
sensory examination is normal. work-up is necessary. However, if a homozygous deletion of SMN1
The clinical course of SMA type 3 is one of slowly progressive is not detectable in a patient with a clinical picture consistent with
limb-girdle weakness, but there may be long periods of stability that last SMA, one can assay for the combination of a deleted SMN allele on
for years. The eventual degree of disability is difficult to predict, but if one gene and a point mutation on the other. PCR is able to distinguish
onset is after the age of 2 years, it is likely that the patient will remain the single nucleotide change in exon 7 that determines SMN2 from
ambulatory into the fifth decade of life and enjoy a normal lifespan. SMN1. It requires measurement because it has prognostic importance.
Spinal muscular atrophy type 4, adult-onset. Most cases of Serum CK may be elevated up to 10 times normal levels in SMA type
autosomal recessive, 5q-associated, adult-onset SMA appear to affect 3 but is typically normal in the infantile and intermediate types. EMG
proximal muscles. The characteristic clinical presentation is that of a is valuable in supporting the diagnosis, although it may be technically
slowly progressive limb-girdle weakness leading to difficulty in walking, limited in children by the need to carry out the test under conscious
climbing stairs, and rising from a chair or the floor. Fasciculations are
an important finding and occur in 75% of patients. Quadriceps muscle
weakness is often a prominent feature. Muscle cramps occur but
are not prominent. Bulbar signs, bony deformities such as scoliosis,
and respiratory weakness are rare. Many cases have a distribution of
weakness reminiscent of the limb-girdle muscular dystrophies, leading
to the older term, pseudomyopathic SMA (Fig. 97.2).
Many cases of autosomal dominant adult-onset SMA (also known
as Finkel-type SMA) are clinically similar to the recessive form described
earlier. Finkel-type SMA usually begins in the third decade of life, is
proximal in distribution, is very slowly progressive, and involves the
legs before the arms. Most patients remain ambulatory for decades
after clinical onset. One of the autosomal dominant missense muta-
tions causing adult-onset Finkel-type SMA affects VAPB. It is interest-
ing that some patients with this mutation develop the clinical features
of ALS rather than SMA (Nishimura et al., 2004). DYNCH1H1 and
BIC2D (both autosomal dominant) can cause a phenotype of lower Fig. 97.2 Patient with mild adult-onset proximal spinal muscular atro-
extremity predominant SMA (SMALED) (Beecroft et al., 2017; Wan phy and marked shoulder-girdle muscle atrophy. Note subluxation at
et al., 2019 ). TRP4V-associated disease is very variable but can include both shoulder joints and marked deltoid muscle atrophy.
sedation. CMAPs may be reduced in amplitude, but conduction of ALS. However, adult-onset SMA progresses very slowly, whereas
velocities and sensory nerve conduction study results are normal. The PMA progresses relatively rapidly (albeit slower than classic ALS).
needle electrode examination may reveal evidence of acute denerva- Furthermore, muscle biopsy and EDX assessment in adult-onset SMA
tion (fibrillation potentials and positive sharp waves) along with fas- reveals a markedly chronic disease, whereas PMA findings are consis-
ciculation potentials and evidence of chronic motor unit remodeling tent with more subacute denervation and thus more modest evidence
due to a chronic process of denervation and reinnervation. Reduced of neurogenic motor unit remodeling.
recruitment of large polyphasic motor units is therefore characteris-
tic, although sedation hampers full voluntary activation. Complex Treatment
repetitive discharges are an electrodiagnostic feature of SMA type 3. A major breakthrough in specific treatment of SMN1 gene SMA has
Muscle biopsy reveals a highly characteristic pattern called grouped been made with the approval of intrathecal antisense oligonucleotide
fascicular atrophy (especially in typical Werdnig-Hoffmann SMA): (ASO) therapy (nusinersen) in SMA types 1, 2, and 3a. Indeed, the
entire fascicles or groups of fascicles are atrophied, whereas neighbor- potential for this therapy to transform Werdnig-Hoffmann disease
ing fascicles (often made up entirely of type 1 fibers) are composed from a universally fatal disorder to a slow chronically progressive dis-
of hypertrophied fibers. It is important to remember that myopathic ease must be considered a medical triumph. ASOs are complemen-
changes, including fiber size variability, fiber splitting, internal nuclei, tary to “sense” strand nucleic acids to which they bind and control
and fibrosis, complicate long-standing denervating disorders such as gene expression: nusinersen binds to the intronic splicing sequencer
childhood and juvenile SMA. N1 (ISS-N1) and thus promotes exon 7 production in the final tran-
While serum CK and aldolase are often normal in adults with SMA script (the production of full-length protein from SMN2). The treat-
type 4, they may be elevated to levels less than 10-fold the normal val- ment improves rates of survival/freedom from use of a ventilator at
ues. Motor nerve conduction studies reveal normal conduction veloc- 24 months. In those with later-onset disease, there are demonstrable
ities and reduced CMAPs in the presence of normal SNAPs. Needle improvements in motor function (Michelson et al., 2018). Intrathecal
electrode studies show marked chronic neurogenic motor unit changes, administration can be challenging in the older age groups due to scoli-
which are modest if any evidence of acute denervation. Myopathic osis and respiratory difficulties and a multidisciplinary approach is rec-
changes due to secondary myopathic degenerative changes in motor ommended (Wurster et al., 2019). An issue with this treatment is the
units are also common. Fasciculation potentials may occur in involved expense of the ASO therapy itself; cost–benefit analyses are important
muscles. When molecular genetic testing fails to help with diagnosis, when considering this form of therapy (Zuluaga-Sanchez et al., 2019).
it can be very useful to get a muscle biopsy, which typically shows evi- Additional treatment focuses on supportive care, including physio-
dence of a markedly chronic denervation similar to that described in therapy, respiratory care, nutritional support, orthotics, and ortho-
SMA type 3 but with more frequent changes of secondary myopathy. pedic interventions. Typical Werdnig-Hoffmann disease is almost
uniformly fatal by age 2 years. However, because some affected infants
Differential Diagnosis survive beyond infancy and live into childhood, aggressive manage-
For infantile SMA type 1, one must exclude all other causes of infan- ment including physiotherapy and respiratory therapy is essential in
tile hypotonia. This includes Pompe disease, centronuclear myopa- all cases.
thy, nemaline myopathy, congenital muscular dystrophy, central core The management objectives in young children with the intermedi-
disease, and congenital or infantile myotonic dystrophy. For older ate form are twofold: (1) maintain active mobility and independence
children with suspected types 2 and 3 SMA, the differential diagnoses as long as possible and (2) prevent the development of contractures
include myasthenia gravis, various muscular dystrophies, inflamma- and kyphoscoliosis. Any devices, even a scooter board, should be con-
tory myopathies, and a variety of structural, metabolic, and endocrine sidered to maintain mobility. Because all patients invariably become
myopathies. Clinical, laboratory, and muscle biopsy features usually wheelchair confined, the use of an electric-powered wheelchair is
distinguish these disorders with relative ease. Limb-girdle muscular required. However, the timing of wheelchair use is critical because it
dystrophy may be difficult to distinguish from adult-onset proximal hastens the development of contractures and scoliosis. Stretching exer-
SMA; it can be autosomal recessive, is often adult-onset, and affects cises in major joints should be part of the patient’s daily routine.
predominantly proximal muscles. The pattern of muscle weak- Patients with SMA have normal or increased intelligence. They
ness often points to the diagnosis; for instance, in adult-onset SMA, attend school and as adults often live and work outside the home.
the triceps muscles may be weaker than the biceps, the opposite of A well-coordinated multidisciplinary approach is essential when
the situation in limb-girdle muscular dystrophy. Muscle biopsy in attempting to optimize residual function, especially during periods of
limb-girdle muscular dystrophy reveals a primary myopathy rather disease progression. Physical therapy, occupational therapy, orthope-
than a neurogenic process, but one should be aware that some degree dic evaluation, and emotional support are essential.
of secondary myopathic changes can occur in long-standing SMA. Maintaining an upright position delays the development of sco-
Immunohistochemistry and Western blotting on muscle biopsy are liosis. Therefore, a specialized evaluation for a wheelchair at a com-
able to distinguish SMA from dystrophinopathies, sarcoglycanopa- prehensive seating clinic is critical. A back brace potentially delays
thies, calpainopathies, and dysferlinopathies. Other myopathies con- the development of scoliosis. However, bracing remains controversial
sidered include polymyositis and adult-onset acid maltase deficiency. because it does little to retard the onset or progression of scoliosis
Chronic inflammatory demyelinating polyneuropathy (CIDP) may and may actually impair function in some patients by reducing spinal
mimic SMA because of chronic proximal muscle weakness, but the flexibility and respiratory vital capacity. Potential benefits from brac-
tendon reflexes are usually diffusely absent in CIDP, whereas some are ing include reduced back discomfort and the ability to sit for longer
preserved in SMA. Electrodiagnostic studies in CIDP reveal a demye- periods.
linating polyradiculoneuropathy, and CSF protein levels are increased. Progressive scoliosis eventually requires surgical correction in most
Hexosaminidase-A deficiency in adults has a similar phenotype to patients with juvenile SMA. In general, delay surgery until growth
adult-onset SMA, but several nonmotor symptoms typically arise. In ceases. However, in some patients who have never ambulated or who
the absence of a family history of SMA, it can be most difficult to dis- lost ambulation very early, consider surgical intervention for severe
tinguish adult-onset distal-predominant SMA from the PMA variant scoliosis even before growth ceases. Improved aesthetics, balance, and
seating comfort are among the benefits; however, lack of body flex- 26 in this coding region, whereas in patients with Kennedy disease, the
ibility, reduced pulmonary function, and general decline in overall repeats range from 40 to 65. Two independent components exist for
motor function may occur after surgery. Pros and cons for scoliosis the symptoms of Kennedy disease, one androgen dependent and the
surgery must be openly discussed with the patient, although for most, other androgen independent. The gynecomastia and testicular atrophy
the benefits outweigh the disadvantages. Preoperative and postoper- seen in Kennedy disease may be associated with the classic function of
ative physical and occupational therapy assessments are critical steps the androgen receptor, and thus the severity of symptoms might relate
for the patient who contemplates spinal fusion for progressive scoliosis directly to the receptor’s affinity for androgen. Studies of cultured
in SMA. scrotal skin fibroblasts found that direct high-affinity dihydrotestos-
terone binding decreases in some patients. The abnormal expansion of
Genetic Counseling and Prenatal Diagnosis CAG repeats involves the first exon, an amino-terminal transactivating
SMA is one of the most devastating diseases of childhood, and the par- domain of the androgen receptor protein. The expansion of the CAG
ents of affected children and their relatives should receive genetic coun- repeat in an androgen receptor causes a linear decrease in the transac-
seling, including determination of carrier status of SMN genes. The tivation function but does not completely eliminate androgen receptor
available carrier detection tests determine the SMN1 and SMN2 gene activity. The residual androgen receptor activity is sufficient to ensure
dosages and are best carried out in a family where an SMN deletion has normal development of male primary and secondary sexual charac-
been found previously in an affected individual or for an individual teristics, as evidenced by the fact that affected men are phenotypically
who is about to marry a known carrier. Noncarriers will have a single male and usually fertile.
copy of the normal SMN1 on each chromosome, whereas carriers will The subtle decline of androgen receptor transactivation may even-
have only one normal and one deleted SMN gene. Determination of tually lead to the loss of integrity of certain tissues that require contin-
the SMN2 gene dosage in the setting of an SMN deletion is of partic- uously high androgen levels. Androgens are crucial for normal male
ular prognostic importance: the more copies of SMN2, the better the development of motor neurons in the rat spinal bulbocavernosus
prognosis. nucleus and for regenerating facial motor neurons in rats and ham-
sters. Therefore, continuous androgen receptor function may be cru-
Kennedy Disease (X-Linked Recessive Bulbospinal cial to maintain normal motor neuron function throughout life.
Neuronopathy) As with most other trinucleotide repeat expansion disorders such
In 1968, Kennedy and colleagues reported a new X-linked recessive as Huntington disease and several spinocerebellar ataxias, the trinu-
SMA with bulbar involvement and gynecomastia. The primary pathol- cleotide repeat expansion mutation appears to confer a toxic gain-
ogy was thought to be in the LMNs, but sensory system involvement of-function on the gene product rather than a loss of function. In
was later recognized, which led to the term bulbospinal neuronopathy. fact, complete absence of the androgen receptor leads to an entirely
Molecular genetics research has shown Kennedy disease to be a trinu- different disorder called androgen-insensitivity syndrome. The mutant
cleotide repeat expansion disease. Though rare, it is more common androgen receptor leads to an altered receptor–DNA interaction or
than adult-onset SMA (Box 97.5). receptor–protein interaction that interferes with neuronal function.
The CAG repeat encodes an unusually long polyglutamine tract in the
Pathogenesis androgen receptor protein, which appears to alter the normal protein
In 1991, La Spada and colleagues found the gene abnormality respon- moiety, resulting in mutant protein aggregation. This may in turn
sible for Kennedy disease: a cytosine-adenine-guanine (CAG) trinucle- interfere with proteasomal breakdown of other cellular proteins and/
otide repeat expansion on the androgen receptor gene located on the or interfere with tubulin-mediated cellular transport. Mutant protein
X chromosome. In normal individuals, the repeats range from 17 to may also interfere with mitochondrial function and transcription reg-
ulation and contribute to endoplasmic reticulum stress (Cortes and La
Spada, 2018).
BOX 97.5 Characteristic Features of
Kennedy Disease Clinical Features
As is often seen in an X-linked syndrome, this is a disorder of men,
Pathogenesis:
who remain largely asymptomatic until after age 30 years. Hand
X-linked recessive inheritance
tremor and subtle speech disturbance are early features that are fol-
Abnormal CAG expansion in the gene encoding androgen receptor protein
lowed by LMN muscle weakness, initially involving either the proximal
Neurological manifestations:
hip extensor or shoulder girdle muscles, and associated with decreased
Slowly progressive limb-girdle muscle weakness
or absent reflexes, muscle atrophy, and occasionally calf pseudohyper-
Early tremor
trophy. Kennedy disease usually causes no respiratory muscle weak-
Slowly progressive moderate bulbar dysfunction
ness. Coarse muscle fasciculations can be prominent in the extremities
Muscle cramps and prominent fasciculations
and trunk and muscle cramps can be a first symptom in many (Rhodes
Facial fasciculations
et al., 2009). Facial and perioral fasciculations are present in more
Systemic manifestations:
than 90% of patients (Video 97.3). The tongue shows chronic atrophy,
Gynecomastia (60%–90%)
often as a longitudinal midline furrow. However, despite weakness of
Endocrine abnormalities (testicular atrophy, feminization, infertility)
facial and tongue muscles, significant bulbar symptoms are usually a
Diabetes mellitus
relatively late feature. Neurological examination of the sensory system
Laboratory studies:
may reveal only modest impairment. Progression is slow, with most
Markedly abnormal sensory nerve conduction studies
cases remaining independent of assist devices until late into the fifth
Elevated serum creatine kinase
decade of life (Atsuna et al., 2006). If bulbar dysfunction is severe, the
Abnormal sex hormone levels
prognosis becomes less favorable. Partial androgen insensitivity is an
Abnormal CAG repeats in the androgen receptor gene
important element of this condition, and gynecomastia is one of the
CAG, Cytosine-adenine-guanine. unique features of Kennedy disease that can be found in 60%–90% of
patients (Fig. 97.3). Other endocrine abnormalities include testicular Differential Diagnosis
atrophy, infertility (40%), and diabetes mellitus (10%–20%). It is now The clinical features (e.g., progressive limb-girdle weakness, bulbar
recognized that female carriers may manifest subtle neurological defi- signs, muscle cramps, prominent fasciculations) resemble those of
cits such as late-onset bulbar dysfunction. ALS, but a careful physical examination should provide sufficient clues
This disorder often exhibits genetic anticipation—that is, the to distinguish one from the other. The most characteristic features are
greater the number of repeats, the younger the age at onset. However, gynecomastia, perioral fasciculations, calf pseudohypertrophy, and
the number of repeats has no correlation with other features such as hand tremor. Generally, ALS progresses rapidly, whereas Kennedy dis-
severity of weakness, serum CK level, and presence or absence of gyne- ease is a largely indolent disorder. The EDX in Kennedy disease shows
comastia, impotence, or sensory neuronopathy. Furthermore, there abnormal sensory nerve conduction studies, which is unusual for any
is marked variation in phenotypical expression within and among motor neuron disease. Kennedy disease may also be easily mistaken for
families. adult-onset SMA because of the slowly progressive limb-girdle weak-
ness in both, but bulbar involvement and gynecomastia are unlikely
Laboratory Studies features of SMA. Hereditary sensorimotor neuropathy, limb-girdle
Molecular genetic testing is available to identify the abnormal expan- dystrophy, or facioscapulohumeral muscular dystrophy also may
sion of the CAG repeat in the exon 1 of the androgen receptor gene on mimic Kennedy disease. Careful clinical examination, EDX studies,
the X chromosome. CK levels may be elevated as high as 10 times nor- and muscle or nerve biopsy distinguishes these disorders. Ultimately,
mal. Serum androgen levels are either normal or decreased, whereas a molecular gene study to identify the abnormal CAG repeats in the
estrogen levels are elevated in some patients. The estrogen-to-andro- androgen receptor gene will yield the answer.
gen ratio increases in some patients, but there is no consistent finding
regarding sex hormone levels, and evidence of partial androgen resis- Manifesting Carrier
tance may not develop for several years after disease onset. The female children and mother of an affected male patient are all obli-
Motor nerve conduction study results are generally normal, gate carriers (except in rare instances of a de novo mutation). Male
although one-third of the patients have reduced amplitudes of children of affected individuals cannot inherit the mutant gene on
CMAPs. EMG examination of these patients is always abnormal and the X chromosome. Female siblings of an affected patient have a 50%
shows modest acute but prominent chronic denervation changes in chance of carrying the affected gene on the X chromosome. Through
motor units. EDX reveals a sensory neuronopathy in 95% of patients a process known as skewed X chromosome inactivation (lyonization),
(Ferrante and Wilbourn, 1997). Another unique change is the presence female carriers can present with neuromuscular symptoms such as
of prominent fasciculation potentials in the face (especially in the peri- exertional muscle pain, cramps, and late-onset bulbar dysfunction,
oral region) and limbs. and the EDX may detect mild chronic denervation in both upper and
Muscle biopsy shows modest denervation, prominent reinnerva- lower limb muscles.
tion, and fiber-type grouping similar to that seen in other forms of
adult-onset SMA. Sural nerve biopsy usually reveals a loss of myelin- Treatment
ated fibers. Supportive and symptomatic therapy is the key to treatment, as out-
lined in the section on adult-onset SMA. Muscle cramps may be prob-
lematic but are often relieved by baclofen, clonazepam, or vitamin
E. Patients with symptomatic diabetes require appropriate medical
management.
In Kennedy disease, dysarthria and dysphagia may cause marked
disability. Although severe loss of bulbar function is rare, offer speech
therapy and appropriate communicative devices when appropriate.
Careful nutritional management is also important. Enteral feeding
provided via gastrostomy is the most effective and practical means to
meet nutritional and fluid requirements. Genetic counseling is import-
ant for patients, potential carriers, and male siblings. A natural histo-
ry-controlled study recently showed that long-term use of leuprorelin,
a gonadotrophin analogue, improves elements of functional decline
and also reduces respiratory complications and death in Kennedy dis-
ease (Hashizume et al., 2017).
Progressive Muscular Atrophy

PMA, first described by Aran in 1850, is a clinical LMN disorder during
its entire clinical course and comprises approximately 5%–8% of all
adult-onset motor neuron diseases. It is an overwhelmingly sporadic
disease, but rare genetic diseases, such as those due to mutations in
dynactin, VAPB, and A4V SOD1, may present with a pure LMN disor-
der, so a careful family history is important. Although PMA occurs in
both sexes, men are more often affected than women. In a recent study,
Fig. 97.3 A man with X-linked recessive bulbospinal muscular atrophy the average age of onset of PMA was about 3 years older than that of
(Kennedy disease), showing gynecomastia. (From Perkin, G.D., Miller, ALS, but other studies report a younger age at onset (Kim et al., 2009;
D.C., Lane, R.J.M., Patel, M.C., Hochberg, F.H., 2011. Atlas of Clinical Murray, 2006). Several studies have demonstrated that PMA pro-
Neurology, third ed. pp. 28–56. © Saunders.) gresses more slowly than ALS, so the average survival is significantly
longer. The mean duration of disease was 159 months in one series evidence of multifocal demyelination conduction blocks and elevated
of cases, and in another study, the 5-year survival was 63.7% in PMA titers of antibodies against GM1 gangliosides. Clinically, patients
versus 36.8% in ALS. Most of the very longest-duration cases of “ALS” develop slowly progressive multifocal muscle weakness but less prom-
have the PMA variant. Interestingly, the recent paper by Kim et al. inent muscle atrophy. The treatment of choice is human IVIG (Van
showed that the development of UMN signs was unrelated to survival den Berg-Vos et al., 2000). The clinical and electrodiagnostic find-
time after diagnosis (Kim et al., 2009; Murray, 2006). However, Visser ings of sensory involvement, high CSF protein levels, and response to
et al. (2007) showed that patients with a low vital capacity baseline with immunotherapy readily separate CIDP and PMA. Important clues that
an early decline in pulmonary function in the first 6 months had an should lead one to suspect inclusion body myositis (IBM) are elevated
especially poor prognosis. serum CK to levels more than expected in typical PMA and a selective
It has been questioned whether PMA is an independent disease or weakness in wrist flexors, finger flexors, and quadriceps muscles, with-
represents one end of the spectrum of ALS. However, if followed over out fasciculations. EMG in IBM should show evidence of a primary
time, many patients with PMA go on to develop clinical features of myopathy with increased insertional activity but without fasciculations.
upper motor neuron disease, which allows reclassification to ALS (and In IBM, additional neurogenic changes are common, and quantitative
thus eligibility for entry into clinical trials). In a recent retrospective EMG may be required to clearly identify the myopathic nature of this
study of 916 cases diagnosed with ALS at a major neurological center, disorder. Muscle biopsy characteristically reveals rimmed vacuoles and
in 91, the original diagnosis was PMA; 20 of these developed UMN nuclear inclusions. Adult-onset SMA is a far more indolent disorder
signs within 61 months of the original diagnosis. Autopsy studies have than PMA, and the very chronic process of denervation and reinner-
also demonstrated UMN involvement in some cases classified as PMA vation in SMA leads to fiber-type grouping on muscle biopsy, which
in life. Studies using magnetic resonance spectroscopy and/or TMS is not a prominent feature of the less-protracted PMA. It is import-
reveal evidence for upper motor neuron involvement in PMA patients. ant to carry out regular follow-up examinations on patients with PMA
Furthermore, cognitive/behavioral changes similar to those seen in to search for signs of UMN involvement that indicate the diagnosis of
ALS are also detected in PMA (Kim et al., 2009; Maragakis et al., 2010; ALS. The pure motor neuropathy forms of CMT (especially heredi-
Rowland, 2006). tary motor neuropathy type V) present with a slowly progressive distal
pattern of weakness and wasting, with no sensory changes. A familial
Etiology pattern is usual, and genetic testing may reveal mutations in different
All hypotheses about the cause of ALS are also applicable to PMA (see genes such as GARS or seipin. A paraneoplastic motor neuronopathy
Etiology, under Amyotrophic Lateral Sclerosis, later in this chapter). has been described with clinical features that are similar to PMA, albeit
with more rapid progression and with later development of nonmo-
Clinical Features tor features. Many such cases have anti-Hu antineuronal antibodies in
By definition, the signs and symptoms of PMA are LMN in type the setting of solid cancers (especially small-cell lung cancer). A similar
throughout the entire clinical course. A common presentation is that subacute presentation may also occur in patients with lymphoma or
of focal asymmetrical muscle weakness in the distal extremities, with other lymphoproliferative disorders, although signs of corticospinal
gradual spread to other contiguous muscles. The weakness and muscle tract dysfunction may become apparent in over 50% of cases. The onset
atrophy are purely LMN in type and eventually involve both the upper of lymphoma may or may not coincide with onset of motor features.
and lower extremities. A less common presentation is that of proximal
rather than distal muscle weakness. Bulbar and respiratory involve- Treatment
ment eventually develops but is not as common in the early stages as The treatment of PMA is identical to that of ALS, as summarized later
in classic “spinal” ALS. in this chapter.
Laboratory Studies Subacute Motor Neuronopathy in Lymphoproliferative

The serum CK concentration may be moderately elevated, especially Disorders
when patients are physically active, but never attains levels more A subacute, progressive, and painless motor neuron syndrome may
than 10 times normal. Patients with PMA do not have high titers of rarely develop in patients who have Hodgkin and non-Hodgkin lym-
anti-GM1 antibodies. The EMG examination reveals findings con- phoma with or without a paraproteinemia (Rowland, 2006; Rudnicki
sistent with a widespread disorder of anterior horn cells and is use- and Dalmau, 2000). The lymphoma may or may not temporally coin-
ful to exclude other diagnostic possibilities such as CIDP, MMNCB, cide with the motor neuron disorder, and one or other disorder may
or myopathy. Muscle biopsy will show denervation atrophy, but it is present first. Although UMN signs may develop later in more than half
usually unnecessary to perform this test unless the clinical features are of all cases, a LMN-onset syndrome is typical, with patchy, asymmet-
unusual enough to suggest an alternative diagnosis. rical, lower extremity–predominant muscle weakness and wasting.
Neuropathology shows a loss of anterior horn cells and ventral root
Differential Diagnosis nerve fibers; some have evidence of inflammation in the anterior horns
PMA is usually a fatal disease and has no cure. Therefore, the diagnosis of the spinal cord, and half have corticospinal tract degeneration. In
of PMA requires the exclusion of all other potentially treatable or defin- some patients, the disease may be relatively benign. The rate of pro-
able diseases. Indeed, PMA-like disease is the most common type of gression of muscle weakness and atrophy tends to slow down with time,
presentation in the “mimic” disorders spectrum (Cortes-Vicente et al., and, in rare instances, the motor syndrome may respond to treatment
2017). In a previous review, 17 of 89 patients originally diagnosed with of the underlying lymphoproliferative disorder. However, the prog-
PMA were later diagnosed with MMNCB, CIDP, inflammatory myop- nosis appears to be less favorable in those who develop a combined
athy, and myasthenia gravis (Visser et al., 2002). MMNCB is the most UMN and LMN disorder. Twenty percent of all cases so far reported
important of the alternative conditions that may present with focal and with motor neuron presentations in the setting of lymphoprolifera-
asymmetrical weakness in the absence of UMN signs (for more detailed tive disease had myeloma or macroglobulinemia. The pathogenesis of
description, see Chapter 106). The classic form is associated with EDX this ALS-like disorder is undetermined, but an immune mechanism
may be at play; small patient series and case reports reveal that some
BOX 97.6 Practical Classification of
patients who develop this LMN syndrome may have various autoan-
tibodies (such as antisulfatide antibody), paraproteinemia, increased
Amyotrophic Lateral Sclerosis
CSF protein, and/or oligoclonal bands. Sporadic or acquired ALS:
Classic (spinal-onset) ALS
Postirradiation Lower Motor Neuron Syndrome Mills hemiplegic variant
Radiation directed to the retroperitoneal paraaortic area for the treat- Pseudoneuritic presentation
ment of testicular or lymphoid cancers can cause a pure LMN syn- Flail-arm presentation
drome in the lower extremities that first appears many years after the Monomelic presentation
irradiation. Sensory abnormalities and sphincter dysfunction are rare, UMN onset
and the EDX findings are consistent with a disorder of the lumbosacral LMN onset
motor neurons or the cauda equina (the SNAPs are spared). Myokymic Bulbar onset
discharges and nonresolving conduction blocks are characteristic elec- Dyspnea onset
trodiagnostic features. The disease usually progresses over the first few Progressive muscular atrophy
years after symptom onset but subsequently becomes stable. There is Primary lateral sclerosis
debate as to the exact mechanism. There is only anecdotal evidence Progressive bulbar palsy
that antiinflammatory therapies may be of benefit (Chamberlain et al., Western Pacific ALS
2011). Familial ALS:
ALS1: SOD1 missense mutations, chr 21q-22.1, adult, AD (rare AR)
ALS2: ALSIN mutations, chr 2q330, juvenile onset, AR
DISORDERS OF BOTH UPPER AND LOWER MOTOR ALS3: gene unknown, chr 18q, adult, AD
NEURONS ALS4: senataxin gene, chr 9q34, juvenile onset, AD
ALS5: linked to chr 15q15, juvenile onset, AR
Amyotrophic Lateral Sclerosis ALS6: FUS/TLS, chr 16p, adult, FTD overlap, AD (some AR)
ALS is a neurodegenerative disorder of undetermined etiology that pri- ALS7: gene unknown, chr 20p, adult, AD
marily affects the motor neuron cell populations in the motor cortex, ALS8: VAPB, chr 20q, adult, AD
brainstem, and spinal cord. It is progressive, and most patients even- ALS9: angiogenin, chr 14q, adult, AD
tually succumb to respiratory failure. The first detailed description was ALS10: TDP-43, chr 1q, adult, FTD overlap, AD
by Jean Martin Charcot in 1869, in which he discussed the clinical and ALS11: FIG4, chr 6q, adult, AD
pathological characteristics of “la sclérose latérale amyotrophique,” a ALS12: optineurin, chr 10p15, AD
disorder of muscle wasting (amyotrophy) and gliotic hardening (scle- ALS13: ATXN2 12q24, association
rosis) of the anterior and lateral corticospinal tracts (Gordon, 2006) ALS14: VCP, Chr 9p13
involving both upper and lower motor neurons. ALS is known by ALS15: UBQLN2, chr X
several other names including Charcot disease, motor neuron disease, ALS16: SIGMAR1, chr 9p13
and, in the United States, “Lou Gehrig disease” in remembrance of the ALS17: CHMP2B, chr 2q, adult, AD
famous “Iron Horse” of baseball who was diagnosed with ALS in 1939. ALS18: PFN1, chr 17p13
The World Federation of Neurology Research Group on ALS19: ERBB4, chr 2q34
Neuromuscular Disorders has classified ALS as a disorder of motor ALS20: HNRNPA1, chr 12q13
neurons of undetermined cause, and several variants are recognized. ALS21: MATR3, chr 5q31.2
Included in this group are PLS and PBP. As previously mentioned, ALS22: TUBA4A, chr 2q35
PMA is also thought to be a variant of ALS, despite its exclusion from ALS23: ANXA11, chr 10q22.3
current clinical research trial criteria. It is important to recognize that ALS24: NEK1, chr 4q33
ALS is a progressive dynamic disorder. Some cases present with the ALS25: KIF5A, chr 12q13.3
classic combination of UMN and LMN signs, but others may have ALS due to rare mutations (e.g., p150 dynactin subunit mutation, DAO
UMN onset, LMN onset, bulbar onset, or dyspnea at onset and only mutation, SQSTM1 mutation, hnRNPA1 mutation, ERLIN2 mutation,
later develop signs of involvement of the other parts of the motor sys- UNC13A mutation, cytochrome oxidase gene mutation, NF heavy chain
tem (Box 97.6). gene mutation, peripherin, APEX nuclease gene mutation)
Between 5% and 10% of ALS is familial rather than sporadic, the FTD-ALS overlap:
most common inheritance pattern being autosomal dominant. Thus ALS-FTD, C9orf72, chr 9p21, adult, AD (can present as pure ALS also or as
one comes across the terms sporadic ALS (SALS) and familial ALS pure FTD)
(FALS). A few other conditions have a phenotypical expression similar FTD with some ALS features; tau gene on chr 17 and progranulin gene on
to that of ALS, including Western Pacific ALS-parkinsonism-dementia chr 17.
complex (PDC) (or Guamanian ALS) and juvenile ALS.
The incidence and prevalence rates for sporadic ALS are surpris- AD, Autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, auto-
somal recessive; chr, chromosome; FTD, frontotemporal dementia;
ingly uniform throughout the world. The estimated incidence in
LMN, lower motor neuron; UMN, upper motor neuron.
North America and Europe is about 2 per 100,000, and the preva-
lence is about 5–7 per 100,000 (Mehta et al., 2016). In sporadic spinal
ALS, the male-to-female ratio is 1.2–1.4 : 1, but a slight female pre- 3 years, but roughly 1 in 5 patients survive to 5 years, and 1 in 10
dominance exists in the bulbar-onset variety. ALS may occur as early patients survive to 10 years (Murray, 2006). The disease process may
as in the second decade of life, but the peak incidence is in the 65- be more aggressive in patients with bulbar onset, older age at onset,
to 74-year-old age bracket (McGuire and Nelson, 2006). The mean and certain genotypes (Al-Chalabi and Hardiman, 2013). No specific
disease duration from symptom onset to death is approximately environmental, occupational, or physical factors link with absolute
certainty to an increased risk of ALS. Areas of interest include chronic strengthened by the observation that exogenous glutamate receptor
exposure to electromagnetic fields, high levels of physical activity agonists result in clinically observable neurotoxicity, as seen in
(e.g., ex-National Football League players; Lehman et al., 2012), lathyrism, Guamanian ALS, and Konzo (see previous section on UMN
high dietary intake of glutamate, environmental toxins, and a history disease). Domoic acid is another potent non-N-methyl-d-aspartic acid
of military service in the Persian Gulf War. Smoking appears to be (NMDA) receptor agonist that can cause motor weakness. An outbreak
an independent risk factor for sporadic ALS, with a higher risk for of food poisoning caused by ingestion of mussels contaminated with
those who have smoked for many years (Armon, 2009; Gallo et al., domoic acid–producing phytoplankton diatoms led to an amnestic
2009). Several environmental trace elements have been evaluated as syndrome and, in some cases, significant muscle weakness (sometimes
potential causative agents for ALS, including selenium, aluminum, manifesting as an alternating hemiplegia) (Costa et al., 2010).
iron, manganese, copper, zinc, cadmium, and lead, but there is no Impaired glutamate transport reduces clearance of glutamate from
convincing evidence that any one of these plays a major part in ALS the synaptic cleft, which may leave excessive amounts of free excitatory
pathogenesis. neurotransmitter to repeatedly stimulate the glutamate receptor and
thus allow calcium ions to enter the neuron. Regional differences in
Pathology the levels of activity of calcium buffering systems and in glutamate
The pathological hallmarks of ALS are the degeneration and loss of receptor subtype expression may explain the selective vulnerability of
motor neurons, with astrocytic gliosis and microglial proliferation certain motor neuron pools within the CNS.
in the presence of intraneuronal inclusions in degenerating neurons Immunological and inflammatory abnormalities. Several pieces
and glial cells. UMN cell loss occurs in the motor cortex, with loss of of evidence implicate an inflammatory process in the pathogenesis, if
Betz cells from Brodmann area 4 and astrocytic gliosis and axonal loss not the initiation, of ALS. It is now understood that there is a complex
in corticospinal tracts. There is loss of LMNs in the brainstem and interplay between astrocytes, microglial cells, proinflammatory
spinal cord, with both TAR DNA binding protein 43-positive and cytokines, and cell adhesion molecules as part of the pathogenesis of
FUS-positive ubiquitinated inclusions in remaining neurons. Small both sporadic and familial ALS. However, immunotherapies have been
eosinophilic cytoplasmic inclusions called Bunina bodies are common. ineffective to date. Whether these inflammatory responses are part of
Extramotor pathology may also be found in the frontotemporal cortex, the pathogenesis or are indeed part of a protective response remains
hippocampus, thalamus, spinocerebellar tracts, dorsal columns, and to be elucidated (Haukedal and Freude, 2019). Unfortunately, various
substantia nigra. strategies aimed at modulation of the immune system have failed to
alter the course of ALS in treatment trials to date.
Etiology Mitochondrial dysfunction. Disturbances in mitochondrial
The cause for sporadic ALS is unknown. A significant body of basic function and structure occur in both human ALS and in transgenic
and clinical research lends strong support to a theory of ALS patho- animal models of the SOD1-associated disease, which suggests a role
genesis which proposes selective motor neuron damage from a com- for aberrant redox chemistry in the earlier stages of disease. In effect,
plex chain of injurious events involving excitotoxins, oxidative stress, mitochondrial damage may impair the cellular energy production
neurofilament dysfunction, altered calcium homeostasis, mitochon- system. Mutant SOD1 aggregates appear to clump together on
drial dysfunction, enhanced motor neuron apoptosis, and proin- mitochondrial membranes and may also interfere with chaperone-
flammatory cytokines. Genetic factors may play a role in “sporadic” assisted mitochondrial protein folding. Furthermore, axonal transport
disease: several proposed ALS susceptibility genes include APOE, of mitochondria along axons may be disrupted (Shi et al., 2010). Recent
SMN, peripherin, apex nuclease gene, and vascular endothelial evidence reports that Betz cells that display TDP-43 inclusions show
growth factor (VEGF) gene. Indeed, it has been proposed that onset dysfunction at the level of the mitochondria, endoplasmic reticulum,
of ALS is a multi-step process in which a genetic mutation represents and the nuclear membrane. Furthermore, these changes emerge early
one of several steps in the development of the disease (Al-Chalabi and in the disease (Gautam et al., 2019). Experimental ALS models also
Hardiman, 2013). display a role for mitochondrial dysfunction in FUS-associated disease
Protein aggregation. One of the pathological hallmarks of sporadic (Cozzolino et al., 2013).
ALS is the presence of TDP43- and FUS-positive ubiquitinated Neurofilament and microtubule dysfunction. Abnormalities of
intraneuronal inclusion bodies in neurons and glial cells. TDP43 axonal transport likely play a significant part in the pathogenesis of
and FUS, both implicated in the pathogenesis of FALS and SALS, are ALS. Mutations in the genes for neurofilament subunits (neurofilament
normally nuclear proteins, but in ALS they are mislocalized to the heavy chain and peripherin), although rare, appear to confer increased
cytoplasm in the form of distinct aggregates (inclusion bodies); how risk for the later development of SALS (Robberecht and Philips,
the mislocalization contributes to neuronal loss is still unclear. Several 2013). It has been shown that mutations in profilin 1 (PFN1), which
other pathological intracellular aggregates described in ALS can contain is an important protein involved in the polymerization of actin, can
neurofilament proteins, chaperone proteins (14-3-3), and copper-zinc cause ALS, as can mutations in VAPB and dynactin (see Familial
superoxide dismutase (SOD1). Furthermore, mutations in other ALS- Amyotrophic Lateral Sclerosis section). Antibodies to phosphorylated
associated genes, such as UBQLN2, C9orf72, SIGMAR1, PFN1, DAO, neurofilament heavy subunit or neurofilament light subunit have
and ATXN2, are also associated with aggregate formation (Finsterer emerged as new diagnostic biomarkers for ALS, although their use
and Burgunder, 2014). It is still unclear whether protein aggregation is in detecting disease progression over time appears to be limited
directly toxic to cells or is a defense mechanism to reduce intracellular (Mitsumoto and Saito, 2018).
aggregation of toxic proteins. Aberrant RNA processing. RNA metabolism refers to the
Glutamate excitotoxicity and free radical injury. Glutamate, which various steps in the life of RNA molecules from pre–mRNA splicing
is the most abundant free amino acid in the CNS, is one of the major through RNA editing and processing, and then on to transport,
excitatory amino acid (EAA) neurotransmitters. Glutamate produces reassembly into polyribosomes, and degradation. An evolving
neuronal excitation and participates in many neuronal functions, theory, and perhaps the most important one in ALS pathogenesis
including neuronal plasticity. In excess, however, it causes neurotoxicity. is that mutations in such proteins as C9orf72, TDP43, FUS/TLS,
The role of glutamate excitotoxicity in neurodegeneration is senataxin, peripherin, SMN1, SOD1, and angiogenin may result
in aberrant interactions in RNA metabolism (Chew et al., 2019, Symptoms of muscle weakness vary, depending on which motor
Finsterer and Burgunder, 2014; Haeusler et al., 2014; Robberecht function is impaired. For example, when weakness begins in the
and Philips, 2013). hand and fingers, patients report difficulty in turning a key, button-
ing, opening a bottle cap, or turning a doorknob (Fig. 97.4). When
Clinical Features weakness begins in the lower leg, foot drop may be the first symptom,
The typical clinical picture in ALS is that of a patient with a pro- or the patient may complain of instability of gait, falling, or fatigue
gressive motor deterioration manifesting with both UMN and LMN when walking (see Video 97.3). When bulbar muscles are affected, the
symptoms and signs. Thus, one should consider this diagnosis when a first symptoms may be slurred speech, hoarseness, or an inability to
patient presents with a combination of marked weakness and wasting sing or shout, soon followed by progressive dysphagia (Fig. 97.4; see
but with brisk reflexes, spasticity, and pathological reflexes. Of course, Video 97.4). Patients with bulbar-onset ALS often initially consult ear,
not all patients present with this classic pattern: muscle weakness nose, and throat (ENT) specialists and not only experience progressive
in ALS usually begins in a focal area, first spreading to contiguous impairment in bulbar function but also excessive drooling (sialorrhea)
muscles in the same region before involvement of another region. and weight loss. Pseudobulbar palsy may present with inappropriate
The first presentation may appear very similar to a focal mononeu- or forced crying or laughter (see Signs and Symptoms of Upper Motor
ropathy, sometimes called the pseudoneuritic or flail leg presentation Neuron Involvement, earlier in this chapter), which is often a source
(Wijesekera et al., 2009). More commonly, however, single-limb of great emotional distress for patients. Excessive forced yawning may
weakness appears to occur in muscles derived from more than one also be a manifestation of pseudobulbar palsy. In the rare patient who
peripheral nerve and/or nerve root distribution; this is a monome- presents with progressive respiratory muscle weakness, the first con-
lic presentation. Onset of muscle weakness is more common in the sultation may be with a pulmonologist or even admission to the inten-
upper than the lower extremities (classic, spinal ALS), but in approxi- sive care unit; the diagnosis of ALS may be established when the patient
mately 25% of patients, weakness begins in bulbar-innervated muscles fails weaning from the ventilator. Head drop (or droop) may be a fea-
(bulbar-onset ALS). On rare occasions (1% or 2% of patients, more ture in ALS, caused by weakness of cervical and thoracic paraspinal
often male), the weakness starts in the respiratory muscles (dyspnea muscles (Fig. 97.6). Fasciculations are not commonly the presenting
or respiratory onset). Some patients present with weakness that is
restricted to one side of the body (Mills hemiplegic variant), and up to
10% of patients appear with bilateral upper-extremity wasting, which
is known as the flail arm or flail person in the barrel variant. The latter
is more commonly seen in males and typically presents in proximal
muscles of the upper limb before spreading distally into the hands,
and then much later (one study used a 12-month interval) into other
regions. Reflexes may be retained or even brisk in the markedly weak-
ened limbs (Video 97.4).
Fig. 97.5 Atrophy of the Tongue in Amyotrophic Lateral Sclerosis.
B
Fig. 97.4 A, B, Severe intrinsic hand muscle atrophy in a patient with
amyotrophic lateral sclerosis. Note the “claw hand” and atrophy of Fig. 97.6 Patient with amyotrophic lateral sclerosis, showing head droop
muscles innervated by both ulnar and medial nerves. caused by weakness of the thoracic and cervical paraspinal muscles.
feature of ALS, but they develop in almost all patients soon after onset, Onufrowicz in the sacral cord are essentially not involved in ALS, and
and their absence should prompt one to reconsider the diagnosis. In thus patients generally do not complain of significant problems with
some patients, waves of fasciculations spread across the chest or back. sphincter control (although some may report mild urgency of mictu-
Muscle cramps are one of most common symptoms in patients with rition). Similarly, eye movements are typically normal in ALS; it takes
ALS and often precede other symptoms by many months. In ALS they detailed quantitative testing to be able to identify abnormal vertical
can occur in unusual muscles such as in the thigh, abdomen, back, or ocular saccades. Approximately 5% of patients with ALS exhibit signs
tongue. Spasticity develops in wasted muscles, and patients may suffer of extrapyramidal tract dysfunction, usually in the form of retropul-
painful flexor spasms in limbs. sions during attempted ambulation.
As dysphagia worsens, reduced caloric intake worsens fatigue and
accelerates muscle weakness. Aspiration of liquids, secretions, and Natural History of the Disease
food becomes a risk. Patients may complain that they produce copi- Evidence exists for a preclinical phase in ALS. Patients lose motor
ous amounts of abnormally thick oral secretions, which may drool neurons before they become aware of weakness. Wohlfart (1958) esti-
excessively from the mouth. This sialorrhea is made worse as perioral mated that collateral reinnervation could offset the development of
muscles weaken and/or head drop develops. Weight loss is often rap- clinical weakness until at least 30% of anterior horn cell motor neu-
idly progressive; this does not simply reflect poor caloric intake but rons had been lost. Swash and Ingram described a case of sporadic ALS
represents a form of ALS cachexia. Marked loss of muscle bulk exposes who complained of muscle fatigue for 6 years before onset of weak-
joints and associated connective tissues to abnormal mechanical ness, wasting, and fasciculations. However, once the clinical phase is
stresses that can lead to joint contractures, joint deformities, painful evident, a generally linear decline in motor function occurs over time.
shoulder pericapsulitis, and bursitis. Sleep disturbances in the form The pattern of disease spread is predictable. When onset is in one arm,
of increased awakenings from hypopnea and hypoxia are common in spread is often first to the contralateral side, then the ipsilateral leg, the
ALS and contribute to daytime sleepiness, morning headaches, and contralateral leg, and finally the bulbar region. Onset in the leg often
fatigue. As respiratory difficulty worsens, patients may be unable to lie follows a similar pattern, yet again with final involvement of the bul-
supine because of worsening diaphragmatic weakness and thus com- bar region. Bulbar-onset ALS tends to spread to the hands first, with
pensate by using multiple pillows. In more advanced stages, patients spread to thoracic myotomes, and then the legs. Overall, the pattern
are unable to lie in bed at all. Other manifestations of ventilatory fail- suggests that rostral-caudal involvement is faster than caudal-rostral
ure include dyspnea on exertion and eventually dyspnea at rest. As spread. During the course of the disease, transitory improvement, pla-
the disease advances, motor function is progressively impaired, and teaus, or sudden worsening can occur, but spontaneous improvement,
activities of daily living (e.g., self-hygiene, bathing, dressing, toilet- although reported, is exceedingly rare.
ing, walking, feeding, and verbal communication) become difficult.
Accordingly, a patient’s quality of life progressively deteriorates. It
Prognosis
may be difficult to distinguish daytime fatigue, broken sleep, affect
lability, and sighing from depression, but it is vitally important to be The median duration of ALS from clinical onset ranges from 22 to 52
aware of the latter, as both fatigue and depression may occur in ALS months and the mean duration from 23 to 43 months, with an average
(McElhiney et al., 2009). 5-year survival rate of 22% (roughly 1 in 5) and a 10-year survival rate
FTD and/or cognitive impairment is present in many patients of 9.4% (roughly 1 in 10) (Murray, 2006). The most robust poor prog-
with ALS, albeit on a spectrum from apparently normal to a florid nostic factors in ALS are older age at onset and bulbar-onset pattern
FTD. These observations lend support to the notion that ALS is (Chio et al., 2009). Other important poor prognostic factors include
not a pure disorder of motor neurons, but rather a disorder that short interval between onset and clinical diagnosis (correlating with
primarily affects motor neurons, with the potential to involve non- a more aggressive presentation), rapid progression rate as assessed on
motor systems. One needs to be cautious when assessing apparently return visits, low body mass index, FTD-ALS presentation, dyspnea at
cognitively normal patients with ALS because the deficits may be onset, and rapid rate of decline in pulmonary function. PLS and PMA
so subtle as to require specific assessments of personality, behav- (clinically UMN- or LMN-only presentations) usually portend a bet-
ior, praxis, verbal fluency, visual attention, and verbal reasoning. ter prognosis, whereas several other clinical subtypes, including Mills
Dysarthria may mask language disturbances (especially anomia). hemiplegic variant, the pseudoneuritic presentation (flail leg), and the
With appropriate testing, cognitive deficits may be found in about flail-arm variant, harbor a better prognosis. Those who have younger
50% of patients with ALS, but the full clinical (Neary) criteria for a age at onset and those who are psychologically well adjusted have a bet-
diagnosis of FTD are met in only about 15%–20% of cases (Lomen- ter prognosis. Those who have low-amplitude CMAPs in the setting of
Hoerth, 2011). Many of the genetic causes of ALS can also present normal sensory potentials (the generalized low motor-normal sensory
with frontotemporal dementia (e.g., C9orf72) (see section on famil- pattern) as revealed by nerve conduction studies appear to have a poor
ial ALS below, Box 97.6). prognosis. Low serum chloride levels are associated with a short-term
survival without ventilatory support because they reflect accumulation
Atypical Features of bicarbonate due to respiratory failure. There may be differences in
Extrapyramidal dysfunction, eye movement abnormalities, auto- natural history and prognoses in different parts of the world; a natural
nomic disturbances, and abnormal sphincter control are extremely history study in China revealed that Chinese ALS is somewhat younger
rare in ALS, and their presence should always prompt one to recon- in onset (mean age, 49.8 years) and with less bulbar presentations and
sider the diagnosis. Eye movement abnormalities, however, occur in a median survival time of 71 months (Chen et al., 2015)
rare cases maintained on ventilators, and sphincter disturbances have
appeared in a few reports. Although sparing of the sensory system is Laboratory Studies
characteristic, some patients do report vague sensory symptoms such The diagnosis of clinically definite ALS can sometimes be established
as numbness or aching, and there is electrophysiological evidence that on the history and clinical examination alone, but owing to the serious-
ascending afferent pathways may be involved, despite the absence of ness of the diagnosis, ancillary investigations are necessary to exclude
objective sensory loss on physical examination. The motor neurons of other possibilities. All such testing is an extension of a thorough history
and physical examination and includes blood tests, the EDX, and made of a special EDX finding, the split-hand phenomenon; in some
neuroimaging. patients with ALS, EDX reveals severe changes in muscles of the lat-
Several blood tests are commonly performed as part of the eval- eral hand (thenar eminence) but relative sparing of the medial hand
uation of patients with suspected ALS. The list includes serum CK (hypothenar eminence). EDX changes should be observed in a certain
concentration, blood count, chemistry panel (including calcium, topographical distribution and ideally should be carried out in at least
phosphate, and magnesium), Venereal Disease Research Laboratories three of the four regions of the neuraxis (bulbar, cervical, thoracic, and
(VDRL) test results, HIV, GM1 autoantibody titers, sedimentation lumbosacral).
rate, serum protein immunofixation or immunoelectrophoresis, The most important role for neuroimaging studies in ALS is to
angiotensin converting enzyme (ACE) and glycosylated hemoglobin exclude structural, inflammatory, or infiltrative disorders that may
(HbA1c), thyroid function studies including thyroid-stimulating hor- mimic this disease, and therefore all patients should undergo appro-
mone, serum parathormone (if calcium is raised), and vitamin B12 priate imaging of brain and spinal cord. On occasion, one may dis-
levels. The serum CK concentration may be modestly elevated, par- cern abnormal signal in the motor tracts when viewed with proton
ticularly early in the disease and in active males. Patients older than 50 density–weighted MRI scans of brain; this signal change is due to
years and smokers of any age should have a chest radiograph taken. If Wallerian degeneration and if seen occurs in patients with more severe
any chest lesion is identifiable, or if the presentation is subacute with disease. FLAIR and T2-weighted fast-spin echo sequences are less spe-
atypical features such as sensory loss, an anti-Hu antibody level should cific in their ability to detect such corticospinal tract signal changes.
be determined. Certain patients may have clinical features that suggest Nonspecific atrophy of the frontal and parietal cortex may also occur.
a disorder of the neuromuscular junction and should have testing for Ultrasound may have a role in detection of tongue fasciculations that
antibodies against the acetylcholine receptor or voltage-gated calcium may not be otherwise found by EMG (Misawa et al., 2011; O’Gorman
channel. If there is biochemical evidence of adrenal insufficiency, it is et al., 2017). The search for ALS biomarkers has led to the investi-
prudent to obtain a VLCFA assay to investigate for possible adrenomy- gation of other imaging techniques such as magnetization transfer
eloneuropathy. Young-onset ALS with atypical clinical features such ratio (MTR) imaging, magnetic resonance voxel-based morphome-
as early dementia, cramps, and tremor should prompt the physician try, magnetic resonance spectroscopy, and DTI (Mazon et al., 2018).
to obtain a leukocyte Hex-A assay. Young age at onset, with perioral Functional imaging studies with blood oxygenation level–dependent
fasciculations and gynecomastia, should prompt genetic assessment (BOLD) functional MRI and magnetoencephalography may reveal
for the trinucleotide repeat expansion on the androgen receptor gene abnormal activity in motor and nonmotor areas in ALS, but further
that is present in Kennedy disease. If there is a positive family history in studies are needed to determine their role in UMN assessment (Agosta
otherwise typical ALS, it is important to counsel the patient in prepa- et al., 2010; Turner et al., 2009). Similarly, additional research is neces-
ration for appropriate mutation analysis. Reserve CSF examination for sary to clarify the role of TMS, whether used alone or in combination
cases with features suggestive of an infectious or infiltrative process with DTI in the evaluation of the UMN system (Foerster et al., 2013;
such as lymphoma or basal meningitis or suspected CIDP. No specific Mitsumoto et al., 2007; Vucic and Rutkove, 2018).
features on muscle biopsy distinguish ALS from other neurogenic dis- While erect forced vital capacity is the most commonly mea-
orders; reserve biopsy for cases that are more suggestive of a myopathy. sured index of pulmonary function in ALS, supine FVC provides a
The EDX is an invaluable tool in the investigation of ALS and its more accurate assessment of diaphragmatic weakness. The maxi-
variants (see Chapter 36). It serves as an adjunct to the clinical exam- mal inspiratory pressure (MIP) and nocturnal oximetry are possi-
ination and is particularly useful in determining the presence or extent bly more effective for the detection of nocturnal hypoventilation.
of LMN disease. Again, none of the EDX findings are ALS specific, Transdiaphragmatic sniff pressure (sniff Pdi) and the sniff nasal
but they can strongly support the diagnosis. Furthermore, repeated pressure (SNP) are also useful indicators of hypercapnia and noctur-
investigations at intervals monitor disease progression. Sensory nerve nal hypoxemia (Carratù et al., 2011; Miller et al., 2009; Niedermeyer
conduction studies are characteristically normal unless the patient et al., 2019).
happens to have a coincidental mononeuropathy or polyneuropathy.
Motor nerve conduction study results may be normal, although the Diagnosis
conduction velocity and CMAP amplitude may diminish in keeping In May 1990, at El Escorial, Spain, the World Federation of Neurology
with the extent of motor axon loss. There should be no evidence of established diagnostic criteria for ALS, which were later modified at
conduction slowing or block, which would suggest a primarily demy- Airlie House, Virginia (1998) (http://www.wfnals.org). These criteria
elinating disorder. Severe motor axon loss may give rise to the “gener- (Table 97.4) include clinical, electrodiagnostic, and pathological com-
alized low motor-normal sensory” EDX pattern, which may portend a ponents. The clinical criteria divide candidates into those with definite,
poorer prognosis. probable, laboratory-supported probable, possible, and FALS-based
The EMG examination characteristically reveals a combination of on a careful history and examination of four regions of the neuraxis:
acute (positive sharp waves and fibrillation potentials) and chronic bulbar, cervical, thoracic, and lumbosacral. The purpose of establish-
(reduced neurogenic firing pattern with evidence of increased ampli- ing these criteria was to facilitate entry of appropriate candidates into
tude and duration, polyphasic MUPS) changes in a widespread distri- clinical research trials, but they prove invaluable in the assessment of
bution that is not in keeping with any single root or peripheral nerve all patients with ALS.
distribution. Fasciculation potentials are common and typically of A patient is referred to as having “definite ALS” if there is clini-
complex morphology; their absence should prompt an investigation cal evidence of both UMN and LMN signs in three or more regions.
for another disorder. The Awaji-shima algorithm for the neurophysio- “Probable ALS” is UMN and LMN signs in two regions. “Possible
logical diagnosis of suspected ALS stresses the importance of fascicula- ALS” implies that a patient either has UMN and LMN signs in one
tion potentials: the presence of fasciculations potentials is evidence of region only or has UMN signs alone in two regions. In addition, “pos-
acute denervation in the same way that one regards fibrillation poten- sible ALS” may be applied to those with LMN signs in two regions as
tials and positive sharp waves. Moment-to-moment amplitude vari- long as these are detected rostrally to the UMN signs. “Probable ALS-
ation, indicating impaired motor unit stability, is also an important laboratory supported” refers to those patients who have clinical evi-
sign of denervation (Carvalho and Swash, 2009). Mention should be dence of possible ALS but also have EDX evidence of more widespread
TABLE 97.4 Diagnostic Criteria for the Clinical Diagnosis of Amyotrophic Lateral Sclerosis
Definite ALS UMN and LMN signs in at least 3 regions (bulbar and 2 spinal regions or 3 spinal regions without bulbar)
Probable ALS UMN and LMN signs in 2 regions, with some UMN signs rostral to LMN signs
Probable ALS, lab-supported UMN and LMN signs in 1 region, with UMN signs alone in another region and EMG evidence of LMN involvement in at least 2 limbs
Possible ALS UMN and LMN signs in 1 region; or UMN signs alone in 2 or more regions; or LMN signs are rostral to UMN signs
Familial ALS, lab-supported Otherwise unexplained UMN or LMN signs in at least 1 region, with gene mutation in the proband or a positive family history of
family member with a disease-causing gene mutation
ALS, Amyotrophic lateral sclerosis; EMG, electromyographic; LMN, lower motor neuron; UMN, upper motor neuron.
Adapted from revised World Federation of Neurology Criteria for the Diagnosis of ALS. Available at http://www.wfnals.org.
LMN involvement. The proposal is that one should apply the Awaji disorder, but some patients also have demyelinating lesions in the CNS
neurophysiological algorithm to the revised El Escorial criteria to that cause additional UMN signs.
clarify the El Escorial electrodiagnostic criteria and improve diagnos- It may be difficult to differentiate PBP from bulbar myasthenia
tic sensitivity. The Awaji algorithm has increased the importance of gravis, as even repetitive stimulation studies and testing for serum
fasciculation potentials as being representative of acute denervation as antibodies against acetylcholine receptor may be negative in the lat-
long as there is evidence of chronic denervation in the same muscles. ter. Follow-up examinations, however, usually reveal the insidiously
Using both sets of criteria together, Carvalho and Swash demonstrated progressive nature of the motor neuron disorder. Bulbar symptoms in
an increased sensitivity in the diagnosis of bulbar-onset ALS from 38% ALS may be mistaken for brainstem stroke, but the progressive nature
with revised El Escorial alone to 87% when both sets of criteria were of bulbar symptoms and negative brainstem MRI will usually clarify
used. Another group achieved a specificity of over 95% when using the picture. On rare occasions, the increased tone, dysarthria, and sia-
both sets of criteria together (Carvalho and Swash, 2009; Douglass lorrhea of Parkinson disease may be confused with ALS. However, the
et al., 2010, Gawel et al., 2014). More recently, a combination of clin- former is characteristically responsive to l-dopa, and tremor is often
ical, electrophysiological, and TMS measures can generate an entity prominent. Multiple-system atrophy may present with a combination
known as the ALS diagnostic index (ALSDI), which may help distin- of UMN and LMN signs together with dysarthria and dysphagia, but
guish suspected ALS from mimics (Geevasinga et al., 2019). Follow-up cerebellar ataxia, eye-movement abnormalities, sphincter disturbance,
examinations may be helpful in assessing patients with ALS, as dis- and dysautonomia are usually prominent features. SCA types 2 and 3
ease progression may move a patient up a category, which not only (Machado-Joseph disease) are also part of the differential diagnosis.
may clarify the diagnosis but also may allow entry of that patient into Other diseases that mimic ALS include adult Hex-A deficiency, adre-
research trials. nomyeloneuropathy, and certain motor paraneoplastic syndromes.
Hyperthyroidism may present with hyperreflexia, weight loss, and
Differential Diagnosis fasciculations but also tremor, heat intolerance, and tachycardia.
The differential diagnosis of ALS is rather extensive; motor symptoms Hyperparathyroidism may present with a LMN or even myopathic
and signs may be present in many other neurological and systemic disorder that mimics PMA. Both the benign fasciculation syndrome
disorders. Because there are no specific diagnostic markers for ALS, and cramp-fasciculation syndrome may lead to referrals for the evalu-
differentiating all other motor neuron diseases that may produce signs ation of ALS, but these patients have no other symptoms or signs that
and symptoms of UMN, LMN, or both UMN and LMN involvement suggest a widespread progressive disorder of motor neurons.
is essential for establishing the correct diagnosis. One may approach
this task in an anatomical fashion and consider how ALS may appear Treatment
similar to other disorders of the brain, brainstem, spinal cord, ante- Treatment of ALS is outlined in Box 97.7 and Table 97.5.
rior horn cell, nerve root, peripheral nerve, neuromuscular junction, Presentation of the diagnosis of amyotrophic lateral sclerosis.
and muscle. Alternatively, one may approach this task in terms of the The first step in the management of ALS is to present the diagnosis
presentation: Is it UMN only, LMN only, combined UMN-LMN, bul- in a compassionate yet informative manner. Allow adequate time to
bar only, and so on? Are there any atypical features such as prominent present the diagnosis. Whenever possible, the patient should not be
bladder or sensory involvement that suggest another diagnosis? For
example, when UMN involvement is prominent, PLS, spastic parapa-
resis, or HAM should be considered, whereas pure LMN involvement BOX 97.7 Comprehensive Care and
suggests that one should also consider PMA, IBM, MMNCB, adult- Management for Patients With Amyotrophic
onset SMA, Lambert-Eaton myasthenic syndrome, or Kennedy disease. Lateral Sclerosis
Severe cervical spondylosis may impinge upon both the cervical
Presentation of the diagnosis of ALS
cord and the nerve roots and thus present with both UMN and LMN
Specific pharmacotherapy
signs. Because pain, spastic bladder, and posterior column signs are
Symptomatic treatment
not always present, EMG and neuroimaging may be required to dis-
Team approach at ALS clinic
tinguish it from ALS. Neuroimaging is also invaluable in assessing
Ethical and legal issues
other disorders of the brainstem and spinal cord that may superficially
Physical rehabilitation
mimic certain features of ALS such as intrinsic or extrinsic tumors,
Speech and communication management
foramen magnum meningiomas, syringobulbia, and syringomyelia.
Nutritional care
MS usually presents with UMN signs, but on rare occasions, LMN
Respiratory care
signs develop when demyelinating plaques affect the ventral root exit
Home care and hospice care
zones. Neuroimaging and lumbar puncture studies should distinguish
the two conditions. CIDP may manifest as a predominantly LMN ALS, Amyotrophic lateral sclerosis.
TABLE 97.5 Symptomatic Treatment in Amyotrophic Lateral Sclerosis

Symptoms Pharmacotherapy Other therapy
Fatigue Pyridostigmine bromide Energy conservation
Antidepressants Work modification
Methylphenidate Sleep study: BiPAP if abnormal
Amantadine
Modafinil
Spasticity Baclofen Physical therapy
Tizanidine Range-of-motion exercises
Dantrolene sodium Botulinum toxin injections
Diazepam
Jaw clenching Benzodiazepines Botulinum toxin injections into masseters
Cramps Quinine sulfate Massage
Baclofen Physical therapy
Vitamin E
Clonazepam
Fasciculations Carbamazepine Assurance
Sialorrhea Hyoscyamine sulphate Suction machine
Diphenhydramine Botulinum toxin injection into salivary glands
Scopolamine patch Parotid gland radiation therapy
Glycopyrrolate Steam inhalation
Atropine Nebulization
TCAs Dark grape juice
Pseudobulbar laughing or crying TCAs
SSRIs, l-dopa/carbidopa
Lithium
Mirtazapine
Venlafaxine
Quinidine/dextromethorphan
Thick phlegm Guaifenesin Insufflation-exsufflation
Nebulized N-acetylcysteine High-flow chest wall oscillation therapy
Nebulized saline Cool mist humidifier
Propranolol Rehydration
Pineapple or papaya juice
Reduced intake of dairy products, caffeine, alcohol
Aspiration Cisapride Modified food consistency
Tracheostomy
Modified laryngectomy and tracheal diversion
Joint pains Antiinflammatory drugs Range-of-motion exercises
Analgesics Heat
Depression TCAs Counseling
SSRIs, venlafaxine, mirtazapine, bupropion Support group meetings, psychiatry
Insomnia Zolpidem tartrate Pressure air pad/gel mattress
Lorazepam Noninvasive positive pressure ventilation where
Opioids appropriate
TCAs
Laryngospasm Sublingual lorazepam
Respiratory failure Bronchodilators Hospital bed
Morphine sulfate Nocturnal noninvasive ventilator IPPB
Constipation Increase oral liquid Exercise
Metamucil “Power pudding”: prune juice, prunes, applesauce,
Dulcolax suppositories bran
Lactulose and other laxative
BiPAP, Bilevel positive airway pressure; IPPB, intermittent positive-pressure breathing; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic
antidepressants.
alone. A second appointment, a short time later, is often required 2018) (see also Chapter 114). Providing information on progress in
because many patients and their families find it difficult to absorb research, available pharmacotherapies, and the possibility of active
the information at first. At the appropriate time, it is important participation in clinical trials may increase hope for patients. It is
to bring up issues such as advance directives and issues regarding also important to convey the concept of the multidisciplinary care
terminal care (Mitsumoto and Rabkin, 2007; Mitsumoto and Saito, team. Owing to the serious nature of the diagnosis, it is important to
facilitate a second opinion if so requested. ALS is almost invariably Aggressive symptomatic treatment. Although specific phar
a relentlessly progressive and terminal disorder, and physicians macotherapy is still markedly limited for the treatment of ALS,
must raise the issues of the living will and durable power of attorney symptomatic treatment can substantially improve a patient’s symptoms
for health care relatively early after diagnosis to allow the patient and discomfort. Table 97.5 summarizes specific pharmacological and
and family to prepare ahead. Such decisions are not final and are nonpharmacological symptomatic treatments (Miller et al., 2009, 2012).
reversible at any time. Furthermore, some patients either do not wish Multidisciplinary team approach at amyotrophic lateral sclerosis
to or cannot make such decisions (Miller et al., 2013). clinic. The care of patients with ALS has become increasingly complex. As
Specific pharmacotherapy. In 1996, the US Food and Drug a consequence, many patients receive care by a multidisciplinary team in a
Administration (FDA) approved riluzole (Rilutek) as the first specialized ALS center rather than by a single treating physician. The team
specific drug for the treatment of ALS. It principally functions as an often consists of neurologists, a nurse coordinator, physical therapists,
antiglutamate agent, but its mechanism of action is uncertain. The occupational therapists, dietitians, speech pathologists, and social
two studies that led to riluzole approval showed that survival was workers. Pulmonary specialists and other health professionals should also
significantly longer in patients with ALS who took 50 mg of riluzole be available. Using this holistic approach, the aim is to maintain physical
twice a day compared with those who took placebo, although this independence for as long as possible and to provide psychosocial support
survival benefit was only modest and was disproportionately beneficial to patients and families. As such, specialized multidisciplinary clinic
in bulbar-onset disease. A Cochrane meta-analysis of the controlled referrals should be offered to patients to optimize and improve quality of
riluzole trials has shown that 100 mg daily results in a 9% increase life and possibly prolong survival (Miller et al., 2009, 2012).
in the probability of survival for 1 year and prolongs median survival Physical rehabilitation. The main goal of rehabilitation for patients
by 2–3 months when taken for 18 months (Miller et al., 2012). Side with ALS is to improve their ability to carry out activities of daily living
effects are relatively uncommon and include fatigue, gastrointestinal for as long as possible without causing undue physical or emotional
upset, dizziness, and an increase in liver function tests. To minimize strain. Physical therapy also prevents complications secondary to disuse
side effects, we recommend 50 mg per day in the evening, and after a of muscles and immobilization, such as a frozen shoulder. Employ
week or two, the patient can increase to the regular dose of 50 mg twice various types of exercise that maintain or enhance strength, endurance,
a day. Not all patients with ALS receive riluzole therapy; the cost of the and range of motion. There have been concerns that exercising ALS-
drug is one of the main factors in this regard, although generic versions affected muscles to the point of fatigue may actually be harmful, but
have mitigated this cost somewhat. this has not been borne out in the literature. The occupational therapist
Intravenous edaravone, a free radical scavenger, has been recently is another valuable member of the ALS care team. A range of assistive
approved in Japan and then the results were presented to the FDA, and adaptive devices are available to improve mobility and comfort
which approved the medication without any additional trials. This and help carry out activities of daily living. For example, walkers,
agent was originally developed for acute stroke treatment in Japan wheelchairs, splints, and collars are useful to manage wrist drop, foot
and subsequently found to be useful in treatment of ALS (Abe et al., drop, head drop, and gait instability. Successful rehabilitation also
2014). A further study was undertaken in responders only (ALS 19 includes an evaluation of the home environment; customized home
Study Group, 2017). Over a 6-month trial period, it has been shown equipment can easily help preserve a patient’s independence and safety.
to improve the ALS Functional Rating Scale-revised (ALSFRS-R) to Speech and communication management. Speech and
a modest degree. However, most patients were also taking concomi- communication dysfunction is one of the most serious factors reducing
tant riluzole and strict inclusion criteria suggest that it may only prove quality of life in the patient with ALS. Ideally, speech pathologists
effective in a small cohort of patients. should assess speech and communication soon after establishing the
Assessment of several agents with antiglutamate activity revealed diagnosis so the patient can maintain independent communication
no clinical benefit, although dextromethorphan-quinidine has benefit for as long as possible. Follow-up is thus required at regular intervals.
in the treatment of pseudobulbar emotional lability. Assessment and care should incorporate intelligibility strategies,
Many other agents have been trialed in ALS, including neurotrophic energy-conserving techniques, nonverbal techniques (gestures and
factors, antiinflammatory agents, creatine, coenzyme Q10, lithium and other body language), and assistive/augmentative communication
minocycline and other antibiotics, but none have been found to be devices. Numerous communication devices are available that vary
effective (Mitsumoto et al., 2014). The rating scale used in most ALS in sophistication and complexity, ranging from simple and relatively
trials is the ALSFRS-R. It has been argued that this measure may fail inexpensive mechanical devices such as alphabet or picture boards to
to show positive outcomes in trials, in part explaining the plethora of specialized computer devices such as a voice synthesizer.
negative ALS trials. Other functional scales such as the King’s College Nutritional care. Dysphagia and aspiration are distressing and
and MiToS staging systems have been proposed to more accurately dangerous complications of ALS and are particularly prominent in
monitor progression of disease in clinical trials (Corcia et al., 2018). the bulbar-onset variety. As oral intake progressively declines, there is
Perhaps one of the reasons for so many disappointing results over the acceleration in weight loss and malnutrition, which not only aggravates
years is that much promising preclinical work was based upon the muscle weakness but also shortens survival. Therefore, in every patient
mutant SOD1 mouse model, which is not representative of the patho- with ALS, evaluate the nutritional status at each visit. Although
genesis of most ALS. It remains to be seen whether novel agents with physicians can take such a history, evaluation by an experienced
relevance to TDP43 or FUS mislocalization might show more promise, dietitian is often most helpful. Initially, patients should change the form
and the search continues for new agents and techniques for the specific and texture of their food and use a high-calorie food supplement, but
treatment of ALS. Research is ongoing into the potential role for stem eventually such measures become insufficient to maintain the patient’s
cell therapy and gene therapy in patients with ALS (Chia et al., 2018; weight, and proactive enteral tube feeding becomes imperative.
Gordon et al., 2013; Madigan et al., 2017; Staff et al., 2016). It is critical Percutaneous endoscopic gastroscopy (PEG) is a standard minor
to improve the selection of candidate therapies, clinical trial methodol- surgical procedure that may improve quality of life but with unproven
ogy, and clinical trial practice. To this end, the Airlie House ALS clini- effect on survival (Katzberg and Benatar, 2011). PEG is also probably
cal trial guidelines have been updated and renewed using the modified effective in helping patients maintain weight/body mass index (Miller
Delphi consensus method. et al., 2009, ProGas Study Group, 2015).
Although it is a relatively simple surgery for otherwise healthy Familial Amyotrophic Lateral Sclerosis
patients who have dysphagia, patients with ALS pose particular diffi- Between 5% and 10% of all ALS is an inherited trait, in which case it is
culties and often have impending respiratory failure that may compli- termed familial ALS (FALS). It is quite possible that the true frequency
cate the procedure. Guidelines advocate placement of a PEG tube in of FALS is higher because anything less than a detailed family history
consenting patients with dysphagia whose seated predicted forced vital may fail to identify an affected family member, and reduced pene-
capacity is more than 50%, but PEG may be performed for patients
trance may account for some apparently sporadic disease. There are
with a forced vital capacity of less than 50% predicted if NIPPV is also
autosomal dominant, autosomal recessive, and X-linked forms, some
used during the procedure (Gregory et al., 2002).
being juvenile onset and others being adult onset (see Box 97.6). Over
Radiologically inserted gastrostomy and percutaneous radiological
30 genes have been implicated as causative, increasing the risk of devel-
gastrostomy are alternative approaches that may be preferable in such
oping ALS, or accelerating the disease, but many of these account for
cases but are not yet in widespread use. It is important to emphasize
only rare cases (Oskarsson et al., 2018). The clinical presentation varies
that those who receive a PEG tube can continue to eat by mouth, and
considerably, not just in terms of age and site of onset but also in terms
that the purpose of enteral feeding is to provide calories and fluid.
of disease duration. FALS is currently classified from ALS1 to ALS25.
Indeed, aspiration is a continued risk to the patient even after PEG
Mutations in C9orf72 (open reading frame 72 on chromosome 9)
tube insertion, and if recurrent aspiration of PEG contents becomes a
are the most common cause of familial ALS (circa 40%) and a sig-
persistent problem, one can either recommend percutaneous enteral
nificant percentage of apparently sporadic ALS (circa 7%) (Balendra
jejunostomy (PEJ), which further reduces (but still does not eliminate)
and Isaacs, 2018). The mutation is one of a hexanucleotide expan-
the risk, or a tracheostomy.
sion repeat. Presentation can be that of ALS, particularly with bulbar
Respiratory care. Respiratory failure is the most common cause
onset. However, it can also present as an ALS-FTD overlap or indeed
of death in ALS. Indeed, dyspnea-onset ALS presents with obvious
a pure behavioral variant FTD (which can include psychosis). Some
ventilatory difficulties, and it is for this reason that it harbors a
versions can include ataxia and parkinsonism and the repeat expan-
particularly poor prognosis. It is important to make patients and
sion has recently been found to cause Huntington disease phenocopies
family members aware that almost all forms of ALS will eventually end
by ventilatory failure, although symptoms may go largely unnoticed (Hensman Moss et al., 2014) (Video 97.5). Age of onset is apparently
until relatively late in the disease course. The patient must be made slightly younger and there is more rapid progression with shorter sur-
aware that although ventilation via a tracheostomy may indefinitely vival. Penetrance of the gene increases with age and in one study was
prolong life, there is no effect on the disease itself. In fact, by prolonging shown to reach 100% above the age of 80 years (Majounie et al., 2012).
the natural history of the disorder, there is a strong possibility that The function of C9orf72 still remains to be clearly elucidated but its
atypical symptoms may arise, such as visual changes or even sensory structure suggests that it might function as a GDP-GTP exchange
loss. Nonetheless, some patients choose to have a tracheostomy and factor for RAB GTPases, in turn implying a role in cell signaling and
invasive ventilation; this option should be a consideration to improve autophagy. The hexanucleotide repeats lead to the formation of patho-
the quality of life of such individuals (Niedermeyer et al., 2019). Most genic DNA-RNA “quadruplexes” which appear to generate abnor-
patients and their physicians opt for the noninvasive ventilation (NIV) mal transcripts that in turn lead to nucleolar stress (Haeusler et al.,
approach. Evidence exists that patients should be offered NIV at 2014). Whether the mutation leads to a loss of function, toxic gain of
the onset of dyspnea when the forced vital capacity falls to less than function, or indeed both, remains to be seen (Robberecht and Philips,
50% predicted or when a rapid, progressive weakness and wasting of 2013). Cerebral imaging may reveal symmetrical frontal and temporal
perioral muscles may prevent adequate use of the NIV mask. Nasal atrophy (Yokoyama and Rosen, 2012).
pillows can be helpful in this circumstance and are often better Up until recently, SOD1 (which encodes superoxide dismutase 1),
tolerated than the mask at all stages. Several factors should be borne in located on chromosome 21q21, was considered the most important
mind when offering this form of treatment. Evidence exists that NIV gene in ALS. ALS1 is a form of late-onset (usually > age 30) motor
improves quality of life and may prolong survival in ALS (Bourke et al., neuron disorder associated with mutations in SOD1 that accounts for
2006; Miller et al., 2009), but NIV does not prolong life indefinitely, 15%–20% of all cases of FALS (and thus 1%–2% of all ALS) (Rosen
and these patients still face the difficult decision of whether to use et al., 1993). Inheritance in most is in an autosomal dominant pattern,
an invasive ventilator. Diaphragmatic pacing has been approved for but a recessive variant occurs (Andersen et al., 1996). Mutations in
use in patients with ALS, but its clinical effectiveness and long-term SOD1 confer toxic gain of function, leading to disease through multiple
safety require further study (Amirjani et al., 2012). When making possible mechanisms, including oxidative stress, protein aggregation,
the decision to withdraw ventilatory support or when noninvasive apoptosis, and impairment of axonal transport. There is a large degree
means of ventilatory assistance are insufficient, it is imperative that of phenotypical variability in the expression of SOD1-associated FALS,
all attempts focus on effective and compassionate palliative end-of- not only between different families but also between individual mem-
life care. Hospice care and judicious amounts of opioids, oxygen, and bers of the same family. Furthermore, penetrance is rather variable and
anxiolytics should be prescribed to allow patients to live their final days age dependent. Generally, establishing the diagnosis of FALS is only
with dignity and in as much comfort as possible. by the fact that other family members in successive generations are, or
Home care and hospice care. When the patient’s condition were, affected by ALS. The clinical features of individual FALS patients
deteriorates, home hospice care or admission to a residential hospice overlap considerably with those of patients with SALS.
care facility is required (Mitsumoto et al., 2005). Close collaboration ALS2 is a rare recessively inherited disorder mapped to a gene on
between patients, their caregivers, home-care nurses, and ideally the chromosome 2q33 that encodes a novel protein called alsin. Analysis of
ALS clinic team will ensure effective and satisfying home care. When the original families revealed that all were due to truncated protein
a patient has no caregiver, choose a site other than the home for product from frameshift or nonsense mutations, but missense muta-
extended care. Hospice care provides highly effective palliative services tions occur. This juvenile ALS, originally described in consanguineous
to patients and their families. Just as important, hospice philosophy families from Tunisia, was also discovered in families from Saudi
strongly affirms life, so that patients who are in the terminal stages Arabia and Kuwait. The phenotype of this disorder varies according to
of their disease can maintain their independence and dignity to the the family of origin; in the Tunisian family, it presents as a slowly pro-
greatest degree possible (Connolly et al., 2015; Mitsumoto, 2009). gressive ALS-like disorder with mean age of onset at age 12 years; in the
Kuwaiti family, the phenotype is similar to early-onset PLS. Sequence TDP43 mutation–associated ALS. TDP43 immunoreactive ubiquiti-
homology analysis of this protein supports that it is a guanine-nucleo- nated inclusions are present in degenerating neurons and glial cells just
tide exchange factor for Rab 5 and is thus important in intracellular cell as they in sporadic ALS (Kuhnlein et al., 2008; Van Deerlin et al., 2008).
signaling, endosomal dynamics, mitochondrial trafficking, and cyto- The TDP43 gene product is a dual DNA/RNA binding protein mainly
skeleton organization. In contrast to the toxic gain-of-function theory expressed in the nucleus and may play an important part in the regula-
of pathogenesis in ALS1, it appears that loss of function of the gene tion of RNA trafficking and translation. TDP43 can modulate human
product is responsible for the selective injury to, and dysfunction of, low-molecular-weight neurofilament mRNA stability, which in turn
the corticospinal tract in ALS2. Alternate splicing of the alsin gene underlies neurofilament aggregates, sometimes seen in ALS (Strong
results in both long and short transcripts. Frameshift and nonsense et al., 2006). TDP43 inclusion bodies are in fact seen in several disor-
mutations cause an ALS phenotype when there is homozygous loss of ders apart from ALS, including FTD, frontotemporal lobar degenera-
both the short and long forms, whereas the PLS presentation occurs tion with motor neuron degeneration, corticobasal degeneration,
with homozygous loss of the long form alone. Missense mutations may Guamanian ALS–PD complex, and hippocampal sclerosis. While this
cause an unstable protein product or lead to a protein product that is might suggest that TDP43 inclusion bodies are a nonspecific marker of
directly toxic to the cell via aberrant regulation of the apoptotic path- neuronal injury or indeed representative of a physiological cell
way. Certain mutations in the alsin gene also give rise to an infantile response to injury, the frequency of TDP43 mutations (30 to date) in
ascending hereditary spastic paraparesis, which demonstrates the link both SALS and FALS suggests a pathogenic role. ALS11 is due to muta-
between ALS and related motor neuron diseases (Eymard-Pierre et al., tions of the FIG4 gene on chromosome 6q21, which encodes a phos-
2006; Panzeri et al., 2006). ALS3 describes a large European family with phoinositide 5-phosphatase, a regulator of a signaling lipid on the
adult-onset autosomal dominant ALS linked to chromosome 18q21 surface of endosomes. Mutations in this gene are known to cause a
(Hand et al., 2002). The gene for this disorder has not yet been identi- recessively inherited severe axonal sensorimotor form of Charcot–
fied. ALS4 is a juvenile-onset, slowly progressive, dominantly inherited Marie–Tooth known as CMT4J, which is usually early onset (although
distal amyotrophy with UMN signs but sparing bulbar features. It is one family presented with an adult disorder resembling ALS). FIG4
caused by mutations in the senataxin gene (SETX) on chromosome mutations can cause an ALS or PLS presentation, and additional per-
9q34, which has a DNA/RNA helicase domain suggesting a role in sonality changes were noted in two cases. Of the nine cases with FIG4
DNA repair and RNA processing. SETX has homology to IGHMBP2, mutations, only three were FALS, the rest apparently being sporadic
the gene responsible for SMARD1, a rare form of SMA. Mutations in (Chow et al., 2009). Mutations in the OPTN gene for optineurin, a
SETX also cause a recessively inherited disorder called oculomotor negative regulator of tumor necrosis factor alpha (TNF-α)–induced
apraxia and cerebellar ataxia. However, it has recently been shown that activation of nuclear factor kappa B (NF-κB) cause ALS12. OPTN may
caution should be exercised as not all missense mutations are patho- also play a role membrane trafficking, exocytosis, and maintenance of
genic and functional assays are required (Arning et al., 2013). A form the Golgi apparatus. Mutations in this gene are known to cause pri-
of slowly progressive, usually mild, recessive juvenile ALS (ALS 5) mary open angle glaucoma. For patients presenting with ALS, the
described in North African and European families is due to mutations inheritance patterns were both autosomal recessive and autosomal
in the spatacsin (SPG11) gene (and thus is also a cause of hereditary dominant, with onset between the ages of 30 and 60 years and long-
spastic paraparesis; see Table 97.2). ALS6 is an autosomal dominant disease duration. One case which came to autopsy showed opti-
ALS that can also be associated with frontotemporal dementia and hal- neurin-positive cytoplasmic inclusion bodies in anterior horn cells; the
lucinations. Mutations on the FUS/TLS (fused in sarcoma/translocated investigators also showed that TDP43- and SOD1-positive inclusions
in liposarcoma) gene on chromosome 16q12 have the pathological in SALS and SOD1 FALS were co-labeled with optineurin, suggesting a
characteristic of FUS-immunoreactive skein-like cytoplasmic inclu- broader role for this protein in the pathogenesis of ALS (Maruyama
sion bodies. FUS is normally a nuclear protein, so this is yet another et al., 2010). It is proposed that certain individuals with ATX2 muta-
example of protein mislocalization in neurodegenerative disease. FUS tions in the intermediate range may suffer an increased risk of ALS
mutations have a worldwide distribution and account for about 5% of (ALS 13) through an interaction between the polyglutamine repeat and
FALS; they are also detectable in about 1% of SALS (Lai et al., 2010). TDP43 resulting in mislocalization of the latter to the cytoplasm
Furthermore, it has recently been shown that FUS-immunoreactive (Elden et al., 2010). Another adult onset autosomal dominant ALS
cytoplasmic inclusions are common in both SALS and non-SOD1 which can be associated with FTD is ALS14, caused by mutations in the
FALS and are also immunoreactive to TDP43 and ubiquitin (Deng VCP gene. Pathologically, ubiquitin positive inclusions can be seen in
et al., 2010). ALS7 is a rare, late-onset, autosomal dominant disorder neurons. Interestingly, VCP mutations can also cause an inclusion
linked to chromosome 20p13. The cause for ALS8 is a mutation in a body myopathy with Paget disease and FTLD. ALS15, due to UBQLN2
vesicle trafficking protein gene called VAPB (vesicle-associated mem- mutations, can in fact be sporadic as well as inherited and again can be
brane protein/synaptobrevin-associated membrane protein B) on a cause of both ALS and FTD. Mutations in this gene lead to distur-
chromosome 20q13.3. The clinical presentation displays quite marked bances in the proteasomal pathway. ALS16 is a juvenile-onset ALS
heterogeneity: some patients develop a slowly progressive ALS-like which is only rarely associated with FTD. It is due to mutations in
picture with prominent tremor and onset between the ages of 31 and SIGMAR1, which normally encodes an endoplasmic reticulum chaper-
45 years, whereas others present with a late-onset SMA or a severe, one protein, thus suggesting a role for altered ER (ER) and Golgi func-
rapidly progressive ALS (Nishimura et al., 2004). ALS9 results from tion in disease pathogenesis. Again, SIGMAR1 mutations can cause
mutations on the angiogenin gene on chromosome 14q. This is an ubiquitinated inclusions in the proximal axon. Mutations in CHMP2B
autosomal dominant disorder of adults (from the fourth to the eighth cause ALS17, an adult-onset, progressive disorder with predominantly
decade). Angiogenin may help protect motor neurons from excito- lower motor neuron involvement, and can also cause FTD. Mutations
toxic- and hypoxia-induced injury, but it may also play an important of the gene appear to confer injury to the motor neurons through
role in RNA transcription as well as interact with cellular cytoskeletal abnormalities in protein breakdown and clearance within cells.
proteins. ALS10, which accounts for 2%–5% of FALS, is caused by Mutations in PFN1 (ALS18), which encodes profilin, can cause an FTD
mutations in the TDP43 gene on chromosome 1 and presents clinically overlap or ALS alone. Profilin is important in axonal transport. ALS19
as ALS with either limb or bulbar onset. Despite the association of TDP is due to mutations in ERBB4, which normally encodes a receptor tyro-
inclusions with some forms of FTD, cognitive deficits do not occur in sine kinase, and mutations of which disrupt neuregulin pathway. This
presents with typical autosomal dominant ALS of late onset. ALS20 is themselves feed on cycad seeds. The incidence of the Guamanian ALS
caused by HNRNPA1 gene mutations on chromosome 12, which may variant has rapidly declined over the past several decades, a process
lead to inclusion body formation due to dysregulated protein polymer- thought to reflect the Westernization of the region. The decline in the
ization. Although not formally classified as a familial ALS (it has been incidence of ALS-PDC in Guam may reflect the dwindling flying fox
described as a spinal and bulbar muscular atrophy), it is apparent that population on Guam through a massive increase in commercial hunt-
mutations in the p150Glued subunit of the dynactin gene may cause ing using firearms introduced to the island in the decades following
ALS-like presentations. Furthermore, a family history is not always evi- World War II. However, other social and dietary shifts have occurred
dent (Munch et al., 2004). Dynactin 1 is a vital component of the in Guam that might be responsible for the decrease.
dynein-dynactin motor complex and is important in retrograde axonal
transport. Puls et al. have described a particular LMN disorder caused Spinocerebellar Ataxia Type 3 (Machado-Joseph
by a mutation in the p150Glued subunit of dynactin 1. The clinical Disease)
phenotype is distinctive, with early bilateral vocal cord paralysis fol- Machado-Joseph disease is an autosomal dominant syndrome with
lowed by prominent involvement of intrinsic hand muscles (especially onset varying from the third to seventh decade of life. Although cere-
those of the thenar eminence), the legs, and the face (Puls et al., 2005). bellar ataxia is the predominant clinical feature, patients often present
with slowly progressive generalized spasticity, cramps, muscle wasting,
Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia and fasciculations of the face and tongue. Other characteristic findings
Complex (Western Pacific Amyotrophic Lateral Sclerosis) include extrapyramidal signs such as dystonia and rigidity, protuber-
In 1954, Mulder and colleagues described an unusually high inci- ant eyes, and progressive external ophthalmoparesis. Affected patients
dence of ALS in the adult native Chamorro population on the Western have a twofold to threefold expansion of a CAG trinucleotide repeat
Pacific island of Guam. Soon afterwards, a related disorder of high on the ataxin-3 gene on chromosome 14q32.1. The expanded trip-
incidence characterized by dementia and parkinsonism was also found let repeat results in a mutant gene product containing an expanded
in this population, with some patients displaying overlap features polyglutamine tract. This appears to aggregate into intranuclear neu-
between ALS, parkinsonism, and dementia. A similar disorder was ronal inclusion bodies and may interfere with the function of the cel-
subsequently described in western New Guinea and the Kii peninsula lular proteasome in degradation of proteins (Schmidt et al., 2002).
of Japan, with an ALS incidence between 50 and 150 times higher than The Machado-Joseph disease phenotype may also occur in SCA-2,
elsewhere (Kaji et al., 2012). Clinically, about 5% of patients develop a with slowly progressive ataxia, eyelid retraction, and facial fascicula-
predominantly ALS type of disorder, whereas 38% manifest principally tions. Patients often have slow saccades or ophthalmoparesis and may
with a combination of parkinsonism and dementia. The pathology of have reduced or absent deep tendon reflexes. The cause of SCA-2 is
this unusual disorder bears similarities to that of Alzheimer disease, an expanded polyglutamine-encoding CAG triple repeat sequence on
with prominent loss of CNS neurons and the presence of abundant chromosome 12q.
tau-immunoreactive neurofibrillary tangles. However, the charac-
teristic pathology of Guamanian ALS and PDC is by TDP43-positive Adult Hexosaminidase-A Deficiency
inclusions in neurons and glial cells. α-Synuclein pathology also is Adult Hex-A deficiency is an autosomal recessively inherited late-
detectable in the amygdala of affected brain tissue (Mimuro et al., onset GM2 gangliosidosis (the other subtypes being infantile and
2018). Multiple members of a single family may be affected, and it has juvenile). All three subtypes are caused by an abnormal accumulation
recently been shown that first-degree relatives of patients with ALS- of GM2 ganglioside in neurons due to a deficiency in the activity of
PDC have a significantly higher risk of developing the disease than the lysosomal enzyme. Hex-A is encoded by a gene on chromosome
controls. Despite these observations and a genetic association study 15q23–q24 and normally degrades GM2 ganglioside. Only about 10%
implicating the tau gene as a susceptibility gene for ALS-PDC, accu- of Hex-A activity is required for normal health, but in the severe infan-
mulated epidemiological evidence strongly suggests that an environ- tile form of this disorder, also known as Tay-Sachs disease, mutations
mental factor rather than a genetic factor is more important in disease in the α subunit of Hex-A result in complete deficiency of enzyme
pathogenesis. Various environmental toxins have been implicated in activity. Juveniles and adults with Hex-A deficiency, however, are com-
the pathogenesis of ALS-PDC, chief among them being neurotoxins pound heterozygotes with varying degrees of residual enzymatic activ-
derived from the native cycad seed. This seed contains β-methylami- ity and thus have a later-onset disorder with considerable variability
no-l-alanine (BMAA), an amino acid that is toxic to cortical and spi- in the phenotype. It is more common in males and those of Ashkenazi
nal motor neurons and thought to be the product of cyanobacterial Jewish ancestry, but females and non-Jewish persons can also develop
activity in the roots of the cycad palm. Cycad seed also contains a this disorder.
carcinogenic substance called cycasin that may act either alone or in The adult form has a mean of onset of about 18 years and usu-
concert with BMAA to damage motor neurons. Toxic sterol glucosides ally presents as slowly progressive weakness of predominantly prox-
have also been isolated from washed cycad flour, and they can cause imal muscles of the upper and lower extremities (Barritt et al., 2017;
the release of glutamate (Khabazian et al., 2002). However, the role Neudorfer et al., 2005). In some patients, severe cramps may present in
of cycad seeds in neurotoxicity is still subject to debate (Snyder et al., association with muscle weakness, mimicking SMA. In others, however,
2011). The cyanobacteria/BMAA hypothesis has wider implications a combination of dysarthria, spasticity, and LMN signs may resemble
for research in SALS worldwide. It has been recently shown that pro- ALS. Additional sensory, cerebellar, cognitive, psychiatric, and extra-
tein-bound BMAA is present in the brains of North American patients pyramidal features may later develop. The EDX may reveal prominent
dying with ALS and Alzheimer disease and it has been hypothesized complex repetitive discharges and abnormal SNAPs. Generally, this
that such patients may be genetically susceptible to BMAA-induced constellation of symptoms and signs is not easily mistaken for ALS, but
neurodegeneration (Bradley and Mash, 2009). The cycad seed has in the relatively early stages, patients with Hex-A deficiency may not
many uses: in West Papua and Guam as a topical medicine for skin manifest many features other than motor system dysfunction. Genetic
lesions and in Japan as an oral medicine (Spencer et al., 2016). Cox and counseling is important before assaying a patient’s serum or leukocytes
Sacks (2002) proposed a process of biomagnification of cycad toxins for deficiency of Hex-A activity.
in Guam through the Chamorro practice of eating flying foxes, which
Allgrove Syndrome (Four-A Syndrome) signs, and some may improve either with treatment of the cancer or
Four-A syndrome (Allgrove syndrome) is a very rare autosomal reces- spontaneously. Elevated CSF protein levels or the presence of a para-
sive disorder that derives its name from the combination of achala- protein in the blood should prompt a detailed investigation for lym-
sia, alacrima, adrenocorticotropic insufficiency, and amyotrophy. The phoma. Although there is insufficient evidence to conclude that there
AAAS gene is located on chromosome 12q13 and encodes a ubiquitous is increased risk of cancer in ALS, a combination of UMN and LMN
protein called aladin which heavily expresses in the neuroendocrine signs has been well described in patients with breast, uterine, ovarian,
system and may be important in regulation of the cell cycle, cell signal- and non–small-cell cancer. This ALS-like disorder is quite rapidly
ing, intracellular transport, and the cell cytoskeleton. The syndrome progressive and does not appear to respond either to treatment of the
can manifest from the first decade of life with dysphagia and adre- underlying cancer or to immune therapies. UMN signs and symptoms
nocortical insufficiency, but a wide a range of neurological problems that mimic PLS may rarely occur in patients with breast tumors and
can arise later in life, including cognitive deterioration, optic atrophy, may in fact precede the cancer diagnosis by a few months. In general,
seizures, autonomic disturbance (dry mouth, postural hypotension, one should investigate for a paraneoplastic disorder if there are atypical
and syncope), and bulbospinal amyotrophy (amyotrophy of limbs and features such as ataxia, sensory loss, and dysautonomia, and it would
tongue, with tongue fasciculations and pyramidal signs) (Ikeda et al., seem to be prudent to carry out breast screening on women with a PLS
2013; Kimber et al., 2003). presentation.
Human Immunodeficiency Virus Type 1-Associated

Adult Polyglucosan Body Disease Motor Neuron Disorder
Polyglucosan body disease is a very rare, late-onset, slowly progres- A retrospective review of 1700 cases of HIV-1-infected patients with
sive disorder characterized by a combination of UMN and LMN signs, neurological symptoms identified 6 cases presenting as a reversible
cognitive decline, distal sensory loss, and disturbances of bladder and ALS-like syndrome (Moulignier et al., 2001), representing a 27-fold
bowel function. MRI of the brain may reveal diffuse white-matter sig- increased risk of developing an ALS-like disorder in that particular
nal increase on T2-weighted images. The diagnosis is clinched by the HIV-1 patient population. Overall, patients were somewhat younger
finding of characteristic pathological changes in tissue from peripheral than the normal ALS population, all but one being younger than
nerve, cerebral cortex, spinal cord, or skin. Axons and neural sheath 40 years at the time of diagnosis. Onset was characteristically in a
cells contain non-membrane-bound cytoplasmic periodic acid–Schiff- monomelic pattern followed by a very rapid spread to other regions
positive polyglucosan bodies. Ultrastructural examination shows that over a period of weeks. There were clinical features of both UMN and
the inclusions consist of 6- to 8-nm branched filaments and are most LMN involvement, with fasciculations, cramps, and bulbar symptoms.
abundant in myelinated nerve fibers. In Ashkenazi Jewish patients (and Two patients also had rapidly progressive dementia, with other fea-
one reported non-Ashkenazi Jewish patient), the disorder was caused tures suggesting an additional diagnosis of AIDS-dementia complex.
by mutations of the glycogen-branching enzyme (GBE) gene, with Sensory and sphincter disturbances were not apparent. CSF protein
subsequent deficiency of the protein product. However, adult poly- levels were sometimes mildly increased, and a lymphocytic pleocyto-
glucosan body disease (APBD) occurs in many different populations, sis was evident in three patients, but all remaining laboratory results
and considerable molecular heterogeneity has been noted, with other- (HIV-1 seropositivity apart) were negative. EDX revealed a widespread
wise typical cases lacking GBE mutations despite deficiency of enzyme disorder of anterior horn cells in the absence of demyelinating con-
activity (Klein et al., 2004). The recent (albeit inadvertent) generation duction block, and MRI in one patient showed diffuse white-matter
of muscle polyglucosan bodies in a transgenic mouse engineered to signal increase suggestive of AIDS-dementia complex. At the patho-
overexpress glycogen synthase in the presence of normal levels of gly- logical level, there are some features that are shared between ALS and
cogen-branching enzyme suggests that an imbalance in the activities HIV encephalitis; HIV cases also develop TDP-43 deposits (Douville
of these two enzymes is the possible molecular mechanism underlying and Nath, 2017).
this unusual disorder (Raben et al., 2001). It is interesting to note that In each case, antiretroviral therapy was beneficial either in stabi-
two types of polyglucosan body may be seen in ALS—Lafora bodies lizing or (in two instances) curing the disease. No similar cases have
and corpora amylacea—although neither is considered a characteristic been identified in this particular study population since the introduc-
pathological feature. tion of highly active antiretroviral combination chemotherapy in the
management of HIV infection. Another case report found similar clin-
Paraneoplastic Motor Neuron Disease ical features in a 32-year-old HIV-positive patient who also enjoyed
There is evidence that motor neuron disease may rarely be a a complete response to antiretroviral therapy. MRI of brain showed
paraneoplastic phenomenon, although there is a possibility that the increased T2-weighted signal in the brachium pontis with some min-
ALS and the neoplasm are chance associations. (Corcia et al., 2014). imal contrast enhancement. The resolution of motor symptoms coin-
Patients may present with features that are rather typical of pure “spi- cided with a lack of detectable HIV in plasma and CSF. In addition,
nal” ALS or manifest in a manner akin either to PMA or to PLS. Other the abnormal MRI signal almost completely resolved (MacGowan
motor neuron manifestations may represent only one part of a larger et al., 2001). Flail-arm ALS-like variants have also been described, with
paraneoplastic syndrome, such as anti-Hu antibody associated enceph- MRI signal changes in the anterior cervical spinal cord (Henning and
alomyelitis, with atypical features such as dysautonomia or ataxia. Hewlett, 2008; Nalini et al., 2009). Other forms of HIV may also relate
Unfortunately, most paraneoplastic motor disorders are unrespon- to the pathogenesis of motor neuron disease; a pure LMN syndrome
sive to treatment of the underlying tumor. Rare motor disorders have occurred in a woman who was seropositive for HIV-2. Overall, there
been described in association with other paraneoplastic antibodies, seems to be sufficient evidence to implicate HIV as a potential cause
including anti-Yo antibody in a patient with ovarian carcinoma and of an ALS-like disorder, but one must also consider the possibility of
a novel antineuronal antibody in a patient with breast cancer. A sub- coincidental HIV infection in patients who have true sporadic ALS.
acute painless and progressive LMN-predominant disorder has been
well characterized in lymphoma (both Hodgkin and non-Hodgkin The complete reference list is available online at https://expertconsult.
types: see earlier discussion). Patients may eventually develop UMN inkling.com/.
CHAPTER 97 Disorders of Upper and Lower Motor Neurons 1567.e1
Video 97.1 Hereditary Spastic Paraparesis.This 73-year-old man pre- Video 97.4 Amyotrophic Lateral Sclerosis.This anarthric patient with
sented with a slowly progressive history of spastic ataxia and dysarthria. advanced amyotrophic lateral sclerosis has a severely weak, wasted
His brother has been diagnosed with atypical multiple sclerosis and his tongue with fasciculations laterally (0:00–0:20), brisk jaw jerk, and snout
sister has a similar presentation. His examination reveals an ataxic gait reflex (0:20–0:31). There is wasting and fasciculations of his upper limbs
(0:00–0:21), but hyperreflexia (0:21–0:31) and positive Babinski signs and trunk (0:31–0:50) but with a prominent Hoffmann sign (0:50–0:53).
are present bilaterally. He is dysarthric (0:31-0:43) and he also has His lower limbs are similarly wasted but his lower limb reflexes are
restricted horizontal eye movements (not shown). In this case, there is a brisk with clonus bilaterally (0:53–1:02). https://www.kollaborate.tv/
mutation of SPG7 gene on chromosome 16. https://www.kollaborate.tv/ player?id=870095
player?id=870092. Video 97.5 C9orf72 Mutation.The overall presentation here is of parkin-
Video 97.2 Fasciculations. https://www.kollaborate.tv/player?id=870093 sonism with bradykinesia, particularly of left side with positive pull test,
Video 97.3 Kennedy Disease (X-Linked Recessive Bulbospinal Neu- stooped posture. In addition, however, the patient has some tongue
ronopathy).This man has Kennedy disease manifesting as moderate fasciculations without overt atrophy and bilateral intrinsic hand muscle
dysarthria (0:00–0:19), coarse perioral fasciculations (0:19–0:58), coarse wasting. This video highlights that C9orf72 can present with features not
fasciculations of his upper trunk and forearms and atrophy of proximal typically seen in ALS such as parkinsonism of Huntington-like features.
upper extremities with gynecomastia (0:58–1:24). https://www.kollabo- (Clip 97.5 Adapted from Movement Disorders, 2012; http://www.ncbi.
rate.tv/player?id=870094 nlm.nih.gov/pmc/articles/PMC3516857/). https://www.kollaborate.tv/
player?id=870096.)
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98
Channelopathies: Episodic
and Electrical Disorders of
the Nervous System
Min K. Kang, Geoffrey A. Kerchner, Louis J. Ptáček
OUTLINE
Ion Channels, 1568 Hereditary Peripheral Nerve Disorders, 1582
Ion Channel Classification, 1571 Paroxysmal Dyskinesia, 1583
Genetic Disorders of Muscular Ion Channels, 1573 Other Inherited Neuronal Channelopathies, 1583
Hypokalemic Periodic Paralysis (hypoKPP), 1574 Epilepsy, 1583
Hyperkalemic Periodic Paralysis (hyperKPP), 1575 Familial Focal Epilepsies, 1583
Paramyotonia Congenita, 1576 Idiopathic Generalized Epilepsies, 1584
Myotonia Congenita, 1576 Theoretical Considerations, 1586
Potassium-Aggravated Myotonia, 1577 Autoimmune Channelopathies, 1586
Andersen-Tawil Syndrome, 1578 Myasthenia Gravis, 1586
Malignant Hyperthermia, 1578 Lambert-Eaton Myasthenic Syndrome, 1587
Congenital Myasthenic Syndromes, 1579 Acquired Neuromyotonia (Isaacs Syndrome), 1587
Genetic Disorders of Neuronal Ion Channels, 1579 Paraneoplastic Cerebellar Degeneration, 1587
Familial Hemiplegic Migraine, 1579 Limbic Encephalitis, 1587
Familial Episodic Ataxias, 1580 Summary, 1588
Hereditary Hyperekplexia, 1581

Channelopathies are disorders caused by ion channel dysfunction. Because ion preferentially conducted (e.g., Na+, K+, Ca2+, Cl−). Ligand-gated ion
of the great diversity of ion channel proteins and their expression in different channels respond instead to specific chemical neurotransmitters (e.g.,
tissues, channelopathies comprise a wide variety of clinical diseases (Table acetylcholine, glutamate, γ-aminobutyric acid [GABA], glycine).
98.1), the discovery of which helps elucidate how ion channels function in Distributed ubiquitously in excitable tissues, voltage-gated ion
both illness and health. The periodic paralyses—the first group of ion chan- channels are critical for establishing a resting membrane potential and
nel disorders characterized at a molecular level—defined the field of chan- generating action potentials, especially in tissues where rapid conduc-
nelopathies, which now encompasses diseases not only in muscle but also in tion of messages is required (e.g., nerves, cardiac cells, or skeletal mus-
the kidney (Bartter syndrome), epithelium (cystic fibrosis), and heart (long cles). Most channels have a similar basic structure, consisting of one
QT syndrome), as well as neurons. Because muscles and neurons are elec- or more pore-forming subunits (generally referred to as α-subunits)
trical organs, it is not surprising that most channelopathies are associated and a variable number of accessory subunits (often denoted β, γ, etc.).
with neurological disease. Despite significant heterogeneity, a pervasive fea- An α-subunit is composed of four homologous domains (I–IV) and
ture of neurological channelopathies is a paroxysmal phenotype of various typically has six transmembrane segments (S1–S6). The S4 segment
neurological presentations, encompassing myopathy, peripheral neuropa- has positively charged residues and serves as “a sensor.” The S5–S6
thy, epilepsy, migraine headache, and episodic movement disorders. After segments usually form the ion pore. These segments determine ion
a brief introduction to ion channels, this chapter describes disorders caused selectivity for the α-subunits, and voltage sensing is conferred by the
by congenital and acquired dysfunction of ion channels expressed in skele- S4 segment, while the remaining accessory subunits act as modulators.
tal muscle, neurons and neuromuscular junction. Voltage-gated channels are “gated” with high sensitivity to changes
in transmembrane potential. The conductance is tightly regulated by
changes in conformations of the channel, as channels exist in one of
ION CHANNELS three states: open, closed, or inactivated. Voltage-gated channels open
One needs a basic understanding of channel structure and function (or activate) with threshold changes in membrane potential, then tran-
before addressing channelopathies and their clinical manifestations. Ion sition after a characteristic interval to either a closed or an inactivated
channels are transmembrane glycoprotein pores that underlie cell excit- state. From the closed state, a channel can reopen with an appropriate
ability by regulating ion flow into and out of cells across the lipid bilayers change in membrane potential. In the inactivated state, a change in
of the cell membrane. They are composed of distinct protein subunits, membrane potential normally sufficient to open the channel is ineffec-
each encoded by a separate gene. The categorization of most channels, tive and the channels will not conduct current. Inactivation is both time
depending on their means of activation, is as voltage-gated or ligand- and voltage dependent, and many channels display both fast and slow
gated. Changes in membrane potentials activate and inactivate volt- components of inactivation. Inactivation is a means of negative regula-
age-gated ion channels. They are named according to the physiological tion of the channel, influencing electrical stability in excitable cells.
1568
CHAPTER 98 Channelopathies: Episodic and Electrical Disorders of the Nervous System 1569
TABLE 98.1 Genetic Channelopathies

Disease Ion Channel Gene Chromosome
Muscular Channelopathies
Andersen-Tawil syndrome Kir2.1*; potassium (inward rectifier) KCNJ2 17q23.1–q24.2
Kir3.4; potassium (inward rectifier) KCNJ5 11q24
Central core disease Calcium (ryanodine receptor) RYR1 19p13.1
Congenital myasthenic syndromes nAChR α1-subunit CHRNA1 2q24–q32
nAChR β1-subunit CHRNB1 17p12–p11
nAChR δ-subunit CHRND 2q33–q34
nAChR ε-subunit CHRNE 17p13–p12
(nAChR anchoring protein: rapsyn) RAPSN 11p11.2–p11.1
Hyperkalemic periodic paralysis Nav1.4; sodium α4-subunit SCN4A 17q23.1–q25.3
Hypokalemic periodic paralysis Cav1.1; calcium (L-type) CACNA1S 1q32
Nav1.4; sodium α4-subunit SCN4A 17q23.1–q25.3
Malignant hyperthermia Calcium (ryanodine receptor) RYR1 19q13.1
Cav1.1; calcium (L-type) CACNA1S 1q32
Myotonia congenita Chloride CLCN1 7q35
Paramyotonia congenita Nav1.4; sodium α4-subunit SCN4A 17q23.1–q25.3
Potassium-aggravated myotonia Nav1.4; sodium α4-subunit SCN4A 17q23.1–q25.3
Neuronal Channelopathies
ADNFLE nAChR α4-subunit CHRNA4 20q13.2–q13.3
nAChR β2-subunit CHRNB2 1q21
KCa4.1; potassium (sodium-activated) KCNT1 9q34.3
ADPEAF (Potassium channel regulator) LGI1 10q24
Alternating hemiplegia of childhood (Na+/K+-ATPase) ATP1A2 1q21–q23
BFNS Kv7.2; potassium (M channel) KCNQ2 20q13.3
Kv7.3; potassium (M channel) KCNQ3 8q24
BFNIS, BFIS Nav1.2; sodium α2-subunit SCN2A 2q23–q24.3
(Na+/K+-ATPase†) ATP1A2 1q21–q23
Childhood absence epilepsy GABAA receptor γ2-subunit GABRG2 5q31.1–q33.1
GABAA receptor β3-subunit GABRB3 15q11.2–q12
Cav3.2; calcium (T-type) CACNA1H‡ 16p13.3
Cav2.1; calcium (P/Q-type) CACNA1A‡ 19p13
Congenital stationary night blindness Cav1.4; calcium (L-type) CACNA1F Xp11.23
Deafness (nonsyndromic type 2) Kv7.4; potassium KCNQ4 1p34
Episodic ataxia 1 Kv1.1; potassium KCNA1 12p13
Episodic ataxia 2 Cav1.4; calcium (P/Q-type) CACNA1A 19p13
Episodic ataxia 5 Calcium β4-subunit CACNB4 2q22–q23
Episodic ataxia 6 (EAAT1†) SLC1A3 5p13
Familial hemiplegic migraine 1 Cav1.4; calcium (P/Q-type) CACNA1A 19p13
Familial hemiplegic migraine 2 (Na+/K+-ATPase) ATP1A2 1q21–q23
Familial hemiplegic migraine 3 Nav1.1; sodium α1-subunit SCN1A 2q24
Familial temporal lobe epilepsy / febrile (Carboxypeptidase†) CPA6 8q13.2
seizures
GEFS+ Nav1.1; sodium α1-subunit SCN1A 2q24
Sodium β1-subunit SCN1B 19q13.1
Nav1.2; sodium α2-subunit SCN2A 2q23–q24.3
Nav1.7; sodium α9-subunit SCN9A 2q24
GABAA receptor γ2-subunit GABRG2 5q31.1–q33.1
GABAA receptor δ-subunit GABRD 1p36.3
Hereditary hyperekplexia Glycine receptor α1-subunit GLRA1 5q32
Glycine receptor β-subunit GLRB 4q31.3
(Glycine transporter†) GLYT2 (SLC6A5) 11p15.2–p15.1
JME GABAA receptor α1-subunit GABRA1 5q34–q35
Calcium β4-subunit CACNB4‡ 2q22–q23
(R-type calcium channel regulator†) EFHC1‡ 6p12–p11
Mental retardation, autosomal dominant Glutamate receptor NR2B subunit GRIN2B 12p13.1
PED (GLUT1†) SLC2A1 1p34.2
PKD (Proline-rich transmembrane protein 2†) PRRT2 16p11.2
Continued
TABLE 98.1 Genetic Channelopathies—cont’d

Disease Ion Channel Gene Chromosome
PNKD with epilepsy KCa1.1; potassium (BK) KCNMA1 10q22.3
PNKD without epilepsy (PNKD protein†) PNKD 2q35
Primary erythermalgia Nav1.7; sodium α9-subunit SCN9A 2q24
Scapuloperoneal spinal muscular atrophy/ TRPV4 TRPV4 12q24.1
congenital distal spinal muscular atrophy/
CMT2C/HMSN2
Spinocerebellar ataxia type 6 Cav2.1; calcium (P/Q-type) CACNA1A 19p13
Nonneurological Channelopathies
Bartter syndrome antenatal 1 Na-K-2Cl cotransporter SLC12A1 15q15–q21.1
Bartter syndrome antenatal 2 Kir1.1; potassium (inward rectifier) KCNJ1 11q24
Bartter syndrome 3 Chloride CLCNKB 1p36
Cystic fibrosis Chloride CFTR 7q31.2
Dent disease Chloride CLCN5 Xp11.22
FPHHI Potassium (accessory subunit) ABCC8 11p15.1
Kir6.2; potassium (inward rectifier) KCNJ11 11p15.1
Liddle syndrome 1 Sodium (non-voltage-gated) SCNN1A 12p13
Sodium (non-voltage-gated) SCNN1B 16p13–p12
Sodium (non-voltage-gated) SCNN1G 16p13–p12
LQT1 Kv7.1; potassium KCNQ1 11p15.5
LQT2 Kv11.1; potassium KCNH2 7q35–36
LQT3 Nav1.5; sodium α5-subunit SCN5A 3p21–24
LQT4 (anchoring protein ankyrin-B†) ANK2 4q25–q27
LQT5 Potassium (accessory subunit) KCNE1 21q22.1–q22.2
LQT6 Potassium (accessory subunit) KCNE2 21q22.1
ADNFLE, Autosomal dominant nocturnal frontal lobe epilepsy; ADPEAF, autosomal dominant partial epilepsy with auditory features; BFNS, benign
familial neonatal seizures; BFNIS, benign familial neonatal–infantile seizures; BFIS, benign familial infantile seizures; CMT2C, Charcot–Marie–Tooth
disease type 2C; EAAT1, excitatory amino acid transporter 1; FHM, familial hemiplegic migraine; FPHHI, familial hyperinsulinemic hypoglycemia of
infancy; GEFS+, generalized epilepsy with febrile seizures plus; HMSN2, hereditary motor and sensory neuropathy type 2; JME, juvenile myoclonic
epilepsy; LQT, long-QT syndrome; nAChR, nicotinic acetylcholine receptor; PED, paroxysmal exercise-induced dyskinesia; PKD, paroxysmal kinesi-
genic dyskinesia; PNKD, paroxysmal nonkinesigenic dyskinesia.
*Where appropriate, ion channel names are provided according to the International Union of Basic and Clinical Pharmacology Committee on Receptor
Nomenclature and Drug Classification (NC-IUPHAR).
†These associated genes/proteins may not be ion channels; they may instead contribute indirectly to ion channel function, regulate neurotransmitter
kinetics, or possess other or unknown functions.

‡Unproven association.
A neuron typically has a resting potential of –75 mV, with the intra- is particularly important in the nervous system, where there is tremen-
cellular side being negative relative to the extracellular space. When dous heterogeneity of the cells with regard to ion channel expression.
the resting potential reaches a threshold or more positive membrane Each subtype is encoded by a different gene, and its expression is highly
potential of –55 mV, depolarization occurs, which leads to the pro- cell specific.
duction of an action potential. This is achieved by opening a specific Depending on the location within the channel, mutations could
ion channel—a voltage-gated sodium channel—in which case sodium alter voltage-dependent activation, ion selectivity, or time and voltage
ions will rush into the cells down the concentration gradient. In order dependence of inactivation. Thus, two different mutations within the
to reach the action potential, the sodium channel changes its confirma- same gene can result in dramatically different physiological effects. For
tion from a closed or resting state to an open state. When the membrane example, a mutation that prevents or slows inactivation could lead to a
potential reaches its peak, about 40 mV, the sodium channels close and persistent ionic current. Conversely, a mutation elsewhere in the same
become inactive. Then, repolarization occurs, due to the opening of gene that prevents activation will decrease ionic current. Phenotypic
another voltage-gated channel, such as a potassium channel. This leads heterogeneity describes how different mutations in a single gene cause
to a rapid return to the resting potential via an outflux of potassium distinct phenotypes. For instance, mutations in the skeletal muscle
ions (down the potassium concentration gradient). Before achieving a voltage-dependent sodium channel can result in hyperkalemic peri-
stable resting potential, the membrane potential becomes “hyperpolar- odic paralysis, hypokalemic periodic paralysis, potassium-aggravated
ized” for a short time. Slowly, the sodium channels return to the closed myotonia (PAM), or paramyotonia congenita (PMC; see Table 98.1
state from the inactivated state. While in the inactivated state, sodium and Fig. 98.1). In contrast, genetic heterogeneity occurs when a consis-
channels are not responsive to voltage changes. However, in the closed tent clinical syndrome results from a variety of underlying mutations
state, they become sensitive to voltage changes again. in distinct genes. For example, familial hypokalemic periodic paralysis
Different tissues and cells express different ion channels; thus, dys- can result from distinct mutations in the SCN4A or CACNA1S genes.
function of a specific ion channel can lead to a broad spectrum of phe- Ion channel mutations may lead to either “loss of function” or
notypes, depending on the tissue/cell type/ion channel involved. This “gain of function” in each case. Generally speaking, loss-of-function
mutations cause reduced permeability, whereas gain of function modifiers, posttranscriptional, and posttranslation changes can also
implies the gain of an abnormal function (e.g., increased permeabil- result in ion channel dysfunction (Fig. 98.2)
ity or altered selectivity vs. normal permeability in the wrong part of
the cell). Furthermore, genetic channelopathies are not restricted to Ion Channel Classification
mutation of the channels, but other mutations involving regulatory, Voltage-gated potassium channels (VGKCs) consist of four homolo-
gous α-subunits that combine to create a functional channel. Humans
possess many distinct VGKC genes, and the resulting channels exhibit
specialized properties and display rich tissue-type and cellular-com-
Genotype Phenotype partment specificity. Each α-subunit of voltage-gated channels con-
tains six transmembrane segments (S1–S6) linked by extracellular
PMC
SCN4A and intracellular loops (Fig. 98.3). The S5–S6 loop penetrates deep
into the central part of the channel and lines the pore. The S4 segment
PAM
contains positively charged amino acids and acts as the voltage sen-
HypoKPP2 sor. These channels serve many functions, most notably to establish
SCN1A the resting membrane potential and to repolarize cells following an
HyperKPP action potential. A unique class of potassium channel, the inwardly
SCN1B
rectifying potassium channel, is homologous to the S5–S6 segments
SCN2A
of the VGKC. Because the voltage-sensing S4 domain is absent, volt-
age dependence results from a voltage-dependent blockade by magne-
GABRG2 GEFS+ sium and polyamines rather than from the movement of the positively
charged S4 domain in response to membrane depolarization.
Voltage-gated sodium and calcium channels are highly homol-
Fig. 98.1 Illustration of the principle that various mutations within a
single gene (e.g., SCN4A) can lead to distinct clinical syndromes; con-
ogous and share homology with VGKCs, from which they evolved.
versely, mutations in different genes may result in a single recognized The α-subunits contain four highly homologous domains in tandem
clinical entity. GEFS+, Generalized epilepsy with febrile seizures plus; within a single transcript (DI–DIV; Fig. 98.4). Each domain resembles
hyperKPP, hyperkalemic periodic paralysis; hypoKPP2, hypokalemic a VGKC α-subunit, with six transmembrane segments, as described
periodic paralysis type 2; PAM, potassium-aggravated myotonia; PMC, earlier. Sodium and calcium channels differ in several regards, despite
paramyotonia congenita. their many similarities. The amino acid sequence forming the selectivity
Trafficking and Transcriptional

localization regulation
channelopathies
Secondary
Posttranslational Interacting proteins

regulation of function regulating function
channelopathies
Primary
Autoantibodies
Ion channels
(acquired channelopathies)
Cell membrane excitability

Developmental
Synaptopathies
Synaptic Developmental
disorders
regulation circuit regulation
Excitability of brain circuits

Ptácek LJ. 2015.
Annu. Rev. Physiol. 77:475-79
Fig. 98.2 Proposed Classification Scheme for Electrical and Episodic Disorders. Channelopathy is
referred to as an abnormal function of ion channels themselves or secondary to disrupted orchestration of
signaling from other proteins.
filter and the modulatory auxiliary subunits are different. The sodium (nAChRs) are examples of ligand-gated ion channels with known
channel is composed of an α- and a β-subunit, and the calcium chan- disease-causing mutations. Although distinguished by their ligand
nel is composed of a pore-forming α1-subunit, an intracellular β-sub- binding and ion permeability, channels gated by GABA, glycine, and
unit, a membrane-spanning γ-subunit, and a membrane-anchoring acetylcholine share several structural similarities. Five intrinsic mem-
α2δ-subunit. Sodium channels mediate fast depolarization and under- brane subunits assemble to form hetero- or homopentamers. Each
lie the action potential, whereas voltage-gated calcium channels subunit contains four transmembrane domains (M1–M4), the second
(VGCCs) mediate neurotransmitter release and allow the calcium of which lines the pore and determines ionic selectivity (Fig. 98.5).
influx that leads to second messenger effects. Subunits contributing to nAChRs at the neuromuscular junction
Ligand-gated ion channels activate on binding with their respec- differ from those expressed in the central nervous system, explaining
tive agonists. GABAA, glycine, and nicotinic acetylcholine receptors why the mutation of one gene may cause seizures without affecting
283 (2 bp)
214W
R
+
Y
A
306T
284C
616 (1 bp)
397 S 544
NH2 – 534 (5 bp)
406 S
COOH
494 (13 bp) S
– 838
+
– (1 bp)
S Splice + Insertion –
– Deletion
516 S 522 (13 bp)
Fig. 98.3 Proposed Structure of the Voltage-Gated Potassium Channel, Kv1.1 (KCNA1), Implicated in
Episodic Ataxia Type 1. Voltage-dependent potassium channels comprise four subunits that form a channel
pore. Each subunit contains six transmembrane domains, with the S4 segment containing positively charged
amino acids that act as the voltage sensor. Mutations associated with episodic ataxia type 1 are illustrated.
Disease-causing mutations are indicated by the one-letter amino acid representation. Amino acids with cir-
cles are wild-type, and the corresponding mutation is indicated by a connecting line with the corresponding
position and amino acid.
I II III IV
1 2 3 4 5 6
+
+
+ T M M
N A
C
704M 1156T 1592V

1360V
Fig. 98.4 Diagram of the Voltage-Gated Sodium Channel and the Four Most Common Mutations Caus-
ing Hyperkalemic Periodic Paralysis. The α-subunit consists of four highly homologous domains (I to IV),
each containing six transmembrane segments (S1–S6). When inserted into the membrane, the four domains
fold so as to encircle a central ion-selective pore lined by the S5–S6 loops. Analogous to the potassium chan-
nel (see Fig. 98.3), the S4 segments contain positively charged residues conferring voltage dependence on
the channel. Auxiliary β-subunits are not shown.
NH2 familial hypokalemic periodic paralysis (hypoKPP), hyperkalemic

a g a
periodic paralysis (hyperKPP), PMC, myotonia congenita, PAM,
b g COOH and Andersen-Tawil syndrome (ATS). The patients with these dis-
orders present with episodic muscle weakness, lasting minutes to
M1 M2 M3 M4
hours, typically with full recovery between episodes. With recur-
A C
rent episodes, one can develop permanent and fixed weakness later
in life. Inheritance is autosomal dominant, with high penetrance,
though for some mutations, there can be sex-dependent pene-
M3 M2 trance. Usually, there are triggers, as mentioned earlier, including
M4 stress, alcohol, recent illness, exercise followed by rest, fasting, or
M1
a b
glucose-rich meals. Weakness can be regional or generalized, while
bulbar and respiratory involvement is rare. Carbonic anhydrase
inhibitors such as acetazolamide can be used to reduce the fre-
b a
g quency of attacks of weakness. Sodium channel blockers like mex-
iletine are sometimes effective in reducing myotonic symptoms and
signs (see Table 98.2).
The patients may describe myotonia as muscle “stiffness” or
B “cramping.” Myotonia can be found clinically, and subclinical myo-
tonia can be detected using electromyography (EMG). Myotonia is
Fig. 98.5 Molecular Structure of the Nicotinic Acetylcholine Receptor.
A, Three-dimensional model showing a pentameric protein forming a
enhanced muscle excitability that leads to sustained bursts of dis-
pore. Two molecules of acetylcholine (ACh) bind to the α-subunits to open charges. Due to hyperexcitability of the muscle, one experiences
the channel. B, Each subunit contains four α-helical domains, labeled M1 involuntary contraction in said muscle, resulting from the inability
to M4. The M2 domain forms the channel pore. C, An enlarged diagram to relax after forceful voluntary contraction. This can be demon-
of the α-subunit showing the extracellular N and C termini and the four strated in the exam room, asking the patient to make a tight fist or
transmembrane domains. The amino acids at boundaries of the M2 forceful eye closure, and it is called “action myotonia.” Percussion
domain are negatively charged, forming a selectivity filter for cations. myotonia is another supporting exam finding of muscle channelop-
athies. When a muscle, such as the gastrocnemius muscle, is tapped
neuromuscular transmission, or vice versa. Binding of acetylcholine with a reflex hammer, a persistent dimpling of the muscle can be
opens the channel, which conducts monovalent cations (Na+ and K+) seen. Myotonia is a nonspecific sign found in several other diseases,
with little or no selectivity, and some are additionally permeable to including myotonic dystrophy 1, myotonic dystrophy 2 (proximal
calcium. Channel activation results in membrane depolarization and myotonic myopathy), myotonia congenita, PMC, and hyperKPP.
excitation of the postsynaptic neuron or muscle fiber. The “paramyotonia” in paramyotonia congenital describes the ability
The GABAA and glycine receptors belong to the nAChR superfam- to demonstrate worsening of myotonic stiffness with repeated mus-
ily and similarly consist of five subunits. GABAA receptors include α-, cle contractions and is best seen in the orbicularis oculi. This can be
β-, and either γ- or δ-subunits. The predominant glycine receptor is a also be precipitated by muscle cooling (i.e., a temperature-sensitive
heteropentamer of three α-subunits and two β-subunits. In either case, phenotype). PMC is one disorder in this group with a distinct clini-
agonist binding opens the channel and allows the flux of chloride (Cl−) cal finding of paramyotonia, commonly demonstrated with repeated
into the cell, generally causing hyperpolarization and decreased excit- forceful eye closure, leading to increasing myotonia of the orbicularis
ability. Therefore, both GABA and glycine mediate inhibitory synaptic oculi.
transmission. Clinical and subclinical myotonia can be demonstrated using EMG,
Channelopathies encompass a variety of diseases in multiple sys- which shows sustained bursts of muscle after-discharges that persist
tems, including neurological, cardiac, endocrine, and kidney disorders, following voluntary contraction or occur in response to insertion of
as summarized in Table 98.1. In the nervous system, most channelop- an EMG needle. It produces a characteristic “dive-bomber” discharge,
athies are characterized by episodic attacks. Phenotypically, it ranges with waxing and waning discharges (20–80 Hz).
from muscle disease and peripheral neuropathy to episodic move- In addition to distinct myotonic discharges using EMG, nerve con-
ment disorders, epilepsy, and migraine headache. Patients experience duction studies (NCS), in particular the short and long exercise tests
recurrent “attacks” throughout life, usually with complete resolution (SET and LET), can be further utilized to narrow down the differential
between attacks. Although there are strikingly diverse presentations, diagnosis (Fournier et al., 2004). The compound motor action poten-
depending on the expression pattern of the gene, this group of disor- tials (CMAPs) are recorded at a basline and every 10 seconds after 10
ders shares many similarities. First, as mentioned earlier, they are epi- seconds of short isometric exercise up to 60 seconds. This 60 second
sodic with various frequencies of attacks. Second, these disorders have set of CMAP recording is repeated twice, with a resting period of 1
triggers or precipitating factors such as stress, sleep deprivation, and minute between each set. It is noteworthy that maintaining a warm
certain dietary factors that often precede the onset of an attack. Third, temperature is important, as cooling may change the pattern with
these disorders typically have a similar natural history, with an onset decreased CMAP amplitude yet increased CMAP duration. The LET
in childhood to young adulthood, worsening through adolescence and is performed by isometric exercise for 5 minutes. CMAPs are recorded
young-adult life, and improvement in middle- and late-adult life. every minute during the exercise, after exercise, and every 5 minutes
after exercise, for 40–45 minutes.
GENETIC DISORDERS OF MUSCULAR ION The pattern of decrement and increment of CMAP amplitude over
time are helpful to identify distinct subgroups of mutations causing
CHANNELS
periodic paralysis. Fournier et al. (2004) analyzed the patterns after
Skeletal muscle channelopathies are characterized by periodic short and long exercises and categorized muscle channelopathies into
paralyses and nondystrophic myotonia. These disorders include 5 groups, as summarized in Table 98.4.
TABLE 98.2 Clinical Features of the Periodic Paralyses and Nondystrophic Myotonias
HypoKPP HyperKPP PMC MC PAM
Age at onset 2nd decade 1st decade Infancy 1st decade 1st–2nd decade
Duration of attack Hours–days Minutes–hours Hours Minutes–hours N/A
Severity of attack Moderate–severe Mild–moderate Mild–moderate Mild–moderate
Triggers Postexercise, CHO load Postexercise, fasting, Cold, postexercise Rest K
K load
Myotonia Absent Present Present Present Present
Serum K+ Usually low Normal or high Variable Normal Normal
Progressive weakness Some patients Some patients Absent Present in Becker myotonia Absent
Treatment for weakness CAI CAI CAI N/A N/A
Treatment for myotonia N/A Mexiletine Mexiletine Mexiletine, phenytoin CAI
CAI, Carbonic anhydrase inhibitor; CHO, carbohydrate; hyperKPP, hyperkalemic periodic paralysis; hypoKPP, hypokalemic periodic paralysis; MC,
myotonia congenita; PAM, potassium-aggravated myotonia; PMC, paramyotonia congenita; K, potassium.
Hypokalemic Periodic Paralysis (hypoKPP) channel implicated in hyperKPP and other disorders described later
Clinical (see Fig. 98.1). Evidence suggests that this sodium channel–associ-
The prevalence of hypoKPP is approximately 1 per 100,000. Episodes ated syndrome is phenotypically different from the more common
of limb weakness accompanied by hypokalemia usually begin during CACNA1S form. A proposed separate clinical entity, hypoKPP2, may
adolescence. Attacks usually occur in the morning and are often trig- be distinguishable from hypoKPP1 associated with CACNA1S by the
gered either by the ingestion of a carbohydrate load and high salt presence of myalgias following paralytic attacks, and the presence of
intake the previous night or by rest following strenuous exercise. tubular aggregates instead of vacuoles in the muscle biopsy. In some
Generalized muscle weakness and reduced or absent tendon reflexes patients, acetazolamide worsens symptoms (Bendahhou et al., 2001;
are characteristic. Heralding the weakness may be sensory changes, Sternberg et al., 2001). In a large retrospective series, hypoKPP2 was
fatigue, or a feeling of heaviness or aching in the legs or back. During associated with an older age of onset and shorter duration of attacks
paralysis, level of consciousness and sensation are preserved. Paralysis than classical hypoKPP1 (Miller et al., 2004).
either spares the facial and respiratory muscles or causes only mild Whether involving SCN4A or CACNA1S, virtually all mutations
weakness, making medical intervention rarely necessary. The fre- causing hypoKPP involve an S4 voltage-sensor domain. In the case
quency, length, and severity of attacks vary. Although attacks may of the sodium channel, these mutations allow a leak current to pass
occur several times a week, they more often occur at intervals of weeks through the “gating pore” at resting membrane potentials, bypassing
or months. Attack duration varies from minutes to days, typically the central channel pore and leading to inappropriate muscle fiber
lasting several hours. Occasionally the attacks are sufficiently brief depolarization and consequent channel inactivation and action poten-
to cause difficulty in documenting the accompanying hypokalemia. tial failure (Sokolov et al., 2007). Speculation exists that this phenom-
Patients usually recover full strength, although mild weakness may enon may also occur in mutated VGCCs.
persist for several days or (more rarely) be permanent. A progressive
permanent myopathy with mild proximal weakness may develop later Diagnosis
in life, although it is rare. An accurate medical history is essential for the diagnosis because
observation of attacks is unusual, and patients are often normal
Pathophysiology between attacks. Characteristic features of hypoKPP that distin-
There are largely two genes that are responsible for hypoKPP. guish it from hyperKPP are that paralytic attacks are less frequent,
HypoKPP1 is up to 70% of cases, and it is caused by mutations in the longer lasting, precipitated by a carbohydrate load, and often begin
CACNA1S gene encoding the α1-subunit of the dihydropyridine-sen- during sleep (see Table 98.2). Potassium concentrations are usually
sitive L-type voltage-gated skeletal muscle calcium channel, Cav1.1, on low during an attack, less than 3.0 mM, although concentrations
chromosome 1q32.1 (Venance et al., 2006). less than 2 mM should suggest a secondary form of periodic paral-
Cav1.1 is the slow-inactivating, L-type calcium channel and can ysis. Electrocardiogram (ECG) changes such as increased PR and
be blocked by 1,4-dihydropyridine (e.g., amlodipine and nifedip- QT intervals, T-wave flattening, and prominent U waves suggest an
ine), phenylalkamines (e.g., verapamil), and benzothiazepines (e.g., underlying hypokalemia. Provocative testing can be dangerous and
diltiazem; Fialho et al., 2018). This channel functions as the voltage is not routine. Test performance requires a hospitalized setting with
sensor of the ryanodine receptor and plays an important role in exci- continuous cardiac monitoring and should be performed only in
tation–contraction coupling in skeletal muscle. Four mutations in patients without cardiac or renal disease. After giving an oral glucose
the S4 segments alter voltage sensitivity. Two mutations, involving load (2–5 g/kg up to a maximum of 100 g) with or without subcutane-
arginine-to-histidine substitutions within the highly conserved S4 ous insulin (0.1 U/kg), one performs serial examinations of strength
segments of DII and DIV (Arg-528-His and Arg-1239-His), account while monitoring serum glucose and potassium concentrations.
for most cases. The others involve arginine-to-glycine substitutions at Myotonia is not found in hypoKPP, either clinically or with EMG.
the same locations. EMG may reveal membrane irritability with myopathic changes but
HypoKPP2 is caused by a mutation in SCN4A gene on chromo- often is normal. Short and long exercise tests reveal Fournier pattern
some 17q23.3 encoding the pore-forming α-subunit of the skeletal V, with decrement CMAPs following the long exercise test without
muscle voltage-gated sodium channel, Nav1.4. Approximately 10%– significant change in the SET. Creatine kinase (CK) can be normal
20% of families with hypoKPP have this mutation. This is the same but may be elevated. Potassium between attacks is normal. Muscle
be of prophylactic benefit in patients with normal renal function

TABLE 98.3 Acetazolamide
in whom other more conservative measures are insufficient. Many
Use Prophylactic agent for some channelopathies (see text). believe that reducing the frequency or severity of paralytic attacks
Mechanism Inhibits carbonic anhydrase. provides protection against the development of myopathy based on
Dosing Adults: start 125 mg daily, titrating as needed up to a anecdotal experience, although this has never been formally tested
maximum daily dose of 1000–1500 mg, divided bid– in a controlled trial. Inhibition of Na, K, Cl cotransporter (NKCLC),
qid. An extended release formulation is available. particularly with bumetanide (which is a NCLC blocker) is currently
Children: consult a pharmacist. in clinical trial.
Side effects Taste changes (especially for carbonated drinks), During an acute attack, the preferred method of treatment is oral
fatigue, paresthesias, metabolic acidosis, blurred potassium chloride given at 0.5–1.0 mEq/kg, not exceeding 200 mEq
vision, myelosuppression, nephrolithiasis, etc. in a 24-hour period. If a patient is unable to take oral potassium (e.g.,
(Increased dietary citrate might be recommended to arrhythmia due to hypokalemia or airway compromise due to altered
compensate for decreased urinary citrate observed mental status), then intravenous potassium (KCl bolus 0.05–0.1 mEq/
during acetazolamide therapy.) kg or 20–40 mEq/L of KCl in 5% mannitol) is indicated. Cardiac mon-
Monitoring Check electrolytes, BUN, creatinine, and CBC at baseline itoring is important during the administration of potassium.
and periodically throughout therapy.
Metabolism None; excreted unchanged by kidneys. Hyperkalemic Periodic Paralysis (hyperKPP)
Clinical
bid, Twice daily; BUN, blood urea nitrogen; CBC, complete blood cell
Characteristic of this disorder is episodic weakness precipitated by
count; qid, four times daily.
Please note that this table is for brief informational purposes only. Pre- hyperkalemia. Although the weakness is generally milder than in
scribing physicians should consult a pharmacist or an appropriate refer- hypoKPP, it can be sufficiently severe in hyperKPP to cause flac-
ence for complete and updated information. cid quadriparesis. As in hypoKPP, respiratory and ocular muscles
are unaffected and consciousness is preserved. The frequency of
attacks varies from several per day to several per year. Attacks are
histology reveals nonrimmed vacuoles within muscle fibers in biop- usually brief, lasting 15–60 minutes, but may last up to days. Unlike
sies in hypoKPP1 or tubular aggregates in hypoKPP2. Genetic test- hypoKPP, myotonia is present between attacks. Onset is usually in
ing should render muscle biopsy and provocative testing obsolete for infancy or childhood, and characteristic attacks occur by adoles-
diagnosis. cence. Triggers include rest after vigorous exercise, foods high in
Thyrotoxic periodic paralysis (TPP) may be clinically indistin- potassium, fasting, stress, and fatigue. Despite its name, hyperKPP
guishable from hypoKPP, except that it is not familial and serum is often associated with a normal serum potassium concentration
potassium levels are often lower than in familial hypoKPP (<2.5). during an attack (see the following Diagnosis section). Most patients
TPP is more common in Asian adults and in men more than women. experience a subacute onset, and some describe paresthesia or a sen-
Some cases may be associated with a mutation in KCNJ18, the gene sation of muscle tension prior to attacks. In these situations, mild
encoding a novel inwardly rectifying potassium channel (Ryan et al., exercise may abort or lessen the severity of the attack. The thigh and
2010). All patients with hypoKPP require screening for hyperthyroid- calf muscles are often involved. Generalized weakness is uncommon,
ism, as the treatment—correction of the thyroid disorder—differs making hyperKPP distinct from hypoKPP. Mild weakness may per-
from that outlined for familial hypoKPP. Treatment of hypothy- sist afterward, and the later development of a progressive myopathy
roidism would prevent further attacks of weakness. Beta-blockade is is common.
often effective in reducing the frequency and severity of the para-
lytic attacks (Amato and James, 2016). One needs to exclude other Pathophysiology
secondary forms of hypokalemic paralysis when serum potassium HyperKPP is an autosomal dominant disorder, with high penetrance,
concentrations remain low between attacks. Renal, adrenal, and gas- and there are some sporadic cases. The disorder links to SCN4A, the
trointestinal causes of persistent hypokalemia are common, and thi- same gene responsible for a minority of hypoKPP cases. Among sev-
azide diuretic use and licorice (glycyrrhizic acid) intoxication must eral identified missense mutations, four account for about two-thirds
also be considered. of cases (see Fig. 98.1). Functional expression of naturally occurring
mutations demonstrated a decrease in the voltage threshold of chan-
Treatment nel activation or abnormally prolonged channel opening or both
An effective holistic approach to treatment includes lifestyle mod- (Bendahhou et al., 2002; Hayward et al., 1999), effectively increasing
ifications and acute and chronic pharmacological intervention. the depolarizing inward current. If sustained long enough, this would
Dietary modification to avoid high carbohydrate loads and refrain- lead to inactivation of the sodium channels, transitory cellular inexcit-
ing from excessive exertion help prevent attacks. Prophylactic use of ability, and weakness.
acetazolamide (Table 98.3) decreases the frequency and severity of
attacks. Dichlorphenamide is another carbonic anhydrase inhibitor Diagnosis
that effectively prevents attacks, as demonstrated in a randomized Despite advances in defining the underlying genetic mutations,
clinical trial (Tawil et al., 2000) where the average dose was 100 a thorough medical and family history and physical examina-
mg daily. More potent than acetazolamide, dichlorphenamide may tion remain the best diagnostic tools. Serum potassium is normal
be useful when the efficacy of the former begins to fail. A clinician between attacks and even during many attacks. Unlike hypoKPP,
may keep in mind that hypoKPP2 caused by SCAN4A has less ben- potassium administration may precipitate an attack. In the absence
efit from carbonic anhydrase inhibitors compared to patients with of provocative testing, the basis for diagnosis is the clinical presenta-
hypoKPP1 (Matthews et al., 2011). Potassium-sparing diuretics (e.g., tion. Hyperkalemia itself can cause weakness; thus secondary causes
loop diuretics) or angiotensin-converting enzyme inhibitors may of hyperkalemia should be considered, especially if the potassium
levels are greater than 7 mEq/L. Myotonia is present in many patients Pathophysiology
between attacks, either spontaneously or after muscle percussion, The cause of PMC is point mutations in the SCN4A gene on chromo-
and failure to produce myotonia discriminates hypoKPP from some 17q. Thus, PMC is allelic to hyperKPP, PAM, and less commonly,
hyperKPP (see Table 98.2). Take care not to confuse subjective mus- hypoKPP. Mutations of the gene, which include substitutions at T1313
cle stiffness with objective changes. Peaked T waves on ECG suggest on the DIII to DIV linker and at R1448 on the DIV–S4 segment, cause
hyperkalemia and are an aid to diagnosis. As in hypoKPP, serum CK defects in sodium channel deactivation and fast inactivation. The rest-
concentrations are often normal but sometimes can be elevated. A ing membrane potential rises from −80 up to −40 mV when intact
potassium-loading test provokes an attack but is not usually neces- muscle fibers cool. Mild depolarization results in repetitive discharges
sary and can be dangerous. (myotonia), whereas greater depolarization results in sodium channel
Electrodiagnostic studies are useful for demonstrating subclinical inactivation and muscle inexcitability (weakness).
myotonic discharges, not seen in hypoKPP. Myopathic findings such
as fibrillation potentials and small polyphasic motor unit potentials Diagnosis
occur during late stages of disease. Interictal NCS are usually nor- A family history of exercise- and cold-induced stiffness or difficulty
mal, but the CMAPs during the attack may be reduced. The SET and of relaxation after forceful contraction strongly supports the diagno-
LET reveal a Fournier pattern IV, (Table 98.4) where the SET shows sis of PMC. When asked to close their eyes forcefully and repeatedly,
increased amplitude after the first trial, which is further increased in affected individuals exhibit progressive difficulty with relaxation and
subsequent trials, and the LET shows a transient increase in ampli- are eventually unable to open their eyes; this is called paramyotonia,
tude after exercise, followed by a gradual decrement in amplitude the name derived from paradoxical reaction to exercise. Furthermore,
over 40 minutes. muscle cooling may elicit an increase in myotonia, a reduction in iso-
metric force of 50% or more, and a prolongation of the relaxation
Treatment time by several seconds after muscle cooling supports the diagnosis.
The goal of therapy is to abort the acute attacks and prevent future Serum potassium concentration may be high, low, or normal during
attacks. Acute attacks are often sufficiently brief and mild, so as not to attacks, and serum CK concentrations may be elevated 5–10 times nor-
require acute intervention. In more severe attacks, aim treatment at mal. Electrodiagnostic studies are useful in establishing the diagnosis.
lowering extracellular potassium levels. Mild exercise or eating a high EMG reveals fibrillation-like potentials and myotonic discharges that
sugar load (juice or a candy bar) may suffice, as insulin drives extra- are accentuated by muscle percussion, needle movement, and muscle
cellular potassium into cells. Thiazide diuretics and inhaled β-adren- cooling. Muscle cooling elicits an initial increase in myotonia, then a
ergic agonists are similarly helpful, and intravenous glucose, insulin, progressive decrease in myotonia, followed by a decrease in CMAP
or calcium gluconate may be used for severe weakness. To prevent amplitude that correlates respectively, with muscle stiffness and weak-
attacks, a diet low in potassium and high in carbohydrates may obvi- ness. The SET commonly reveals postexercise myotonic potentials
ate the need for prophylactic drug therapy. Patients are also advised (PEMPs) after a short exercise on the motor conduction studies. CMAP
to avoid fasting, strenuous exercise, and cold. Oral dichlorphenam- amplitudes show delayed decrement after second and third trials, par-
ide (50–150 mg/day) was useful for prophylaxis in one randomized ticularly in patients with T1313M mutation. The SET in patients with
controlled trial (Tawil et al., 2000). Acetazolamide (see Table 98.3) Q270K mutation shows prominent decrement with cooling. The LET
and thiazide diuretics are useful as well. Successful prophylaxis may shows decrement in CMAP amplitudes during and after exercise with-
decrease the later onset of myopathy, although direct proof of this out return to its baseline. These SET and LET patterns are categorized
hypothesis is lacking. Finally, myotonic symptoms are troublesome to Fournier pattern I, which is distinctive for PMC (Table 98.4). Muscle
in some patients; sodium channel blockers, such as mexiletine, can be pathology shows only nonspecific changes, and biopsy is unnecessary.
used for symptomatic management. Obtaining ECGs is advised due
to QT prolongation. (Amato et al., 2016) Treatment
Symptoms are generally mild and infrequent. Direct treatment, when
Paramyotonia Congenita required, at either myotonia or weakness or both. Sodium channel
Clinical blockers such as mexiletine are effective in reducing the frequency and
The characteristic features of PMC are paradoxical myotonia, severity of myotonia, as shown in a randomized trial (Statland et al.,
cold-induced myotonia, and weakness after prolonged cold expo- 2012). Patients with weakness often respond to agents used to treat
sure. Unlike classic myotonia, which shows a warm-up phenom- hyperKPP (e.g., thiazides, acetazolamide). A single case report suggests
enon (see the later section Myotonia Congenita), patients with the possible use of pyridostigmine (Khadilkar et al., 2010). Cold avoid-
PMC often show exacerbation of myotonia after repeated muscle ance reduces the frequency of attacks.
contraction. Symptoms may be recognized in infants and cer-
tainly by childhood and usually remain unchanged throughout life, Myotonia Congenita
although one may develop progressive permanent weakness over Clinical
time. Infants may be noted to have difficulty opening their eyes Inheritance of myotonia congenita (MC) is either as an autosomal
after crying due to myotonia of the orbicularis oculi. Myotonia dominant (Thomsen disease) or recessive (Becker myotonia) trait.
affects all skeletal muscles, although the facial muscles and muscles The main feature is myotonia or delayed muscle relaxation after con-
of the neck and hands are the most common sites of myotonia in traction. Forceful movement abruptly initiated after several minutes of
the winter. The onset of weakness is often during the day, lasts sev- rest causes the most pronounced myotonic stiffness. The myotonia of
eral hours, and is exacerbated by cold, stress, and rest after exercise. MC displays a warm-up phenomenon in which the myotonia decreases
Many patients are asymptomatic when warm. However, cold-in- or vanishes completely when repeating the same movement several
duced stiffness may persist for hours even after the body warms, times, in contrast to the myotonia seen in patients with PMC. Unlike
and percussion myotonia is present even when the patient is other- PMC, cold temperature does not exacerbate the clinical or electrical
wise asymptomatic. myotonia or weakness (Subramony et al., 1983) The onset of Thomsen
TABLE 98.4 Electrodiagnostic Pattern

Fournier Pattern Short Exercise Test Long Exercise Test Clinical Phenotype
I Postexercise amplitude decrement that Postexercise amplitude decrement that does not Paramyotonia congenita (T1313M or
worsens with each trial return to baseline over 40 minutes R1448C sodium)
II Postexercise amplitude decrement that No postexercise amplitude change or small transient Myotonia congenita (chloride channel
improves with each trials decrement mutation)
III No postexercise amplitude change No postexercise amplitude change Other forms of myotonia (G1306A,
1693T sodium)
IV Postexercise amplitude increment that Transient postexercise amplitude increment followed HyperKPP (T704M sodium)
increases with each trial by late continuous decrement over 40 minutes
V No postexercise amplitude change Late continuous postexercise amplitude decrement HypoKPP-1 (R528H calcium)
over 40 minutes
disease is often within the first decade, whereas the onset of Becker 98.4). This pattern is seen more commonly in individuals with the
myotonia is generally at 10–14 years of age. Although myotonia can autosomal recessive form. Greater than 20% decrement of amplitude-
affect all skeletal muscles, it is especially prominent in the legs, where and-area during SET is specific for MC (Tan et al., 2011). Biopsy is
it is occasionally severe enough to impede a patient’s ability to walk usually nonspecific, showing enlarged fibers in hypertrophied muscle,
or run. In rare cases, sudden noise causes sufficient generalized stiff- increased numbers of internalized nuclei, and decreased type 2B fibers
ness to make the patient fall to the ground and remain rigid for several (Table 98.4).
seconds. The recessive and dominant forms share many similarities,
but some clinical features help distinguish the two. In general, patients Treatment
with recessive disease experience transitory bouts of weakness after Many patients (especially with Thomsen disease) experience only mild
periods of disuse and may develop progressive myopathy (Kornblum symptoms and do not require treatment. For those with more severe
et al., 2010); in addition, muscle hypertrophy and disease severity are myotonia (especially with Becker myotonia), sodium channel block-
greater than in the dominant form. Becker myotonia is more common ing agents remain the mainstay of treatment. Mexiletine is the most
than Thomsen disease. In contrast to myotonic dystrophies, affected commonly used and was shown to be effective in treating myotonia
individuals have no systemic disorders such as cardiomyopathy, cata- in a preliminary randomized placebo-controlled study (Statland et al.,
racts, endocrinopathies, ventilatory weakness, and skeletal deformities. 2012). Other sodium channel blockers such as tocainide, phenytoin,
procainamide, and quinine exhibit variable degrees of efficacy.
Pathophysiology
Electrical instability of the sarcolemma leads to muscle stiffness by Potassium-Aggravated Myotonia
causing repetitive electric discharges of affected muscle fibers. Early Clinical
in vivo studies in myotonic goats revealed greatly diminished sarco- PAM is a rare autosomal dominant disorder with clinical features simi-
lemmal chloride conductance in affected muscle fibers. This causes a lar to MC, except that the myotonia fluctuates and worsens with potas-
depolarization of the sarcolemmal membrane and muscle hyperexcit- sium administration. Distinguishing PAM from other nondystrophic
ability. Genetic linkage analysis for both recessive and dominant forms myopathies is important because PAM patients respond to carbonic
of MC pointed to a locus on chromosome 7q, where the responsible anhydrase inhibitors. Episodic weakness and progressive myopathy do
gene, CLCN1, encodes the major skeletal muscle chloride channel. not occur. Symptom severity varies, with some patients experiencing
More than 70 mutations have been identified within CLCN1, and, only mild fluctuating stiffness and others a more protracted painful
interestingly, some of these mutations are recognized to cause both myotonia. PAM now encompasses the conditions previously known as
dominant and recessive forms (Zhang et al., 2000). Examination of the myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive
functional effects of several myotonia-causing CLCN1 mutations in myotonia. Exercise or rest after exercise, potassium loads, and depo-
heterologous expression systems reveals effects on channel gating or larizing neuromuscular blocking agents aggravate myotonia, whereas
membrane expression levels, usually resulting in a decreased chloride cold exposure has no objective effect. Prominent myotonia of the orbi-
conductance (Desaphy et al., 2014; Zhang et al., 2000). cularis oculi and painful myotonia suggest the diagnosis.
Diagnosis Pathophysiology
On clinical exam, patients may display muscle hypertrophy, often giv- PAM links to chromosome 17q, where mutations in the SCN4A gene
ing patients a muscular or athletic appearance. Muscle strength and cause the disease. This sodium channel is the same one implicated in
reflexes are normal, although there may be mild proximal weakness. hyperKPP, PMC, and the sodium channel subtype of hypoKPP (see the
Tapping the belly of a muscle with a percussion hammer can elicit per- earlier discussion and Fig. 98.1). Functional expression studies reveal
cussion myotonia that lasts for several seconds. Action myotonia can that the disease-causing mutations lead to a large persistent sodium
be also demonstrated by having patients make a strong grip or closing current secondary to an increased rate of recovery from inactivation
the eyes tightly and then opening them. With repetitive contractions, and an increased frequency of late channel openings (Wu et al., 2001).
one may find relaxation easier, due to a warm-up phenomenon. The cause of myotonia is enhanced inward current, which leads to pro-
Electrodiagnostic testing is also helpful. NCS may find decremen- longed depolarization and subsequent membrane hyperexcitability.
tal CMAP amplitudes on repetitive stimulation at 10 Hz or higher.
EMG also demonstrates myotonia. The SET and LET may show tran- Diagnosis
sient decrease in CMAP after the first trial and no significant change Diagnosis can often be made clinically and screening for the mutated
in amplitudes after exercise, respectively (Fournier pattern II, Table gene is becoming more available. Distinguishing PAM from other
episodic nondystrophic myotonias may be difficult. Unlike hyperKPP suspected and the standard ECG is normal. Cardiac monitoring under
and PMC, PAM patients do not experience weakness. Another distinc- provocative maneuvers such as tilt-table testing or graded exercise pro-
tion between PAM and PMC is the lack of response to muscle cooling, tocols may allow dysrhythmias to surface and should be utilized when
either clinically or on EMG. The SET and LET show no change or dec- the diagnosis of ATS is highly suggested but prior cardiac evaluation is
rement (Fournier pattern III), although other patterns have been seen. unremarkable.
(Table 98.4) Creatine kinase concentrations are often normal during episodes
of weakness but are occasionally elevated. Depending on the particular
Treatment mutation, potassium concentrations during an attack are usually low
Carbonic anhydrase inhibitors markedly reduce the severity and fre- but can be high or normal. Provocative testing in any case of periodic
quency of attacks of myotonia. Acetazolamide is most commonly used paralysis may be risky, and hypokalemic challenges in ATS may be par-
(see Table 98.3). ticularly dangerous because of the potential to exacerbate preexisting
QT prolongation and trigger life-threatening ventricular arrhythmias.
Andersen-Tawil Syndrome
Clinical Treatment
ATS is a rare autosomal dominant disorder characterized by the tet- The goal of therapy is to control underlying cardiac arrhythmias and
rad of periodic paralysis, cardiac arrhythmias, dysmorphic features to decrease the frequency, severity, and duration of attacks of weak-
(including hypertelorism, micrognathia, low-set ears, high-arched ness. Unfortunately, in some families, treatments for arrhythmias
or cleft palate, dental findings, short stature, and clinodactyly) and can produce weakness, and treatments for weakness may exacerbate
distinct neurocognitive deficits in executive function and abstract cardiac dysrhythmias. The periodic paralysis usually responds to car-
reasoning (Yoon et al., 2006a, 2006b). The periodic paralysis, often bonic anhydrase inhibitors. In ATS with hypokalemic weakness, oral
triggered by rest after exercise, prolonged rest, and stress, is often the potassium ingestion treats acute attacks. Prophylaxis with daily sus-
presenting symptom and can be hypo-, normo-, or hyperkalemic. The tained-release potassium tablets may prevent attacks of weakness.
cardiac phenotype, often discovered later, includes prolonged QT Maintaining a high serum potassium level (>4.5 mEq/L) also has the
intervals, but bidirectional ventricular tachycardia is common. Despite additional advantage of narrowing the QT interval, thus reducing the
the known association of cardiac arrhythmias in rare periodic paraly- likelihood of developing ventricular arrhythmias.
sis patients, ATS was only recognized as a separate entity in 1971. In Treatment of the prolonged QT interval depends on the severity
families segregating an ATS allele, the phenotypic expressivity can vary of the underlying arrhythmias. The use of beta-blockers is a main-
greatly. Patients can manifest one, two, three, or four features of the stay of treatment in long QT. Clinical experience shows that patients
tetrad, and the severity of any single feature can be extremely variable. with ATS tolerate these agents well. In the presence of syncope due
Rare individuals are asymptomatic disease-gene carriers. to sustained ventricular tachycardia, the placement of an implantable
defibrillator is useful. Some evidence suggests that flecainide may be
Pathophysiology effective in the treatment of severe ATS-associated ventricular arrhyth-
Mutations in the KCNJ2 gene on chromosome 17q account for approx- mias (Bökenkamp et al., 2007; Pellizzón et al., 2008).
imately two-thirds of ATS probands. KCNJ2 encodes a widely expressed
inwardly rectifying potassium channel (Plaster et al., 2001). Interestingly, Malignant Hyperthermia
among all identified probands, about 50% have an autosomal dominant Malignant hyperthermia is an uncommon syndrome that manifests as
disorder, and identification of sporadic cases with de novo mutations is a hypermetabolic reaction to volatile anesthetics and depolarizing neu-
common. The mechanisms of channel dysfunction are heterogeneous, romuscular blocking agents. Inheritance is usually autosomal domi-
including impaired phospholipid binding, pore function, or protein nant, but multifactorial inheritance also occurs. Further complicating
trafficking. Because VGKCs are tetrameric complexes, many (if not efforts to define the inheritance and the incidence is that many people
all) of the mutations are dominant negative. KCNJ5, encoding another with malignant hyperthermia do not develop symptoms on all expo-
inwardly rectifying potassium channel, may represent a second ATS- sures, and some never experience exposure to inciting agents.
associated gene, as a mutation there was identified in one patient with Malignant hyperthermia displays genetic heterogeneity. Disease-
ATS who did not harbor any KCNJ2 mutation (Kokunai et al., 2014). causing mutations have been identified in RYR1, the gene encoding the
skeletal muscle ryanodine receptor, and CACNA1S, the L-type VGCC
Diagnosis implicated in hypoKPP. The ryanodine receptor is a calcium channel
Previous studies that took into account the variable penetrance of expressed on the endoplasmic reticulum mediating calcium release in
ATS classified individuals as affected if two of three criteria were met: excitation–contraction coupling. To date, more than 20 disease-caus-
paroxysmal weakness, prolonged QT interval with or without vening point mutations in RYR1 have been identified in humans, account-
tricular dysrhythmias, or characteristic dysmorphic features (Yoon ing for half of affected families.
et al., 2006a). ATS should be included in the differential diagnosis Clinical manifestations of malignant hyperthermia include tachyp
of any individual with documented long-QT syndrome, even in the nea, tachycardia, rigidity, acidosis, rhabdomyolysis, and hyperthermia.
absence of periodic paralysis or dysmorphism. Some family members Unfortunately, an intraoperative diagnosis often becomes apparent
of patients with the full clinical triad show only prolonged QT inter- when symptoms develop. In patients in whom there is a family history
vals. Similarly, perform ECG on all patients with suspected periodic suggestive of the diagnosis or in those who have had an event during
paralysis for careful measurement of the QT interval. previous anesthesia, the caffeine-contracture test remains the best-
Often the diagnosis of ATS is established when an individual with available test for diagnosis. A thin strip of explanted muscle is stimulated
paroxysmal weakness presents during an acute phase with ECG abnor- electrically to achieve maximal contraction and then exposed to caffeine;
malities. However, one often overlooks the diagnosis because the car- increased contracture signifies the disease. Although this test is useful,
diac abnormalities, as with periodic muscle weakness, can be transitory results are highly operator dependent. Therefore, if any possibility of
and missed on routine ECG. A Holter monitor can capture episodic this condition exists, the standard of practice is the pretreatment of every
dysrhythmias or longer tracings for QT-interval analysis when ATS is patient undergoing anesthesia with dantrolene. Although malignant
hyperthermia is always a consideration in patients who become weak

with anesthesia, a periodic paralysis—distinguished by flaccidity rather
than rigidity—may be uncovered during periods of stress.
Immediate termination of exposure to anesthesia, immediate
effective core cooling, and the administration of dantrolene sodium, FHM2
an inhibitor of calcium release from the sarcoplasmic reticulum, are FHM3
Seizure Migraine
the mainstays of treatment for this condition and have significantly AHC
reduced mortality since their introduction into clinical use.
EA2?
Congenital Myasthenic Syndromes SMEI
Paroxysmal FHM1
The congenital myasthenic syndromes are a rare, heterogeneous, non-
dyskinesias? EA2
immune group of disorders of neuromuscular transmission. Chapter
108 covers these disorders in detail.
GENETIC DISORDERS OF NEURONAL ION Ataxia

CHANNELS
The disorders considered here involve inherited ion channel defects
in neurons. Like muscle channelopathies, these defects also result in
episodic phenotypes. Many such mutations cause epilepsy, considered
separately in a later section. Fig. 98.6 Venn Diagram Showing Phenotypic Overlap Among Var-
ious Channelopathies. AHC, Alternating hemiplegia of childhood; EA,
Familial Hemiplegic Migraine episodic ataxia; FHM, familial hemiplegic migraine; SMEI, severe myo
Clinical clonic epilepsy of infancy.
Familial hemiplegic migraine (FHM) is a rare autosomal dominant
subtype of migraine with motor aura, characterized by lateralized
motor weakness of variable intensity—hemiparesis to hemiplegia. linkage to chromosome 19p13, with causative missense mutations
Other aura symptoms such as visual aura, paresthesia, ataxia, fever, or in the CACNA1A gene (Ophoff et al., 1996). This gene encodes the
lethargy may present during the attack. Motor symptoms often start pore-forming α1A-subunit of the neuronal P/Q-type VGCC, which is
in the hand and gradually spread to other areas, over 20–30 minutes, distributed widely throughout the brain. It is present at motor nerve
although it may occur suddenly mimicking a stroke. The duration of terminals and the neuromuscular junction and is the principal cal-
the symptoms can be variable, from a few hours to weeks. The diagnos- cium channel expressed by cerebellar Purkinje and granular neurons.
tic hallmark is episodic, reversible, unilateral motor weakness, along These channels play an integral role in the action potential–triggered
with at least one other kind of aura. presynaptic calcium influx at nerve terminals that triggers vesicular
Cortical spreading depression (CSD) is a widely accepted physiol- fusion, playing an important role in neurotransmitter release. At least
ogy underlying the migraine aura. CSD is a slow self-propagating wave 17 different missense mutations and one nonsense mutation (Jen et al.,
of neuronal and glial depolarization, followed by hyperpolarization. 1999) are reported in CACNA1A (Fig. 98.7). These cause a variety of
Four subtypes, genetically defined (see later discussion), are dis- altered but not lost functions: changes in channel conductance, kinet-
tinguishable by clinical characteristics. FHM type 1 (FHM1) accounts ics of inactivation, and current density (Hans et al., 1999; Kraus et al.,
for about 50%–75% of families. FHM1 is commonly associated with 2000). Indeed, these mutations may confer gain of function, because
cerebellar degeneration. In addition to weakness, auras always involve many appear to cause a hyperpolarizing shift in the activation voltage,
additional symptoms, including sensory, visual, and language distur- meaning that channels open and permit calcium influx at abnormally
bances (Ducros et al., 2001). Severe aura attacks may last days or weeks low membrane potentials. In one extreme case, the S218L mutation
and may involve fever, meningismus, and impaired consciousness, confers both the tendency to open near the resting potential of many
ranging from confusion to coma. Recovery between attacks is typically neurons (−60 to −50 mV) and overall slowing and reduction in chan-
complete, although 30%–50% of patients with FHM1 exhibit perma- nel inactivation, thus causing marked increases in overall calcium
nent progressive cerebellar signs that include nystagmus, gait or limb influx. In keeping with this extreme biophysical profile, S218L pro-
ataxia, or dysarthria. These manifestations of FHM1 overlap with epi- duces a severe clinical phenotype of aura attacks triggered by minor
sodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (Fig. 98.6), head trauma and leading to deep coma and prolonged cerebral edema
which are allelic with CACNA1A mutations (see the following discus- (Tottene et al., 2005). On the other hand, some loss-of-function muta-
sion). By contrast, the characteristic features of FHM2 are an absence tions associated with episodic ataxia type 2 (EA2) may also cause
of cerebellar signs and a tendency for lower penetrance than in FHM1. migraine symptoms (Jen et al., 2004), suggesting that a direct correla-
FHM2 accounts for less than 25% of cases. Ataxia does not occur in tion between presynaptic VGCC-mediated calcium entry and disease
FHM3, a rarer and more recently defined entity. FHM4 is diagnosed severity is too simplistic. Importantly, the mechanism linking altered
if there is no known genetic mutation of FHM. Importantly, patients channel biophysics to disease expression is controversial and defies a
with FHM exhibit a spectrum of disease expression, and subtype clas- simple model.
sification is likely to evolve with our knowledge of underlying genetics. As mentioned earlier, other mutations in CACNA1A cause dif-
ferent dominantly inherited neurological disorders, including EA2
Pathophysiology and spinocerebellar ataxia type 6 (SCA6). Although most patients
FHM is a genetically heterogeneous condition that links to three loci with FHM1 also suffer persistent cerebellar deficits, a few mutations
on chromosomes 1q, 2q, and 19p; other loci are possible (Ducros et al., in CACNA1A cause only hemiplegic migraine (Ducros et al., 2001),
1997). FHM1 includes the 50%–75% of families that show genetic and one mutation appears to cause classical migraine with aura but
I II III IV
192Q 583Q 1667W
666M 1457
T V
R
R R
V Y
D V I
N K W
1811L C
714A 715E 1384C
1335E
1695I 1683R
Fig. 98.7 P/Q-Type Calcium Channel and the Mutations Causing Familial Hemiplegic Migraine Type 2.
Voltage-gated calcium channels are classified into transient (T-type), long-lasting (L-type), N (neuronal), P/Q
(Purkinje cell), and R (toxin-resistant) channels. Shown is the CACNA1A-encoded α1A-subunit, which forms
the voltage sensor and pore of the channel. Disease-causing missense mutations are illustrated.
no weakness (Serra et al., 2010). These observations suggest that a to experience motor, speech, and sensory symptoms. Furthermore,
spectrum of disease exists from pure ataxia at one extreme to classical the duration of the headache, as well as the duration of the visual and
migraine at the other. sensory components of the aura, are typically greater in FHM patients
Patients with FHM2, representing 10%–20% of all FHM sufferers, (Thomsen et al., 2002). Although patients with classical migraine often
exhibit mutations in the ATP1A2 gene encoding the α2-subunit of experience the aura in isolation from the headache, FHM patients
the Na+/K+-ATPase, a protein responsible for maintaining the mem- experience an associated headache virtually all the time. Infrequently,
brane potential in neurons and other cells (De Fusco et al., 2003). This FHM patients may experience bilateral weakness, whereas this is gen-
pump plays a critical role in establishing transmembrane ionic gradi- erally not the case in patients with classical migraine. Finally, although
ents and is in this way directly integral to the function of innumerable defined genetically, one might clinically suspect FHM based on an
ion channels and other proteins. Many missense mutations have been association with cerebellar abnormalities or seizures (see Fig. 98.6).
identified, probably resulting in a loss of function but not loss of sur-
face expression (De Fusco et al., 2003), possibly by a reduced affinity Treatment
for potassium (Segall et al., 2004). Although an ionic mechanism is Anecdotal evidence suggests that acetazolamide reduces the frequency
likely, the precise pathophysiological connection to hemiplegic aura of migraine attacks (Battistini et al., 1999; Jen et al., 2004). As sug-
or head pain remains obscure. Additional mutations in ATP1A2 may gested by functionally enhanced calcium currents in many cases
also cause a form of benign familial infantile seizures (see the later sec- of FHM, the calcium channel blocker verapamil aborted an attack
tion on Epilepsy; Vanmolkot et al., 2003) and alternating hemiplegia when administered intravenously (Yu and Horowitz, 2001). To date,
of childhood (Swoboda et al., 2004). A single mutation was found to no controlled study has tested the efficacy of these or other agents in
cause hemiplegic migraine with cerebellar findings (Spadaro et al., FHM. The guidelines for treating common migraine may be applied,
2004), challenging the conception that this association is specific for except that triptans and ergotamine are not used, out of concern—
CACNA1A mutations. possibly unwarranted—for stroke (Artto et al., 2007). Nimodipine is
FHM3 involves mutations in the SCN1A gene on chromosome contraindicated because of the risk of worsening symptoms (Mjåset
2q24 that encodes a neuronal voltage-gated sodium channel α1-sub- and Russell, 2008).
unit. To date, three missense mutations have been identified, and the
two that have been characterized electrophysiologically each confer Familial Episodic Ataxias
upon the channel more rapid recovery from fast inactivation and thus The familial episodic ataxias (EAs) are rare, dominantly inherited dis-
the potential for faster firing frequency and neuronal hyperexcitabil- eases characterized by episodes of ataxia of early onset, often with com-
ity (Castro et al., 2009; Dichgans et al., 2005). Other mutations in pletely normal cerebellar function between attacks (Jen et al., 2007). Of
SCN1A cause some cases of severe myoclonic epilepsy of infancy and the seven syndromes now recognized (EA1–EA7), the two most com-
generalized epilepsy with febrile seizures plus (see the later section on mon forms, EA1 and EA2, are best described.
Epilepsy). Interestingly, mutations causing epilepsy occur near those
causing FHM3, and one mutation—L263V—causes both clinical phe- Clinical
notypes (Castro et al., 2009). Epilepsy has also been reported in cases Characteristic of EA1 are attacks of cerebellar incoordination with
of FHM1 and FHM2, pointing to the intriguing possibility of a patho- jerking limb movements, often accompanied by slurred speech, that
genic link between seizure and migraine. last for seconds to minutes. The episodes can occur spontaneously, but
common triggers include exertion, infection, stress, or startle. Between
Diagnosis attacks, patients may show myokymia, muscle rippling resulting from
Genetic testing is now commercially available, but the diagnosis is motor nerve hyperexcitability, especially in the hands and around the
mostly made clinically. Family history is clearly helpful in demon- eyes. Symptom onset is in infancy, with spontaneous resolution in the
strating autosomal dominance, but it is important to note that typical second to third decade. Frequency, duration, and intensity of attacks
migraine syndromes may also show a strong (if less regular) familial vary greatly. EA1 is associated with epilepsy and hearing impairment
pattern. Certain clinical elements of FHM help distinguish it from (Spillane et al., 2016).
classical migraine with aura. Although the aura symptoms may be Patients with EA2 experience episodes of truncal ataxia lasting
similar to those in classical migraine, FHM patients are more likely hours to days, precipitated by exertion and stress. Age of onset varies
between childhood and young adulthood but is most frequently in

the second decade. Vertigo, nausea, and vomiting are present in more
than half of patients, and many exhibit spontaneous nystagmus that is
not seen interictally. Between episodes, the patient returns to normal
but frequently displays gaze-evoked nystagmus with features typical of
rebound nystagmus (Jen et al., 2007). Less commonly, positional and,
later in the disease course, spontaneous downbeat nystagmus occurs.
Approximately half of EA2 patients report headaches that meet criteria
for migraine. Since mutations causing EA2 are in the same gene as in
FHM1, this is not surprising.
Pathophysiology
The mutation underlying EA1 is on chromosome 12. At least 15 mis-
sense mutations have been described in the responsible gene, KCNA1,
which encodes a delayed rectifier VGKC (Kv1.1) that opens with a
delay after membrane depolarization, allowing K+ efflux and mem-
brane repolarization (see Fig. 98.3). Co-expression of mutant and
wild-type channels results in delayed outward potassium current and
impaired membrane repolarization following an action potential (Zerr Fig. 98.8 Sagittal Magnetic Resonance Image From a Patient with
et al., 1998), a dominant-negative effect that could lead to increased Episodic Ataxia Type 2. Note the significant cerebellar atrophy from
neuronal excitability and neurotransmitter release. The delayed recti- this relatively advanced case. Type 1 patients do not display cerebellar
fier potassium channel is widely expressed in the nervous system, with atrophy (not shown).
highest levels in the cerebellum and myelinated axons of peripheral
nerves. In the cerebellum, an imbalance between inhibition and exci-
tation could result in brief episodic incoordination. Similarly, in the complain of diplopia, they do not have nystagmus, which helps distin-
peripheral motor nerves, impaired repolarization could lead to repet- guish them from EA2 patients. The brevity of attacks and the persistent
itive neuronal activity and resultant myokymia. Suggesting that these interictal myokymia seen in EA1 also help distinguish this from EA2.
two effects may be mechanistically distinct is a KCNA1 missense muta- EA2 patients may demonstrate interictal end-point tremor or impaired
tion that causes an episodic ataxia more akin to EA2 without myo- suppression of the vestibulo-ocular reflex. They tend to have subtle
kymia (Lee et al., 2004a) and another missense mutation resulting in and slowly progressive interictal cerebellar signs, particularly gaze-
myokymia without ataxia (Rea et al., 2002). evoked nystagmus. Although progressive ataxia often develops, it is
EA2 is caused by mutations in CACNA1A, which encodes Cav2.1, rarely severe enough to prevent walking without assistance. Magnetic
a pore-forming α1A subunit of the calcium channel (Ophoff et al., resonance imaging (MRI) may detect cerebellar atrophy, especially of
1996). In addition to FHM1, CACNA1A mutations also causes SCA6, the anterior vermis (Fig. 98.8), whereas EA1 patients have no cerebellar
resulting in cerebellar dysfunction. While FHM and EA are paroxys- atrophy. Interestingly, there appears to be an increased incidence of
mal, SCA is not paroxysmal but characterized by progressive cerebellar epilepsy in both EA1 and EA2 patients, emphasizing the overlapping
degeneration. Various mutations have been found; however, the com- symptoms, possibly due to shared mechanisms (see Fig. 98.6). Genetic
mon pathophysiology appears to be cortical depression from neural testing is available clinically and on a research basis.
hyperexcitability (Vincent et al., 2007). Whereas FHM1 is associated
with missense mutations in the same gene, the genetic alterations asso- Treatment
ciated with EA2 seem more dramatic. Of the approximately 30 muta- Acetazolamide reduces the severity of attacks. Response to treatment
tions described so far, most are truncating, a few are missense, one varies among families, but generally, patients with EA2 have a greater
is insertional, and one is due to expansion of a triplet CAG domain. response than those with EA1. Carbamazepine or 4-aminopyridine
Functional expression studies of some of these mutations reveal loss of (Strupp et al., 2004) are beneficial in some patients. Because stress and
voltage sensitivity or complete loss of channel function (Guida et al., strenuous exercise often exacerbate attacks, lifestyle modification can
2001), suggesting that haploinsufficiency may underlie the phenotype. be quite effective.
Some mutations may additionally interfere with protein folding and
trafficking (Wan et al., 2005). Hereditary Hyperekplexia
EA5 results from mutation of the VGCC β4-subunit gene CACNB4, Clinical
also implicated in idiopathic generalized epilepsy (see the later section Human startle disease, or hereditary hyperekplexia, is a rare heredi-
on Epilepsy); it is clinically similar to EA2, except that seizures are an tary disease characterized by an exaggerated startle response to sen-
additional feature (Escayg et al., 2000a). Mutations in SLC1A3, the sory stimuli, plus neonatal hypertonia, hyperreflexia, and myoclonic
gene encoding the excitatory amino acid transporter EAAT1, cause jerks. It was first described in a Swedish family with startle reflexes
EA6, an episodic ataxia associated with hemiplegia and seizures (Jen and violent falls due to generalized stiffness (Kirstein et al., 1958). The
et al., 2005). The genes for EA3 (1q42), EA4, or EA7 (19q13) have not usual inheritance is autosomal dominant, but several recessive muta-
been identified. tions exist. Patients have generalized stiffness immediately after birth,
which resolve over time (Koning-Tijsssen et al. 2000). The normal
Diagnosis startle response is a primitive reflex that manifests as a stereotyped
Diagnosis is mostly clinical. Family history is helpful in making the sequence of blinking, grimacing, neck flexion, and arm abduction and
diagnosis, despite rare cases of de novo mutations. The probability of flexion. Both pathological and normal startle responses originate from
examining a patient during an attack is low, so careful examination the caudal brainstem, spreading rostro-caudally, as demonstrated
for interictal signs is important. Although almost half of EA1 patients using EMG in different muscles (Bakker et al., 2009). Patients exhibit
NH2 heterozygous patient with spontaneous hyperekplexia possessing

a missense mutation on one allele and a splice-site mutation on the
other (Rees et al., 2002). Electrophysiological studies showed reduced
276E sensitivity of the mutant channel to agonist, suggesting impaired bind-
ing of glycine to the channel.
K 279C
Finally, loss-of-function mutations in GLYT2 (also named
COOH SLC6A5), the gene encoding the presynaptic glycine transporter 2
271 L/Q Y
protein, have been identified in three families with hereditary hyper-
R ekplexia. Glycine transporters mediate synaptic reuptake of the neu-
rotransmitter, and its genetic deletion reproduces hyperekplexia in
mice (Eulenburg et al., 2006). Reduction of glycine transporter func-
Q
tion is expected to prolong glycine neurotransmission; how this leads
to hyperekplexia is unknown.
Diagnosis
Physical examination may reveal diffuse hyperreflexia. The diffuse
266H hypertonicity in infancy generally resolves with time, and adults have
I P
224A normal tone between attacks. An exaggerated head-retraction reflex is
I common in these patients. Tapping the forehead or root of the nose
250T
244N downward with a reflex hammer causes a brisk involuntary backward
Fig. 98.9 The α1-Subunit of the Human Glycine Receptor and jerk of the head. This reflex is generally absent in unaffected individu-
Pathogenic Mutations Underlying Hyperekplexia. The glycine recep- als. Distinguish this condition from startle epilepsy, a rare seizure dis-
tor shares significant homology with the nicotinic acetylcholine recep- order characterized by startle-induced tonic spasm of a limb followed
tor, possessing five subunits to form a channel pore. by a complex partial seizure; asymmetrical tonic posturing occurs
during spells, and patients often have developmental delay and focal
neurological signs. Neuroimaging in startle epilepsy reveals cortical
an overreaction to unexpected visual, tactile, or particularly auditory dysplasia, although an interictal electroencephalogram (EEG) rarely
stimuli, with sudden generalized myoclonic jerks followed by stiffness, shows a clear seizure focus. By contrast, familial hyperekplexia patients
often resulting in uncontrolled falling during standing and walking. typically have normal development, display no ictal EEG findings to
Following a startle reflex, there is generalized stiffness for a few seconds suggest a seizure disorder, have normal brain imaging, and maintain
(Suhren et al., 1966). Consequently, patients often develop a character- full consciousness during attacks. Brainstem pathology, including
istic slow, wide-based, cautious gait. Consciousness is preserved during pontine hemorrhage or infarction, multiple sclerosis, vascular brain-
the attacks, which helps distinguish this from startle epilepsy. Attack stem compression, and brainstem encephalitis, may cause a syndrome
frequency may increase during times of stress, fear, lack of sleep, or similar to hyperekplexia. Rarely, sporadic cases of hyperekplexia occur;
the expectation of being frightened. The onset of symptoms may be as therefore, do not exclude the diagnosis in patients lacking a family
early as the neonatal period, with rigidity or generalized hypertonia, history.
nocturnal limb jerking, and an exaggerated startle response. Attacks
vary in severity and frequency and may be so severe as to cause apneic Treatment
episodes and even death. Affected children may show a slight delay Treatment with benzodiazepines helps reduce neonatal hypertonia
in motor development. A minor form of hyperekplexia, less common and significantly reduces the severity and frequency of startle-induced
than the major form, manifests as an exaggerated startle response with- attacks in some patients. Although clonazepam is the standard treat-
out associated symptoms, such as neonatal stiffness. ment, low-dose clobazam is effective in the treatment of hyperekplexia
and well tolerated in infants. Benzodiazepines act by increasing GABA-
Pathophysiology mediated inhibition and have no effect on glycinergic transmission.
Since being first reported in 1958, there are many reported mutations This suggests that enhancing the GABA-mediated inhibition may
responsible for hereditary hyperekplexia, including GLRA1, GLRB, compensate for glycinergic dysfunction.
GPHN, GLYT2 (also named SLC6A5), and ARHGEF9 (Harvey et al.,
2004, Rees et al., 2002, 2003). Eighty percent of hereditary hyperek- Hereditary Peripheral Nerve Disorders
plexia is caused by a mutation in the GLRA1 gene on chromosome SCN9A Mutation
5q encoding the glycine receptor α1-subunit. The glycine receptor is Primary erythromelalgia (PE), also known as familial erythromelalgia or
a heteropentameric ligand-gated chloride channel composed of three Weir Mitchell disease, is an autosomal dominant disorder characterized
ligand-binding α1-subunits and two β-subunits, located in postsyn- by burning pain and redness in the limbs in response to warmth or
aptic membrane, mediating fast inhibitory neurotransmission in the moderate exercise (Dib-Hajj et al., 2008; Yang et al., 2004). Paroxysmal
brainstem and spinal cord. Several dominant, recessive, and de novo extreme pain disorder (PEPD), previously known as familial rectal
GLRA1 missense point mutations are seen in familial hyperekplexia pain syndrome, is characterized by burning pain in the rectal, ocu-
patients. Most mutations flank the M2 pore-forming domain (Fig. lar, and mandibular areas accompanied by autonomic dysfunction,
98.9). The physiological consequence of mutations in the α1-subunit such as skin flushing (Hayden, 1959). Both PE and PEPD are caused
is decreased glycine sensitivity, impaired channel opening, and uncou- by mutations in SCN9A, encoding a voltage-gated sodium channel
pling of agonist binding from channel activation. These changes reduce selectively expressed in small-diameter dorsal root ganglion neurons
glycinergic inhibition and increase neuronal excitability. (mostly nociceptors) and sympathetic ganglion neurons. The muta-
Mutations in the gene encoding the glycine receptor β-sub- tions responsible for PE are gain-of-function mutations that enhance
unit (GLRB) also cause hyperekplexia. An example is a compound current through the channels by decreasing the voltage threshold for
activation, among other effects, while mutations causing PEPD impair Another related disorder is PKD. It involves attacks triggered by
the fast inactivation of the sodium channel. The discovery that expres- sudden movement, change in direction or startle, often with auras as
sion of this sodium channel is narrowly restricted to a population of in PNKD. Attacks commonly manifest with choreoathetosis and dys-
pain-mediating neurons, and that its enhanced function can result tonia, typically lasting for 5–10 seconds. It may occur as frequently
in pain, raises the exciting hypothesis that selective channel block- as daily or only a few times per year. Mutations in the proline-rich
ade may result in relief of chronic pain. Mexiletine and topical lido- transmembrane protein 2 (PRRT2) gene on chromosome 16q cause
caine are used for PE, and carbamazepine has shown benefit in PEPD. PKD and benign familial infantile seizures (as discussed later; Chen
Supporting a more general role for this gene, some polymorphisms et al., 2011; Lee et al., 2012). PRRT2 function is not known but thought
correlate with a lowered pain threshold in patients without primary to be involved in neurotransmitter release and synaptic vesicle fusion
erythermalgia (Reimann et al., 2010). Loss-of-function mutations in (Valtorta et al., 2016). Distinguishing PKD from PNKD is beneficial,
the same gene lead to an inherited insensitivity to pain (hereditary sen- as PKD usually responds dramatically to antiepileptic therapy, like car-
sory and autonomic neuropathy type IID). A selective antagonist of bamazepine and phenytoin (Bruno et al, 2004).
this channel does not yet exist. Paroxysmal exercise-induced dyskinesia (PED) is less common than
PKD and PNKD and involves lower limb dystonia lasting up to 30
TRPV4 Mutation minutes, triggered by exercise. Unlike PKD, where sudden movement
Scapuloperoneal spinal muscular atrophy, congenital distal spinal muscular may precipitate attacks immediately, PED attacks occur after 15–20
atrophy, and Charcot-Marie-Tooth disease type 2C (or hereditary motor minutes of vigorous exercise. The episode lasts from 5 to 30 minutes,
sensory neuropathy type 2) are related disorders. Characteristic of all are and patients with PED usually do not experience aura. SLC2A1 on
autosomal dominant inheritance, muscle weakness and wasting, and chromosome 1p is the gene encoding the GLUT1 glucose transporter
other features that can include arthrogryposis, scoliosis, or vocal cord protein, and mutations cause PED (Weber et al., 2008) or idiopathic
paralysis. These disorders result from mutations in TRPV4, the gene on generalized absence seizures (Suls et al., 2008); some mutations in
chromosome 12q encoding the vanilloid transient receptor potential SLC2A1 may cause more severe clinical phenotypes that include cog-
(TRP) protein, a peripheral nerve nonselective cation channel activated nitive dysfunction and microcephaly. PED is usually autosomal domi-
by many noxious stimuli such as heat, mechanical stress, osmotic pres- nantly inherited. Treatments include trigger avoidance and a ketogenic
sure, and inflammatory cytokines (Auer-Grumbach et al., 2010; Deng diet.
et al., 2010; Landoure et al., 2010). Although the pathogenic mechanism A theme emerges from these disorders, such that mutations in cer-
remains unclear, all known mutations affect the ankyrin repeat region tain genes may give rise to phenotypic heterogeneity, involving a spec-
of the protein, where regulatory proteins, second messengers, and other trum of paroxysmal dyskinesia and epilepsy.
TRPV4 channels normally bind. Unlike most disorders in this chapter,
the phenotypes resulting from TRPV4 mutations are not episodic. Other Inherited Neuronal Channelopathies
The rapid proliferation and lowering cost of whole-exome sequenc-
Paroxysmal Dyskinesia ing have led to frequent discoveries of new, rare genetic disorders. As
The paroxysmal dyskinesias are rare syndromes characterized by one example, de novo mutations in GRIN2B, the gene encoding the
recurrent, episodic attacks of involuntary movements, such as dys- N-methyl-d-aspartate receptor (NMDA) subunit 2B protein, associ-
tonia, chorea, athetosis, ballism, or a combination. While some cases ate with mental retardation (Endele et al., 2010; O’Roak et al., 2012).
may be sporadic, most exhibit autosomal dominant inheritance. NMDA receptors are well known to neuroscientists as the subtype
Paroxysmal non-kinesigenic dyskinesia (PNKD) involves attacks of of glutamate receptor that mediates long-term potentiation, a form
dystonia, chorea, or athetosis, occurring spontaneously or triggered of synaptic plasticity thought to underlie learning and memory, and
by alcohol, coffee, stress, or fatigue. An aura of paresthesia, tension, the 2B subunit in particular has special importance in the developing
or dizziness may precede abnormal movements that typically involve brain; it is not surprising that disruption of this receptor would result
the limbs. The attacks last for minutes to hours, which is longer in in impaired learning.
duration and less frequent than paroxysmal kinesigenic dyskinesia
(PKD). In a family with an autosomal dominant pattern of PKND
EPILEPSY
and generalized epilepsy (mostly absence attacks, as discussed later), a
mutation of KCNMA1 on chromosome 10q was identified (Du et al., Epilepsy is a disorder with recurrent seizures that affects 1%–2% of the
2005). This gene encodes the α-subunit of the BK channel, a potassium general population. Ion channels are crucial in regulating the excitabil-
channel that normally activates with both membrane depolarization ity of the neurons. Thus the dysfunction of ion channels is believed to
and a rise in intracellular calcium; the mutation heightens calcium cause excessive electrical excitability and resultant seizure activity. In
sensitivity, enhancing channel activity. Ethanol may also activate the some cases, channel mutations leading to lower excitability in inhib-
BK channel (Davies et al., 2003), suggesting a mechanism whereby itory neurons could have led to a common final pathway of seizures.
alcohol consumption in synergy with the mutation may precipitate a Among 977 identified epilepsy-associated genes, 60 genes are ion chan-
dyskinetic attack (Du et al., 2005). PNKD without epilepsy is linked nel genes (Wang et al., 2016). Although most epilepsies have a complex
to mutation of the PNKD gene (previously called the myofibrillogen- mode of inheritance, some rare idiopathic epilepsies are monogenic,
esis regulator gene, MR1) on chromosome 2 (Lee et al., 2004b); sub- most of which are autosomal dominant. Discussed here are syndromes
sequently, the protein encoded by this gene has been shown to encode associated with an identified gene. As might be expected from diseases
a novel synaptic protein regulating exocytosis (Shen et al., 2015). characterized by abnormal electrical activity in the brain, familial epi-
Studies in a mouse model of the human mutations recapitulated caf- lepsy syndromes often result from aberrant ion channel function.
feine- and ethanol-sensitive attacks and abnormal dopamine signaling.
Neuropharmacological experiments showed that the abnormal signal- Familial Focal Epilepsies
ing is being mediated through the indirect pathway of the striatum Unlike generalized epilepsy syndromes, which exhibit a strong genetic
(Lee et al. 2012). Treatment of PNKD involves avoidance of triggers; pattern, few focal epilepsy syndromes are genetic. Of these syndromes,
benzodiazepines, including clonazepam, often help. only two have known causative mutations.
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy more common mesial form by characteristic auditory auras, is in the
A syndrome characterized by clusters of brief partial seizures that occur second or third decade, and transmission is autosomal dominant with
during light sleep, autosomal dominant nocturnal frontal lobe epilepsy incomplete penetrance. Approximately 50% of cases involve muta-
(ADNFLE) is a monogenic disorder with a penetrance of 70%–80%. tions in the leucine-rich, glioma-inactivated gene 1 (LGI1) on chro-
The motor seizures, which manifest as hyperkinetic tonic stiffening mosome 10q (Kalachikov et al., 2002; Morante-Redolat et al., 2002),
and clonic jerking movements, may occur several times per night, whose product was shown to complex with presynaptic A-type VGKCs
usually shortly after falling asleep or just before awakening. Aura may (Schulte et al., 2006). Normally, LGI1 appears to reduce channel inac-
precede seizures, manifesting as various somatosensory, sensory, and tivation, and its dysfunction results in faster inactivation kinetics and,
psychic phenomena. Episodes often start with a gasp, grunt, or vocal- likely, neuronal hyperexcitability. A different gene, CPA6 on chromo-
ization, followed by eye opening or staring. Secondary generalization some 8q, encodes a carboxypeptidase enzyme (not an ion channel), in
is unusual, and patients remain conscious during the seizures. Patients which partial loss of function associates with familial temporal lobe
become symptomatic within the first or second decade of life, although epilepsy (heterozygous mutations) or febrile seizures (homozygous;
later onset occurs. Seizures generally persist throughout adult life, Salzmann et al., 2012).
becoming less severe beyond the fifth decade. Suggesting an important
contribution of genetic background, intrafamilial variability in seizure Idiopathic Generalized Epilepsies
frequency and severity is significant, with some patients experiencing The idiopathic generalized epilepsies (IGEs) are among the most com-
several seizures nightly and others remaining seizure-free for months. mon seizure disorders, occurring at an overall frequency of 15%–20%
Interictal EEG is normal, and ictal EEG may show bifrontal epilepti- among cohorts of adults and children (Jallon and Latour, 2005). A
form discharges. Because of the clinical similarities, ADNFLE is often strong genetic component to IGE transmission exists, but the pattern
mistaken for benign nocturnal parasomnia or night terror. Therefore, of inheritance varies between individual disorders. Some rare syn-
nocturnal video polysomnography is very useful in distinguishing dromes, including benign familial neonatal seizures (BFNS) and gen-
ADNFLE from these other conditions. eralized epilepsy with febrile seizures plus, are monogenic autosomal
ADNFLE was initially shown to be caused by a point mutation in dominant traits, now known to be due to mutations in ion channel
the nAChR α4-subunit gene CHRNA4 on chromosome 20q (Steinlein genes. Other more common syndromes—juvenile myoclonic epilepsy
et al., 1995). The nAChRs are acetylcholine-activated cation chan- (JME), childhood absence epilepsy (CAE), juvenile absence epilepsy
nels that play an important role in postsynaptic excitation and neu- (JAE), and epilepsy with grand mal seizures on awakening (EGMA)—
rotransmitter release. Four mutations in CHRNA4 were identified in exhibit a more complex pattern of inheritance. These disorders, which
several ethnic groups. Mutations have also been identified in CHRNB2 relate to each other by a continuum of clinical phenotypes and similar
(Phillips et al., 2001) and CHRNA2 (Aridon et al., 2006), encoding the EEG findings (see Chapter 100), probably encompass a broad range of
nAChR β2- and α2-subunits. The β2-subunit associates closely with individual diseases. We now know that aberrant ion channels underlie
the α4-subunit, and the α4–β2 combination is the dominant subtype at least some of these diseases.
of nAChR in the brain. Mutations in CHRNA4 and CHRNB2 involve
M2, the second transmembrane domain and the part of the protein Benign Familial Neonatal Seizures
thought to line the channel pore. Some cases of ADNFLE link to chro- BFNS is a rare autosomal dominant disorder. Multifocal or generalized
mosome 15q24, close to a cluster of three other nAChR subunits, tonic-clonic convulsions appear after the third day of life. Myoclonic
although the responsible mutations have not been elucidated (Philips seizures are rare. Seizures are generally brief and well controlled by
et al., 1998). Mutations result in increased sensitivity both to activation antiepileptic medications, although status epilepticus occurs. Age of
by acetylcholine and to block by carbamazepine. This latter in vitro onset may extend up to the fourth month of life, and in most cases, sei-
observation bears clinical relevance because ADNFLE patients have a zures disappear spontaneously after a few weeks or months. Although
good therapeutic response to carbamazepine. Given the wide distribu- these children usually have normal neurological examination and
tion of nAChRs within the brain, it remains unclear why the epilepsy is development, the risk of recurring seizures later in life is about 15%.
focal and why the seizures arise selectively in the frontal lobes. These later seizures, often provoked by auditory stimuli or emotional
Missense mutations in the sodium-gated potassium channel gene stress, are easily controllable with antiepileptic medications. Interictal
KCNT1 on chromosome 9q were found to cause a severe form of EEG activity is usually normal, whereas the ictal EEG attenuates at the
ADNFLE. As KCNT1 is highly expressed in frontal lobes, this may onset, followed by slow waves, spikes, and a burst–suppression pattern.
explain cognitive dysfunction and psychiatric symptoms (Heron et al., Two BFNS-causing genes have been identified—one on chro-
2012). The same gene is implicated in malignant migrating partial mosome 20q and the other on chromosome 8q. The mutated genes
seizures of infancy (Barcia et al., 2012), in which mutations disrupt a both encode VGKCs: KCNQ2 and KCNQ3, respectively (Biervert
protein kinase C phosphorylation site and lead to constitutive channel et al., 1998; Charlier et al., 1998; Singh et al., 1998). These channels
hyperactivation, the postulated pathophysiological mechanism (Barcia activate by membrane depolarization and contribute to the repolar-
et al., 2012). Furthermore, a missense mutation in the corticotro- ization of the action potential. Reports appear of missense amino
pin-releasing hormone (CRH) gene has been detected in one Italian acid deletion, splice-site frameshift mutations, and gene deletions;
family with ADNFLE. It is an interesting finding, as this seems not most involve the KCNQ2 gene (Fig. 98.10). Functional expression of
directly related to channelopathy (Sansoni et al. 2013). Further physi- mutant channels results in reduced potassium current, likely leading
ological connection is to be elucidated. to impaired membrane repolarization and thus increased neuronal
excitation. KCNQ2- and KCNQ3-encoded products combine to form
Familial Temporal Lobe Epilepsies a heteromeric channel underlying the M-current (Wang et al., 1998),
Temporal lobe epilepsies exist in both sporadic and inherited forms, a potassium conductance found widely in the central nervous sys-
and the genetics of familial syndromes remain largely unknown tem that plays a crucial role in the regulation of neuronal excitability.
(Andermann et al., 2005). The onset of familial lateral temporal lobe Co-expressing the mutant gene (KCNQ2 or KCNQ3) together with its
epilepsy (FLTLE), or autosomal dominant partial epilepsy with audi- wild-type allele and its wild-type partner results in mild (25%) reduc-
tory features (ADPEAF), a benign syndrome distinguished from the tion in M-current amplitude. Although it is unclear how the mutated
channels either independently or in the form of the M-current lead to plus, approximately 30% of patients may experience other generalized
seizures, KCNQ2 channels are concentrated in the septum and hippo- epilepsy phenotypes, such as absence, myoclonic, and atonic spells,
campus, areas key for control of rhythmic brain activity and neuronal and even partial seizures with secondary generalization. More severe
synchronization, and both associated with the generation of epileptic phenotypes include myoclonic-astatic epilepsy and severe myoclonic
seizures. Thus, even slight alterations in neuronal excitability through epilepsy of infancy. EEG may show irregular 2.5- to 4-Hz generalized
impaired KCNQ2/KCNQ3 channel-mediated repolarization could spike-and-wave or polyspike-wave discharges.
presumably lead to aberrant neuronal synchronization and seizures. A high level of genetic heterogeneity exists in GEFS+ (see Fig. 98.1).
In light of reports that lamotrigine and carbamazepine enhance neo- Mutations in four voltage-gated sodium channel genes (SCN1B on
cortical potassium currents in vitro, they may be of particular use in chromosome 19q and SCN1A, SCN2A, and SCN9A on chromosome
BFNS patients. 2q; Escayg et al., 2000b; Singh et al., 2009; Sugawara et al., 2001; Wallace
et al., 1998) and two GABAA receptor genes (GABRG2 and GABRD)
Generalized Epilepsy with Febrile Seizures Plus encoding the γ2- and δ-subunits (Baulac et al., 2001; Dibbens et al.,
Febrile seizures are the most common seizure disorder in children, 2004) cause GEFS+ (Fig. 98.11). Evidence exists for other mutated
affecting 2%–5% of all children younger than 6 years. Although most genes not yet identified. Functional analysis of several mutated sodium
febrile seizures show complex inheritance, a small proportion trans- channels reveals slow inactivation, enhanced inward sodium current,
mits in an autosomal dominant pattern. The disorder termed general- and thus neuronal hyperexcitability (Lossin et al., 2002). Functional
ized epilepsy with febrile seizures plus (GEFS+) refers to the phenotype studies of the two GABRG2 mutations showed reduced channel con-
of individuals who have febrile seizures extending beyond 6 years ductance in one case and abolished benzodiazepine sensitivity in the
of age, with or without afebrile generalized tonic-clonic seizures. other. The GABRD mutations reduce current amplitude, each lead-
Although most patients experience only febrile or febrile seizures ing in different ways to a decrease in synaptic inhibition and thus
an increase in neuronal excitability. These functional observations
evoke compelling molecular explanations for clinical disease and, like
ADNFLE and BFNS, illustrate how heterogeneous genetic defects may
226S/
converge on a single clinical phenotype.
A/R
184C SCN2A Mutation and Other Early Childhood Seizures
Other rare convulsive disorders of early childhood include benign
F familial infantile seizures and benign familial neonatal-infantile sei-
T
zures, differentiated from BFNS by the age of onset. At least some cases
V R V
involve mutations in the sodium channel α2-subunit gene, SCN2A, the
I same gene affected in some cases of GEFS+ (see the preceding section).
V 404I
A Two mutations are present in families with seizures beginning at 1–3
174F 408T
239S G E 325D R months of age and ending at around 4 months (“neonatal-infantile”;
176R PF 311S Heron et al., 2002). Both mutations occur in cytoplasmic loops, inhib-
NH2 242P 417 stop
iting channel inactivation. A third mutation, also affecting a cytoplas-
244H 249I COOH
mic loop, was identified in a family with similar seizures beginning at
4–12 months of age (“infantile”; Striano et al., 2006). Of note, ATP1A2
mutations account for some cases of benign familial infantile seizures
Fig. 98.10 The neuronal potassium channel α-subunit encoded by the (see the earlier section, Familial Hemiplegic Migraine).
KCNQ2 gene, and the proposed pathogenic mutations causing benign
familial neonatal seizures. The majority of mutations have been identi- Juvenile Myoclonic Epilepsy
fied in this channel, which is believed to coassemble with the KCNQ3 JME accounts for 4%–10% of all epilepsy (Jallon and Latour, 2005).
gene product and underlie the M-current. Featuring myoclonic jerks, generalized tonic-clonic seizures, and
121W
I II III IV C
4 5
1 2 3 + 6
+ R
+ T V I
D W
188V 875M 1353L 1656M

1204R 1648H
A B
Fig. 98.11 Mutations in the voltage-gated Na+ channel causing generalized epilepsy with febrile seizures
plus (GEFS+). The α-subunit is encoded by SCN1A (A), and the β1-subunit (B) is encoded by the SCN1B
gene. Disease-causing mutations are shown. Mutations in other genes, including SCN2A and GABRG2, also
cause GEFS+ (see Fig. 98.1).
absence spells, JME typically begins during adolescence (see Chapter Childhood Absence Epilepsy
100). A genetic pattern is clear, but the mixed inheritance pattern sug- CAE, a syndrome less common than JME and typified by brief, fre-
gests multiple heritable causes. One French-Canadian family suffers quent absence spells (see Chapter 100), exhibits a multigenic pattern
an autosomal dominant form of JME associated with a mutation in of inheritance. Mutations in GABRB3, encoding the GABAA receptor
the GABAA receptor α1-subunit gene, GABRA1 (Cossette et al., 2002), β3-subunit, appear to cause CAE in some families (Tanaka et al., 2008;
that results in loss of function and possible neuronal hyperexcitabil- Urak et al., 2006). A mutation in the GABAA receptor γ2-subunit gene,
ity (Krampfl et al., 2005). Less well described is the possible role of GABRG2, on chromosome 5q, conferring loss of benzodiazepine-in-
the VGCC β4-subunit gene, CACNB4, in JME and episodic ataxia (see duced enhancement of GABA-induced currents in vitro, is present
the previous discussion; Escayg et al., 2000a). GABRD variations may in a family with CAE and an increased incidence of febrile seizures
influence susceptibility to JME (Dibbens et al., 2004). (Wallace et al., 2001). The GABAA receptor mediates phasic or tonic
EFHC1 is a gene on chromosome 6p, and five missense mutations inhibitory transmission leading to hyperpolarization by allowing chlo-
have been identified in 6 of 44 JME families in whom it was sequenced ride anion influx through its pore (Hirose et al, 2014). Mutations in the
(Suzuki et al., 2004). Although the precise function of the EFHC1 pro- T-type VGCC gene, CACNA1H, may contribute to some cases of CAE
tein is unknown, it binds specifically to R-type VGCCs, alters their (Chen et al., 2003) and influence susceptibility to other IGEs (Heron
function, and perhaps thereby influences cell death pathways when et al., 2007). Mutations in other genes—CACNA1A, GABRA1, and a
transfected into cells in vitro. Whether or not this model turns out to locus on chromosome 8q24—may also play a role.
be correct, it illustrates that an inherited channelopathy may result not
only from mutation of a channel gene itself but also of genes whose Theoretical Considerations
products regulate the function of otherwise normal channels (Fig. The phenotypic and EEG characteristics of various IGEs overlap to a
98.12). considerable extent, implying that the boundaries separating some of
Chromosome 15q has genetic loci implicated by linkage studies as these disorders may be blurred. Moreover, the relationships between
possible contributors to some cases of JME. This area is known to con- molecular defects and clinical expression are irregular. Mutations in
tain, among other genes, the α7-subunit of the nicotinic acetylcholine some genes (e.g., SCN2A, GABRG2) lead to heterogeneous clinical
receptor, CHRNA7 (Elmslie et al., 1997). syndromes or genotype–phenotype divergence. Genotype-phenotype
Similar to JME is familial adult myoclonic epilepsy (FAME) and convergence is typified by ADNFLE, BFNS, and GEFS+, each of which
autosomal dominant cortical myoclonus and epilepsy (ADCME), may result from myriad underlying genetic roots (see Fig. 98.1). These
characterized by autosomal dominant inheritance, adult onset, considerations challenge existing definitions of disease, which will
varying degrees of myoclonus in the limbs, rare tonic-clonic sei- likely shift as knowledge advances. Cheaper and more widely avail-
zures, and a benign course. These syndromes bear some similarity able genetic tests will eventually free clinicians from the ambiguities of
to JME, except for the adult onset and the highly penetrant autoso- syndromic classification, and the elucidation of the molecular basis of
mal dominant transmission. Whereas the genes are not yet known, familial epilepsy syndromes will eventually lead to tailored pharmaco-
the FAME gene has been mapped to chromosome 8q24 (Plaster logical treatments.
et al., 1999) and the ADCME gene to chromosome 2q11.1–q12.2
(Guerrini et al., 2001).
AUTOIMMUNE CHANNELOPATHIES
Most channelopathies result from genetic mutation and are present
Channel from conception, usually with a family history of similar disorders.
However, some ion channel disorders may develop in a previously
normal individual. Beyond the obvious roles of drugs, toxins, and
electrolyte disturbances in disrupting the function of structurally
normal channels, circulating autoantibodies are the next most com-
mon known cause of acquired channelopathies. In some cases, these
Regulator are autoimmune disorders, and, in some cases, they are paraneoplas-
Anchoring tic phenomena. A paraneoplastic syndrome is a remote nonmalignant
protein effect of a primary tumor, thought to be caused by a cross-reactive
autoimmune response against a tumor antigen. The syndrome is often
apparent before the tumor itself is recognized. Therefore, paraneo-
plastic channelopathies are important to recognize, not only for their
Targeting own sake but also because they may herald a more morbid underlying
process.
Myasthenia Gravis
The best characterized autoimmune disease, myasthenia gravis, is
characterized by “fatigable weakness.” This results in most cases
Protein expression, from circulating antibodies directed against nAChRs. Polyclonal
posttranslational immunoglobulin G (IgG) reacts against variable extracellular
modification, etc. nAChR epitopes at the neuromuscular junction, with the main
immunogenic region located on each of two α-subunits of the het-
Fig. 98.12 Normal Ion Channel Function Relies Not Only on a Nor- eropentameric receptor complex (Tzartos et al., 1998). Antibodies
mal Channel Protein. Illustrated are examples of other processes that produce disease by activating complement, causing lysis of the mus-
when defective may theoretically result in aberrant ion channel function cle membrane, and by cross-linking AChRs, leading to accelerated
and disease. protein degradation. In addition to AChR antibodies (blocking,
modulating, and binding), antibodies against muscle-specific tyro- Other antibodies have been also identified in patients with Issacs
sine kinase (MuSK) or LDL receptor-related protein 4 (LRP) 4 also and Morvan syndrome. Patients with CASPR2 antibodies may present
have been found in myasthenic patients lacking the AChR antibod- with neuromyotonia alone, limbic encephalitis, or Morvan syndrome.
ies. Understanding of the cause of autoantibody production is poor, CASPR2 is not an ion channel, but this protein is important in cluster-
but it probably results from multiple disease processes, sometimes ing of Kv1.1 and Kv1.2, located in the juxtaparanodal regions of both
involving thymoma or thymic hyperplasia (see Chapter 108). peripheral and CNS axon (Amato and James, 2016). Other associated
antibodies are often paraneoplastic and include nAChR, CRMP-5,
Lambert-Eaton Myasthenic Syndrome amphiphysin, and antinuclear neuronal type 4.
Like myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS)
produces weakness by obstructing neuromuscular transmission. Paraneoplastic Cerebellar Degeneration
LEMS is caused by defected postsynaptic neurotransmitter transmis- Paraneoplastic cerebellar degeneration (PCD), presenting as a rap-
sion, typically presenting with proximal leg weakness and fatigue in idly progressive ataxic syndrome, most commonly occurs in cases of
middle-aged adults. Autoantibodies directed against P/Q-type VGCCs breast, ovarian, and lung malignancies. PCD probably represents a
impair presynaptic calcium influx, thereby reducing action poten- spectrum of diseases associated with distinct autoimmune targets.
tial-triggered vesicle release. These autoantibodies are not specific Among these may be the anti-P/Q-type VGCC antibodies found in
to the neuromuscular junction, and patients also exhibit autonomic small-cell cancer. Although these antibodies more typically cause
dysfunction. However, the antibodies probably do not cross the peripheral disease (LEMS), they are found less commonly in the CSF
blood–brain barrier to a sufficient extent to cause diseases mimick- of patients with PCD (Graus et al., 2002). Purkinje cell loss is the
ing CACNA1A mutants—FHM1, EA2, SCA6, or seizures—although pathological hallmark of PCD; these cells express high levels of P/Q-
some patients may exhibit ataxia (see the later section Paraneoplastic type VGCCs, and it seems likely that antibodies directed against these
Cerebellar Degeneration). Conversely, weakness is not a typical feature channels are pathogenic. PCD associated with small-cell lung cancer
in patients with loss-of-function CACNA1A mutations, although EMG may occur with or without neuromuscular dysfunction, and the fac-
studies reveal expected neuromuscular abnormalities (Jen et al., 2001). tors predisposing to central versus peripheral action of the paraneo-
Small-cell lung cancer cells express VGCCs, likely triggering immuno- plastic antibodies are unknown. Finally, despite the fact that the same
genesis in the large proportion of patients in whom LEMS turns out molecule may be the target of pathology in PCD and CACNA1A-
to be a paraneoplastic phenomenon. As in myasthenia gravis, poly- associated diseases (FHM1, EA2, SCA6), PCD is not an episodic dis-
clonal antibodies may be detectable in LEMS. The extracellular S5–S6 order but rather characterized by rapid deterioration, perhaps due to
linker regions of the α-subunit are the proposed pathogenic epitopes target cell destruction.
(Takamori, 2004).
Limbic Encephalitis
Acquired Neuromyotonia (Isaacs Syndrome) The term limbic encephalitis encompasses an array of autoimmune
Isaacs syndrome presents with painful muscle cramps and stiffness, disorders associated with psychiatric symptoms, cognitive dysfunc-
slow muscle relaxation after contraction, commonly affecting adoles- tion, and seizures, often in the context of an underlying malignancy.
cents and young adults. Characteristic features of acquired neuromyo- Some of these disorders result from an autoantibody directed against
tonia are fasciculations and myokymic and neuromyotonic discharges a brain ion channel. VGKC antibody-associated limbic encephali-
on EMG, reflecting motor nerve hyperactivity driven by abnormal tis, mentioned earlier, is one example. Anti–N-methyl-d-aspartate
peripheral nerve firing. Due to excessive muscle fiber activities, the (NMDA) receptor limbic encephalitis is the most common anti-
patients with Issacs syndrome often present with weight loss, muscle body-mediated encephalitis (Dalmau et al., 2008). This syndrome,
hypertrophy, and hyperhidrosis. The syndrome may occur in asso- which occurs mainly in women, causes psychiatric symptoms, sei-
ciation with thymoma. The autoimmune target is the VGKC found zures, delirium, and other neurological symptoms. Like PCD,
along peripheral motor axons and responsible for repolarization after anti-NMDA receptor encephalitis strongly suggests an underlying
action potential firing (Shillito et al., 1995). This is the same channel malignancy—typically ovarian teratoma. NMDA receptors represent
affected in EA1, and the mechanism of interictal myokymia is identi- one of three classes of glutamate-gated ion channels in the brain;
cal: reduced potassium efflux from axons and nerve terminals leads α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
to higher membrane potentials, inappropriate action potential firing, receptors represent another class, and antibodies against those recep-
and acetylcholine release. This same phenomenon probably also affects tors may also cause limbic encephalitis (Lai et al., 2009). Antibodies
autonomic fibers, explaining why excessive sweating, salivation, and against GABAB receptors were isolated in a series of patients with
lacrimation are often observed. The action of these antibodies is com- limbic encephalitis and prominent seizures (Lancaster et al., 2010).
plement-independent and appears to involve cross-linking of channels While not an ion channel, this G protein-coupled GABA receptor
(Tomimitsu et al., 2004). regulates ion channels and synaptic transmission. Leucine-rich gli-
VGKC antibodies probably also cause Morvan syndrome, which oma inactivated-1 (LGI-1) and CASPR2 are the proteins that com-
encompasses all the clinical features of acquired neuromyotonia plus a plex with a voltage-gated potassium channel. LGI-1 is rich in the
fluctuating delirium (Barber et al., 2000; Lee et al., 1998). Supporting hippocampus and neocortex. Dysfunction of LGI-1 causes secondary
a role for circulating autoantibodies is the effectiveness of plasma channel dysfunction, causing reduction of the synaptic AMPA recep-
exchange in the treatment of these patients (Liguori et al., 2001). tor. Patients with LGI-1 antibodies often present with focal seizure,
VGKC antibodies were present in a series of patients suffering from an and approximately 50% of them have pathognomonic faciobrachial
encephalopathy indistinguishable from limbic encephalitis, with tem- dystonic seizures. Seizures progress over time to an established lim-
poral lobe-onset seizures and behavioral and cognitive disturbances, bic encephalitis.
but no neuromuscular abnormality (Thieben et al., 2004). Thus, a As for PCD, acquired neuromyotonia, and LEMS, limbic enceph-
peripheral-to-central spectrum of disease may exist, with acquired alitis should be treated with intravenous immune globulin (IVIG),
neuromyotonia on the one extreme and VGKC antibody-associated plasma exchange, steroids, or other immunosuppressant therapies in
limbic encephalitis on the other. parallel with an aggressive search for an underlying neoplasm.
with simple Mendelian traits segregating from generation to genera-

SUMMARY
tion. Whether clues from Mendelian episodic neurological disease ulti-
Advances in molecular biology and electrophysiology have allowed mately bear on the complex genetics of epilepsy and migraine remains
discovery and the characterization of a new group of disorders termed to be seen.
the channelopathies. Understanding the underlying pathophysiology of The example of thyrotoxic hypoKPP is quite exciting. Worldwide,
these diseases has not only expanded our knowledge of basic ion chan- thyrotoxic hypoKPP is about 10 times more common than all the
nel physiology but, more importantly, has also provided insight into familial periodic paralyses put together. However, since it is a spo-
mechanisms of common neurological disorders such as epilepsy and radic disorder, mapping of causative genes is impossible. Clues from
migraine. The channelopathies, a seemingly heterogeneous group of the familial periodic paralyses motivated the hypothesis that led to the
diseases, share striking similarities. Most have intermittent symptoms, identification of inwardly rectifying potassium channel mutations in
despite the invariant presence of the mutation, with interictal return to some of these patients (Ryan et al., 2010). In this case, the mutations
a normal state. Exacerbating factors such as stress, exertion, and fatigue are segregating in families but are only “uncovered” in those (sporadic)
are common to many of the channelopathies. Response to treatment individuals who develop thyrotoxicosis. Additional insights into many
with carbonic anhydrase inhibitors (acetazolamide) is a common fea- common and sporadic diseases will continue to be gained through the
ture among these genetic disorders (see Table 98.3), leading some clini- study of rare familial cases and better understanding of the genetics
cians to use acetazolamide responsiveness as a diagnostic litmus test for and pathophysiology.
the channelopathies. The mechanism by which acetazolamide prevents Despite considerable progress in the understanding of channelop-
and ameliorates attacks is not completely understood, although recent athies, several unanswered questions remain, such as why these syn-
evidence suggests the activation of potassium channels may play a role. dromes are episodic, why acetazolamide is effective in such a diverse
These similarities suggest a common underlying pathophysiologi- group of disorders, and how identical mutations within a gene can
cal basis shared among the channelopathies. In fact, many of the chan- cause dominant or recessive behavior. Although disease-targeted
nelopathies, such as EA2 and FHM, share several characteristics. This pharmacological therapy is ideal, this has largely remained theoretical,
chapter has attempted to provide a clinical approach to the recogni- and such work is still in early stages. Understanding where a certain
tion, diagnosis, and treatment of the channelopathies. Furthermore, mutation lies within a gene does not fully reveal the intricacies of the
knowing where the genetic mutation is located does not necessarily clinical phenotype, and mutational effects in vivo are likely to be con-
predict the clinical phenotype. Diagnostic confusion arises from phe- siderably more complicated than those demonstrated in vitro. Thus
notypic variability within a given syndrome and phenotypic similarities future advances in defining the various channelopathy phenotypes and
among different syndromes, as well as the realization that mutations in understanding the underlying molecular mechanism will greatly con-
the same gene can produce seemingly unrelated phenotypes (see Fig. tribute to the understanding of these and other related disorders.
98.1). This underscores the importance of careful clinical assessment. Finally, disruption of ion channel function may occur in more com-
The clinician’s most useful diagnostic tool remains a detailed history plex ways than simply by mutation in an ion channel gene or by an auto-
and physical examination. antibody to the channel protein itself. Our appreciation of the complex
Genetic contributions to common seizure and headache syndromes association of ion channels with other proteins that target, anchor, reg-
are well known but more difficult to dissect at a molecular level. This ulate, or otherwise influence their behavior is growing (see Fig. 98.12).
is due to the large number of genes/proteins that almost certainly con- Examples include EFHC1 and LGI1, discussed earlier in the chapter,
tribute to headache and epilepsy susceptibility. Further complicating which encode ion channel-regulating proteins and cause ion channel
this genetic heterogeneity is the complex interaction of genes and the dysfunction when mutated. Mutation in ankyrin-B, an anchoring protein
environment. Normal variations in proteins, like those discussed ear- that co-localizes a diverse range of ion channels and other membrane pro-
lier, occur in the general population. One exciting hypothesis is that teins, causes long-QT syndrome type 4 (Mohler et al., 2003). Mutations
some of these “normal” variations have functional consequences for in similar anchoring proteins are likely to be discovered in neurological
channels (and other proteins, too). Innumerable factors contribute to disease; perhaps Schwartz-Jampel syndrome is an example. This rare auto-
net neuronal excitability, circuit dynamics, and brain function. These somal recessive syndrome characterized by myotonia and chondrodys-
factors subtly increase or decrease by polymorphisms in the many ion plasia results from mutations in HSPG2, the gene encoding perlecan, the
channel proteins and in other proteins expressed by a neuron. In most heparan sulfate proteoglycan enriched in basement membranes and car-
families, these many polymorphisms average each other out, resulting tilage (Stum et al., 2006); the pathophysiological link between perlecan
in “normal” excitability. However, in occasional families segregating and myotonia has yet to be established. The spectrum of episodic and
multiple hyperexcitability alleles, offspring may be more susceptible to electrical disorders of the nervous system will continue to grow.
seizure or headache than the general population and experience attacks
unmasked by appropriate precipitating conditions. This model is con- The complete reference list is available online at https://expertconsult.
sistent with familial clustering of such disorders, but it is inconsistent inkling.com/.
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99
Neurocutaneous Syndromes
Monica P. Islam, E. Steve Roach
OUTLINE
Tuberous Sclerosis, 1590 Neurological Features, 1604
Cutaneous Features, 1590 Immunodeficiency and Cancer Risk, 1604
Neurological Features, 1591 Laboratory Diagnosis, 1604
Retinal Features, 1593 Epidermal Nevus Syndrome, 1604
Cardiac Features, 1593 Cutaneous Features, 1605
Renal Features, 1593 Neurological Features, 1605
Pulmonary Features, 1593 Other Features, 1605
Neurofibromatosis Type 1, 1593 Neuroimaging, 1605
Cutaneous Features, 1594 Neurocutaneous Melanosis, 1605
Neurological Features, 1595 Cutaneous Features, 1605
Systemic Features, 1595 Neurological Features, 1606
Neurofibromatosis Type 2, 1597 Laboratory Findings, 1606
Clinical Features, 1597 Neuroimaging, 1606
Sturge-Weber Syndrome, 1597 Ehlers-Danlos Syndrome, 1607
Cutaneous Features, 1597 Neurovascular Features, 1608
Ocular Features, 1598 Cerebrotendinous Xanthomatosis, 1608
Neurological Features, 1598 Neurological Features, 1608
Diagnostic Studies, 1599 Xanthomas, 1608
Treatment, 1599 Other Clinical Features, 1608
Von Hippel-Lindau Syndrome, 1600 Treatment, 1609
Neurological Features, 1600 Progressive Facial Hemiatrophy, 1609
Ocular Features, 1600 Clinical Features, 1609
Systemic Features, 1600 Kinky Hair Syndrome (Menkes Disease), 1609
Molecular Genetics, 1601 Cutaneous Features, 1610
Treatment, 1601 Other Clinical Features, 1610
Hereditary Hemorrhagic Telangiectasia, 1601 Neurological Features, 1610
Neurological Features, 1601 Neuroimaging, 1610
Treatment, 1602 Genetic Studies, 1611
Hypomelanosis of Ito, 1602 Diagnosis and Treatment, 1611
Cutaneous Features, 1602 Xeroderma Pigmentosum, 1611
Neurological Features, 1602 Complementation Groups, 1611
Systemic Features, 1602 Related Syndromes, 1611
Incontinentia Pigmenti, 1602 Cutaneous and Ocular Features, 1611
Cutaneous Features, 1602 Treatment, 1612
Neurological Features, 1603 Other Neurological Conditions With Cutaneous Manifestations,
Genetics, 1603 1613
Ataxia-Telangiectasia, 1603 Conclusions, 1613
Cutaneous Features, 1604

Neurocutaneous disorders are congenital or hereditary conditions that some of the sporadic disorders result from somatic mosaicism.
feature lesions of both the skin and nervous system. Although each Advances in clinical genetics have established the molecular basis for
condition, or phakomatosis, is distinct and characterized by a unique some of the disorders, although recognition and treatment still require
pathophysiology, the concept of neurocutaneous disorders unifies those an appreciation of the cutaneous and systemic symptoms. This chap-
neurological disorders, whose identification depends primarily on ter reviews the clinical features of the more common neurocutaneous
simple visual diagnosis. These disorders may be inherited or sporadic; syndromes.
1589
TUBEROUS SCLEROSIS BOX 99.1 Updated Diagnostic Criteria for

Tuberous sclerosis complex (TSC) is a disorder of cellular differenti-
Tuberous Sclerosis Complex 2012
ation and proliferation that can affect the brain, skin, kidneys, heart, A. Genetic Diagnostic Criteria
and other organs. Many clinical features of TSC result from hamar- The identification of a pathogenic mutation in either TSC1 or TSC2 is sufficient to
tomas, but true neoplasms also occur, particularly in the kidney and make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation
brain. Abnormal neuronal migration plays a major additional role in that clearly inactivates the function of the TSC1 or TSC2 proteins (e.g., out-of-
neurological dysfunction (Roach, 2016; Roach & Sparagana, 2004). frame indel or nonsense mutation), prevents protein synthesis (e.g., large genomic
Population-based studies suggest a prevalence of one per 6000 indi- deletion), or is a missense mutation whose effect on protein function has been
viduals. However, because of the striking variability of clinical expres- established. Other TSC1 or TSC2 variants whose effect on function is less certain
sion, establishing the diagnosis of TSC can be difficult in individuals do not meet these criteria and are insufficient to support a definite diagnosis of
with subtle findings, and the true prevalence may be considerably TSC. Note that 10%–25% of TSC patients have no mutation identified by conven-
higher. Cutaneous findings are usually the first clue that a patient has tional genetic testing, so a normal result does not exclude TSC or affect the use of
TSC, but other features may lead to the diagnosis. In infants, cardiac clinical diagnostic criteria to diagnose TSC.
involvement and seizures frequently are presenting signs, whereas der-
matological, pulmonary, or renal involvement may lead to diagnosis in B. Clinical Diagnostic Criteria
older individuals. Updated guidelines have introduced genetic testing Major Features
as the potential sole diagnostic criterion in addition to clinical findings 1. Hypomelanotic macules (≥3, at least 5-mm diameter)
(Box 99.1). 2. Angiofibromas (≥3) or fibrous cephalic plaque
The inheritance of TSC is autosomal dominant with variable pene- 3. Ungual fibromas (≥2)
trance. The estimated spontaneous mutation rate for TSC varies from 4. Shagreen patch
66% to 86%, depending in part on the completeness of investigation 5. Multiple retinal hamartomas
of the extended family. Two genes are responsible for TSC: TSC1, cod- 6. Cortical dysplasias*
ing for hamartin at chromosome 9q34.3; and TSC2, coding for tuberin 7. Subependymal nodules
adjacent to the gene for adult polycystic kidney disease at chromosome 8. Subependymal giant-cell astrocytoma
16p13.3. The clinical features of TSC1 and TSC2 overlap, since the two 9. Cardiac rhabdomyoma
gene products form a single functional unit that is an upstream modu- 10. Lymphangioleiomyomatosis (LAM)†
lator in the mammalian target of rapamycin (mTOR) signaling path- 11. Angiomyolipomas (≥2)†
way. Both gene products downregulate small G-protein Ras-homolog
enriched in brain (RHEB) activity in this pathway. However, geno- Minor Features
type-phenotype studies indicate that individuals with a TSC2 mutation 1. “Confetti” skin lesions
tend to have more severe disease, and the frequency of TSC2 mutations 2. Dental enamel pits (≥3)
is greater among individuals with spontaneous mutations (Sancak et al., 3. Intraoral fibromas (≥2)
2005). Multiple mutation types exist in different regions of each gene, 4. Retinal achromic patch
and even individuals with identical genetic mutations can have different 5. Multiple renal cysts
phenotypes. Molecular diagnostic testing—including prenatal testing— 6. Nonrenal hamartomas
has been available since the early 2000s, and a disease-causing muta- Definite diagnosis: Two major features or one major feature with ≥2 minor
tion is identified in about 85% of the individuals who meet the clinical features
diagnostic criteria. Some of the individuals with no mutation identified Possible diagnosis: Either one major feature or ≥2 minor features
via routine gene analysis prove to have mosaicism (Roach, 2016). Large *Includes tubers and cerebral white-matter radial migration lines.
genomic deletions and rearrangements are more common in the TSC2 †A combination of the two major clinical features (LAM and angiomyolipo-
gene than in TSC1, and more mutations have been identified for TSC2 mas) without other features does not meet criteria for a definite diagnosis.
than for TSC1. TSC2 mutations appear more commonly than TSC1 TSC, Tuberous sclerosis complex.
in patients with subependymal nodules (SENs), intellectual disability, Adapted from: Northrup, H., Krueger, D.A., 2013. Tuberous sclerosis
renal angiomyolipomas, and retinal phakomas. Intellectual disability complex diagnostic criteria update: Recommendations of the 2012
International Tuberous Sclerosis Complex Consensus conference.
and other neuropsychiatric involvement are more likely in individuals
Pediatr Neurol 49, 243–254.
with TSC2 than in those with TSC1 mutation (Au et al., 2007).
Cutaneous Features angiofibromas are relatively specific for TSC, they are found in only
The cutaneous lesions of TSC include hypomelanotic macules, the three-fourths of affected individuals and often appear several years
shagreen patch, ungual fibromas, and facial angiofibromas (Fig. 99.1). after the diagnosis has been established by other means. The lesions
Hypomelanotic macules (ash leaf spots) occur in over 90% of affected typically become apparent during the preschool years as a few small red
individuals (Fig. 99.2). The lesions usually are present at birth but may macules on the malar region; they gradually become papular, larger,
be evident in the newborn only with an ultraviolet light (Wood’s lamp). and more numerous, sometimes extending down the nasolabial folds
Other pigmentary abnormalities include confetti lesions (areas with or onto the chin. Angiofibromas often become less prominent after
stippled hypopigmentation, typically on the extremities) and poliosis starting an mTOR inhibitor, and topical application has been studied
(a white patch or forelock) of the scalp, hair, or eyelids. Hypomelanotic (Koenig et al., 2018). Forehead plaques or fibrous facial plaques resem-
macules are common in normal individuals (Table 99.1), but three or ble angiofibromas histologically, though they are not papular.
more hypomelanotic macules greater than 5 mm is a major diagnostic The shagreen patch most often is found on the back or flank area; it
criterion for TSC. is an irregularly shaped, slightly raised, or textured skin lesion. About
Facial angiofibromas (previously termed adenoma sebaceum) consist 20%–30% of patients with TSC have a shagreen patch, which may not
of vascular and connective tissue elements. Although multiple facial be seen in young children.
CHAPTER 99 Neurocutaneous Syndromes 1591
Fig. 99.2 A Hypomelanotic Macule (Ash Leaf Spot) (Arrow) From

the Leg of a Patient With Tuberous Sclerosis. (Reprinted with per-
mission from Weiner, D.M., Ewalt, D.H., Roach, E.S., et al., 1998. The
tuberous sclerosis complex: a comprehensive review. J Am Coll Surg
187, 548–561.)
B progenitors in the caudothalamic groove near the foramen of Monro.

These lesions can grow over time, but usually only into adolescence,
after which time they calcify. These remain asymptomatic unless they
transform into subependymal giant-cell astrocytomas (SEGAs). Tubers
frequently extend from the ventricle wall to the cortical surface, with
a linear or wedge-shaped distribution. Similar to normal brain, tubers
develop between 14 and 16 weeks, gestation, such that the tuber load
is established before birth, though they may not be visible on imaging
until later childhood, given myelination status. These focal malforma-
tions of cortical development most frequently involve one gyrus at a
time, but more diffuse involvement such as hemimegalencephaly can
occur as well. Histology of these areas demonstrates disorganized cor-
tical lamination and underlying abnormal myelination with indistinct
gray-white-matter junction architecture. Calcification frequently is
C present. Dysmorphic neurons are often present, and other abnormal
Fig. 99.1 Classic cutaneous manifestations of tuberous sclerosis
astrocytes similar to those seen in sporadic focal cortical dysplasias are
include (A) ungual fibromas, (B) shagreen patch on the lower back, termed balloon cells or giant cells for their abundant cytoplasm (Wong,
and (C) facial angiofibromas. (A, Reprinted with permission from 2008).
Roach, E.S., Delgado, M.R., 1995. Tuberous sclerosis. Dermatol Clin Seizures of various types occur in 80%–90% of patients. Most
13, 151–161.) develop during the first year of life, which is a poor prognosticator for
autism and poor cognitive development. TSC is the most common
cause of infantile spasms, and one-third of children with TSC develop
Ungual fibromas are nodular or fleshy lesions that arise adjacent to them. Children with infantile spasms are more likely to have a high
(periungual) or underneath (subungual) the nails. The presence of two burden of cortical lesions demonstrated by magnetic resonance imag-
or more is considered a major criterion as a single lesion can develop ing (MRI) and are more likely to exhibit long-term cognitive impair-
after trauma in individuals without TSC. Ungual fibromas are among ment. For many, vigabatrin has been a more effective treatment option
the latest cutaneous manifestation of TSC, present in up to 80% of than adrenocorticotropic hormone (ACTH). Resective epilepsy sur-
older adults but only 20% overall (Northrup et al., 2013). gery is a consideration in individuals with seizures localizing to one or
two tubers. Corpus callosotomy is an option in some children. Some
Neurological Features individuals with prolonged seizure freedom while taking medication
The predominant neurological manifestations of TSC are intellectual can successfully discontinue anti-seizure medication (Sparagana et al.,
disability, epilepsy, and behavioral abnormalities, although milder 2003).
forms of the disease with little or no neurological impairment are Many TSC patients have intellectual disability, but many have
common. Impaired cellular interaction results in disrupted neuronal normal intelligence. As seen with early-onset epilepsy in general,
migration along radial glial fibers and abnormal proliferation of glial intellectual disability in TSC often accompanies epilepsy that man-
elements. Neuropathological lesions of TSC include SENs, cortical and ifests earlier in life and that is refractory. The number of subependy-
subcortical hamartomas (tubers), areas of focal cortical dysplasia, and mal lesions does not correlate with the clinical severity of TSC, but
heterotopic gray matter. SENs commonly arise from germinal matrix MRI evidence of numerous cortical lesions is associated with more
TABLE 99.1 Frequency of Lesions in Individuals With Tuberous Sclerosis Versus Other
Individuals
Lesion Tuberous Sclerosis Complex Other Individuals
Hypomelanotic macules Occur in over 95% of TSC patients, often with many lesions Occur in up to 5% of the population (but usually fewer than
three lesions per person)
Facial angiofibromas Eventually seen in 75% but less often in children Seen in individuals with multiple endocrine neoplasia type 1
and in a few sporadic families
Shagreen patch Up to 48% Occasional
Ungual fibromas Seen in 15% but often not until adulthood Occasionally sporadic or after nail trauma (but typically one
lesion)
Rhabdomyomas One or more tumors seen in 47%–65% but much more common In 14%–49% of rhabdomyoma patients, there are no other
below 2 years signs of TSC
Up to 51% of patients with rhabdomyomas have TSC
Renal AML Often multiple AML occur in up to 80% of TSC patients by age 10 Sporadic AML occur but are typically solitary
Renal cysts Polycystic kidneys occur in 3%–5% of TSC patients There are both dominant and recessive polycystic kidney
Smaller numbers of renal cysts are present in 15%–20% diseases
A few cysts are frequent sporadic findings in adults
Cortical dysplasia/tubers 90%–95% and usually multiple lesions are present (magnetic reso- Sporadic cortical dysplasia (typically one lesion) is common
nance imaging yields highest detection rate) among individuals who have epilepsy not due to TSC
Subependymal nodules 83%–93% Rare, especially if calcified
Subependymal giant-cell tumors Up to 15% (using radiographic criteria) Rare in the absence of TSC
AML, Angiomyolipoma; TSC, tuberous sclerosis.
From Roach, E.S., Sparagana, S.P., 2010. Diagnostic criteria for tuberous sclerosis complex. In: Kwiatkowski, D.J., Whittemore, V.H., Thiele, E.A.
(Eds.), Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Wiley-VCH Verlag, Weinheim, pp. 21–25. Used with permission.
significant cognitive impairment and seizure intractability. The most

abnormal regions seen on MRI tend to coincide with focal abnormal-
ities of the electroencephalogram (EEG). The severity of intellectual
disability ranges from borderline to profound intellectual disability.
In addition to intellectual disability, many children with TSC have
significant behavioral and psychiatric dysfunction. Autism, hyper-
kinesis, aggressiveness, psychosocial difficulties, and even psychosis
can occur, either as isolated problems or in combination. The preva-
lence of autistic spectrum disorders is 25%–50% and equal between
boys and girls. Behavioral problems are frequent and independent of
intellectual ability. Mood disorders also are increased. De Vries and
colleagues described the array of behavioral and psychiatric symp-
toms resulting from TSC as tuberous sclerosis associated neuropsychi-
atric disorders (TAND), and they developed a useful clinical screening
tool (de Vries et al., 2015).
Computed tomography (CT) best demonstrates the calcified
SENs that characterize TSC (Fig. 99.3). CT sometimes shows super-
ficial cerebral lesions, but they are far more obvious with brain MRI
(Fig. 99.4). T2-weighted sequences show evidence of abnormal neu-
ronal migration in some patients as high-signal linear lesions running
perpendicular to the cortex. SENs along the ventricular surface give the
characteristic appearance of “candle guttering.” More than one-fourth
Fig. 99.3 Computed cranial tomography scan from a child with tuber-
of patients with TSC show cerebellar anomalies.
ous sclerosis complex demonstrates typical calcified subependymal
SEGAs develop in 6%–14% of patients with TSC. Unlike the more nodules; a large calcified parenchymal lesion (arrowhead) and low-den-
common cortical tubers and SENs, SEGAs can enlarge (Fig. 99.5) sity cortical lesions (arrows) are seen as well. (Reprinted with permis-
and cause symptoms of increased intracranial pressure, particularly sion from Roach, E.S., Kerr, J., Mendelsohn, D., et al., 1991. Diagnosis
if extension into the lateral ventricles creates an obstructive hydro- of symptomatic and asymptomatic gene carriers of tuberous sclerosis
cephalus. Clinical features include new focal neurological deficits, by CT and MRI. Ann N Y Acad Sci 615, 112–122.)
unexplained behavior change, deterioration of seizure control, or
symptoms of increased intracranial pressure. Acute or subacute onset SEGAs are usually benign but locally invasive, and early surgery
of neurological dysfunction may result from sudden obstruction of the can be curative. Identification of an enlarging SEGA before the onset
ventricular system by an intraventricular SEGA. Rarely, acute deterio- of symptoms of increased intracranial pressure or appearance of new
ration occurs because of hemorrhage into the tumor itself. neurological deficits is ideal. Periodic screening for identifying SEGA
by lack of sufficient normal myocardium to maintain perfusion. Some

patients stabilize after medical treatment with digoxin and diuretics
and eventually improve; others require surgery. Echocardiography and
electrocardiography (ECG) establish the diagnosis. Arterial aneurysms
can occur. Surveillance studies every 6–12 months help monitor exist-
ing rhabdomyomas until stabilization or involution occurs. The size of
these lesions may increase with hormone exposure—a consideration
in the neonate, pubertal individual, and child treated with ACTH for
infantile spasms.
Renal Features
Renal angiomyolipomas occur in up to three-fourths of patients with
TSC, usually presenting by 10 years of age. Most of these lesions are
histologically benign tumors with varying amounts of vascular tis-
sue, fat, and smooth muscle (Fig. 99.8). Bilateral tumors and multi-
ple tumors in a kidney are common. The prevalence and size of renal
tumors increase with age, and tumors larger than 4 cm are much more
likely to become symptomatic than smaller tumors. Renal cell carci-
noma or other malignancies can affect TSC patients less commonly
and at younger ages than the general population. Coalescing angio-
myolipomas can contribute to end-stage renal disease. Endovascular
embolization of the larger renal angiomyolipomas prevents hemor-
rhage and other complications (Ewalt et al., 2005). Rapamycin and
everolimus limit the growth of these tumors, at least transiently.
Single or multiple renal cysts are also a feature of TSC; these tend to
Fig. 99.4 Noncontrast T2-weighted magnetic resonance imaging scan appear earlier than the renal tumors. Ultrasound or cranial CT easily
from a child with tuberous sclerosis demonstrates extensive high-signal identifies larger cysts, and the combination of renal cysts and angiomy-
cortical lesions typical of tuberous sclerosis. olipomas is characteristic of TSC. Individual renal cysts may disappear.
Surveillance imaging is recommended, at least every 2–3 years—more
may improve surgical outcome. Recent work suggests that rapamycin frequently in those with existing or symptomatic renal involvement.
and the oral mTOR inhibitor everolimus inhibit the growth of SEGAs.
Everolimus has approval from the US Food and Drug Administration Pulmonary Features
(FDA) for the treatment of SEGAs, renal angiomyolipomas, and, most Pulmonary disease presents after puberty in the form of LAM and is
recently, seizures due to TSC (Krueger et al., 2013). There also have five times more common in females than in males. Pulmonary lesions,
been reports of improvement in pulmonary lymphangioleiomyomato- symptomatic or asymptomatic, can be demonstrated in almost half of
sis (LAM) and facial angiofibromas (Franz, 2013). women with TSC who undergo chest CT. Baseline pulmonary function
testing, 6-minute walk test, and high-resolution CT of the chest are
Retinal Features recommended in all symptomatic patients and asymptomatic females
The frequency of retinal hamartomas in TSC varies from almost at age 18 years. Spontaneous and recurrent pneumothorax, dyspnea,
negligible to 87% of patients, probably reflecting the expertise and cough, and hemoptysis are typical symptoms of pulmonary TSC. Of
technique of the examiner. Pupillary dilatation and indirect ophthal- those who develop symptoms, 10%–12% die within 10 years of symp-
moscopy are important, particularly in children who may be unco- tom onset from complications of pulmonary TSC (Cudzilo et al.,
operative. Findings vary from classic mulberry lesions adjacent to the 2013). Tamoxifen and progesterone may be helpful in some patients,
optic disc (Fig. 99.6) to plaque-like hamartoma or depigmented reti- and mTOR inhibitors have been additional treatment options.
nal lesions. Most retinal lesions are clinically insignificant, but some
patients have visual impairment caused by large macular lesions, and
very few patients have visual loss caused by retinal detachment, vitre-
NEUROFIBROMATOSIS TYPE 1
ous hemorrhage, or hamartoma enlargement. Occasionally, patients Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is
have a pigmentary defect of the iris. Funduscopic examination is valu- the most common of the neurocutaneous syndromes, occurring in
able at the time of diagnosis, to monitor existing abnormalities or to approximately 1 in 3000 people. Inheritance is autosomal dominant,
evaluate for new symptoms. but approximately half of NF1 cases result from a spontaneous muta-
tion. The clinical features are highly variable.
Cardiac Features A mutation of the 60-exon NF1 gene on chromosome 17q11.2
Approximately two-thirds of individuals with TSC have a cardiac rhab- causes NF1. The NF1 gene product, neurofibromin, is a tumor-sup-
domyoma, but few demonstrate clinical symptoms. Cardiac rhabdo- pressor GTPase-activating protein functioning to inhibit Ras-mediated
myomas are hamartomas, tend to be multiple, and involute with time. cell proliferation. Despite identification of approximately 100 muta-
These lesions sometimes are evident on prenatal ultrasound testing tions of NF1 in various regions of the gene, none correlates to a specific
(Fig. 99.7), usually after 24 weeks, gestational age. Most individuals who clinical phenotype (Pasmant et al., 2012).
develop cardiac dysfunction present soon after birth with heart failure. Several patients have developed a somatic NF1 mutation affecting
A few children later develop cardiac arrhythmias or cerebral throm- only a limited region of the body. With this mosaic NF1, one extrem-
boembolism from the rhabdomyomas. The cause of congestive heart ity may have café-au-lait lesions, subcutaneous neurofibromas, and
failure is either by obstruction of blood flow via intraluminal tumor or other signs of NF1, but the rest of the body is unaffected (Garcia-
A B
Fig. 99.5 A, Noncontrast T1-weighted magnetic resonance imaging scan from a child with tuberous sclero-
sis shows an irregular mass (arrow) with a central signal void caused by calcification protruding into the left
frontal horn. B, Another scan with gadolinium a few months later shows contrast enhancement and minimal
tumor growth.
Fig. 99.7 Prenatal ultrasound study reveals a large cardiac rhabdomy-

oma (arrow) and two smaller rhabdomyomas (arrowheads) in a child
who subsequently proved to have tuberous sclerosis. (Reprinted with
permission from Weiner, D.M., Ewalt, D.E., Roach, E. S., et al., 1998.
The tuberous sclerosis complex: a comprehensive review. J Am Coll
Surg 187, 548–561.)
Fig. 99.6 A retinal astrocytoma (mulberry lesion) adjacent to the optic for the NF1 gene is technically difficult because the gene is large and
nerve is typical of those found in tuberous sclerosis. (Reprinted with several different mutations are causative. Commercially available stud-
permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pedi- ies have a 30% false-negative rate.
atr Clin North Am 39, 591–620.)
Cutaneous Features
Cutaneous lesions of NF1 (Fig. 99.9) include café-au-lait spots,
Romero et al.,). Similarly, some patients with germline mosaicism have subcutaneous neurofibromas, plexiform neurofibromas, and axil-
no outward manifestations of NF1 but have multiple affected offspring. lary freckling. Café-au-lait spots are flat, hyperpigmented areas
If several characteristics are present and the physician is astute, the that vary in shape and size. They typically are present at birth but
diagnosis of NF1 is obvious, especially when another family member is increase in size and number during the first few years of life. Later
affected. The diagnosis is difficult when the clinical features are atypical in childhood, skin freckling, 1–3 mm in diameter, often occurs
and the family history is negative. Very young children may have fewer symmetrically in the axillae (Crowe sign) and other intertriginous
apparent lesions, making definitive diagnosis difficult. Diagnostic cri- regions. Most children with six or more café-au-lait spots as their
teria (Box 99.2) help to resolve some of these questionable cases, but only diagnostic criterion will go on to meet diagnostic criteria, usu-
specific gene testing is replacing the use of clinical criteria. Screening ally by age 6 years.
peripheral nerve sheath tumors (MPNSTs). MPNSTs carry poor 5-year

survival rates despite treatment with surgery, chemotherapy, and radi-
ation. PNFs and MPNSTs are difficult to distinguish radiographically
and sometimes even pathologically.
Neurological Features
NF1 affects the nervous system in several ways, but the clinical fea-
tures vary even within the same family. Tumors occur in the brain,
spinal cord, and peripheral nerves. Compared to the general pop-
ulation, there is higher incidence of learning disability and atten-
tion disorders. Accompanying moyamoya syndrome predisposes to
stroke.
Optic nerve glioma (Fig. 99.10) is the most common CNS tumor
caused by NF1. Approximately 15% of patients with NF1 have uni-
lateral or bilateral optic glioma. The growth rate of these tumors var-
ies, but they tend to behave less aggressively in patients with NF1 than
those without NF1. When symptomatic, the presenting features are
optic atrophy, progressive vision loss, pain, or proptosis. Precocious
Fig. 99.8 A large angiomyolipoma of the lower pole of a kidney removed puberty is a common presenting feature of chiasmatic optic nerve
at surgery; several smaller angiomyolipomas (arrows) can be seen in tumors in children with NF1. Management options include observa-
the same specimen. (Reprinted with permission from Weiner, D.M.,
tion with serial brain MRI or treatment with radiation, chemotherapy,
Ewalt, D.E., Roach, E.S., et al., 1998. The tuberous sclerosis complex: a
comprehensive review. J Am Coll Surg 187, 548–561.)
or small-molecule therapies that specifically target signaling pathways
downstream of activated Ras. Radiation is less favored, especially given
possible exacerbation of vasculopathy in this population.
Ependymomas and meningiomas of the CNS occur in patients
BOX 99.2 Diagnostic Criteria for with NF1 less often than in patients with neurofibromatosis type 2.
Neurofibromatosis Neurofibromas and schwannomas are common but not always symp-
tomatic; they develop on either cranial nerves or spinal nerve roots.
Neurofibromatosis Type 1 (Any Two or More) The symptoms from these tumors (discomfort, pain, numbness, weak-
Six or more café-au-lait lesions more than 5 mm in diameter before puberty ness, and bowel/bladder dysfunction) reflect their size, location, and
and more than 15 mm in diameter afterward rate of growth.
Freckling in the axillary or inguinal areas Macrocephaly is seen in half of NF1 patients, typically attribut-
Optic glioma able to megalencephaly related to increases in white-matter volume.
Two or more neurofibromas or one plexiform neurofibroma Macrocephaly is independent of hydrocephalus accompanying aque-
A first-degree relative with neurofibromatosis type 1 ductal stenosis, which also occurs in this disorder. Approximately 60%–
Two or more Lisch nodules 78% of patients with NF1 have increased signal lesions within the basal
A characteristic bony lesion (sphenoid dysplasia, thinning of the cortex of long ganglia, thalamus, brainstem, and cerebellum on T2-weighted MRIs
bones, with or without pseudoarthrosis) (Fig. 99.11). These areas are not routinely visible with CT. The origin
and significance of these radiographic lesions are unclear, and they are
Neurofibromatosis Type 2
referred to at times as unidentified bright objects (UBOs). Whether these
Bilateral eighth nerve tumor (shown by magnetic resonance imaging, com-
MRI lesions correlate with the likelihood of cognitive impairment is still
puted tomography, or histological confirmation)
debatable; radiographic findings do not correlate with neurological defi-
A first-degree relative with neurofibromatosis type 2 and a unilateral eighth
cits. Patients with NF1 tend to have full-scale intelligence quotient (IQ)
nerve tumor
scores within the low-normal range and to exhibit behavioral problems.
A first-degree relative with neurofibromatosis type 2 and any two of the fol-
Deep gray-matter radiological findings tend to decrease with time, while
lowing lesions: neurofibroma, meningioma, schwannoma, glioma, or juvenile
cortical and subcortical findings do not decrease or increase.
posterior subcapsular lenticular opacity
Data derived from Neurofibromatosis. Conference statement, 1988. Systemic Features

National Institutes of Health Consensus Development Conference. Lisch nodules are pigmented iris hamartomas (Fig. 99.12). They are
Arch Neurol 45, 575–578. pathognomonic for NF1. Lisch nodules do not cause symptoms;
their significance lies in their implications for the diagnosis of NF1.
Lisch nodules are often not apparent during early childhood, so
Neurofibromas are benign tumors arising from peripheral nerves. their absence does not exclude the diagnosis of NF1. Rarely, chil-
These tumors are composed predominantly of Schwann cells and dren with NF1 have retinal hamartomas, but these usually remain
fibroblasts but contain endothelial, pericyte, and mast cell compo- asymptomatic.
nents. Neurofibromas can develop at any time; their size and number Dysplasia of the renal or carotid arteries occurs in a small per-
often increase after puberty. centage of patients with NF1. Renal artery stenosis causes systemic
Plexiform neurofibromas often occur on the face and can cause sub- hypertension. Another potential cause of hypertension is pheochro-
stantial deformity. Patients with plexiform tumors of the head, face, or mocytoma. Several forms of cerebral artery dysplasia occur, most
neck and those who presented before 10 years of age are more likely commonly moyamoya syndrome, which promotes cerebral infarc-
to do poorly (Needle et al., 1997). Plexiform neurofibromas have tion in children and brain hemorrhage in adults. Arterial aneurysms
a 5%–13% lifetime risk of malignant degeneration into malignant occur as well.
A B
Fig. 99.9 A, Typical café-au-lait spots and axillary freckling in an individual with neurofibromatosis type 1. B,
Plexiform neurofibroma in a boy with neurofibromatosis type 1. (B, Reprinted with permission from Roach,
E.S., 1988. Diagnosis and management of neurocutaneous syndromes. Semin Neurol 8, 83–96.)
Fig. 99.10 Computed cranial tomography scan from a child with neu-
rofibromatosis type 1 shows bilateral optic nerve gliomas, larger in the
right optic nerve (arrow) than the left. (Reprinted with permission from
Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am
39, 591–620.)
The most common skeletal manifestations in NF1 consist of short Fig. 99.11 Coronal T2-weighted magnetic resonance imaging scan
stature and macrocephaly. Other skeletal abnormalities include long- shows bilateral high-signal lesions in the basal ganglia, abnormalities
bone dysplasia (resulting in pathological fractures and subsequent typical of neurofibromatosis type 1.
pseudoarthrosis), scoliosis, and bony erosion secondary to adjacent
tumor. Dysplasia of the sphenoid wing is common. disorder whose features also include café-au-lait spots and obstructive car-
A mimic of NF1 is LEOPARD syndrome (lentigenes, ECG conduction diomyopathy. The café-au-lait spots and cardiac abnormalities may suggest
abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal (male) NF1. Legius syndrome is another autosomal dominant NF-like syndrome;
genitalia, retardation of growth, deafness) is an autosomal dominant it is characterized by similar cutaneous features but little tumorigenesis.
Fig. 99.13 Cranial magnetic resonance imaging scan from a child with
neurofibromatosis type 2 shows bilateral vestibular tumors (arrows).
As these grow larger, there is an increased likelihood of symptoms.
Fig. 99.12 Lisch Nodules of the Iris in a Patient With Neurofibroma- (Reprinted with permission from Roach, E.S., 1992 Neurocutaneous
tosis Type 1. syndromes. Pediatr Clin North Am 39, 591–620.)
features of these tumors depend primarily on their location within the

NEUROFIBROMATOSIS TYPE 2 brain and spinal cord. Schwannomas of other cranial nerves occur in
Designated fully a separate entity from NF1 in the late 20th century, some patients. Meningiomas, ependymomas, and astrocytomas also
neurofibromatosis type 2 (NF2) is characterized by bilateral vestib- occur with increased frequency. Patients with NF2 may develop mul-
ular schwannomas and often is associated with other brain or spinal tiple simultaneous tumor types, and baseline imaging at the time of
cord tumors. Similar to NF1, the inheritance is autosomal dominant. diagnosis should include the brain and spinal cord.
Some suggest the diagnosis of NF2 based on multiple meningiomas Merlin is a novel regulator of TSC/mTORC1 signaling, so mTOR
or nonvestibular schwannomas even without family history or classic inhibitors are being evaluated in the management of NF2 tumors
bilateral vestibular schwannomas. NF2 occurs in only 1 in 35,000 to (James et al., 2009) and also have been under study for the treatment
50,000 people. of plexiform neurofibromas in NF1.
A mutation of the NF2 gene on chromosome 22 causes NF2. The
NF2 protein product is schwannomin or merlin, moesin-ezrin-radixin-
STURGE-WEBER SYNDROME
like protein. The NF2 gene is a tumor suppressor. Dysfunction of the
NF2 gene accounts for the occurrence of multiple central nervous sys- The characteristic features of Sturge-Weber syndrome (SWS) are a
tem (CNS) tumors in patients with NF2. Several different mutations facial cutaneous angioma (port-wine nevus) and an associated lep-
have been documented in the NF2 gene. The clinical severity may be tomeningeal and brain angioma. The findings usually are ipsilateral
related to the nature of the NF2 mutation; missense mutations that but can be bilateral or even contralateral. In addition to the facial
allow some protein function tend to produce milder clinical forms, nevus, other findings include intellectual disability, seizures, contra-
whereas frameshift and nonsense mutations that produce stop codons lateral hemiparesis and hemiatrophy, and homonymous hemianopia
preventing the production of any protein often cause severe disease (Thomas-Sohl et al., 2004). However, the clinical features are vari-
(Halliday et al., 2017). able, and individuals with cutaneous lesions and seizures but with
normal intelligence and no focal neurological deficits are common.
Clinical Features The syndrome occurs sporadically and in all races. A somatic muta-
Patients with NF2 have few cutaneous lesions, and these tend to be tion in GNAQ has been identified in patients with port-wine stains
subtle. Instead, patients often have multiple types of CNS tumors with or without SWS. This activating mutation disrupts the q class of
(thus, the designation of central NF). Café-au-lait spots and subcu- G-protein alpha subunits and contributes to reduced GTPase activ-
taneous neurofibromas are less common than in NF1. Some patients ity; this results in increased cell signaling activity (Shirley et al., 2013).
exhibit presenile posterior subcapsular cataracts.
Most patients who meet established diagnostic criteria for NF2 Cutaneous Features
(see Box 99.2) eventually develop bilateral vestibular schwannomas, The nevus typically involves the forehead and upper eyelid but also
previously termed acoustic neuromas (Fig. 99.13). Symptoms of NF2 may involve both sides of the face and extend onto the trunk and limbs
typically develop in adolescence or early adulthood but can begin in (Fig. 99.14). Nevi that involve only the trunk, or facial nevi that spare
childhood. Common complaints with large acoustic tumors include the upper face, rarely are associated with an intracranial angioma. The
hearing loss, tinnitus, vertigo, facial weakness, poor balance, and head- facial angioma is usually obvious at birth; it may thicken over time
ache. Unilateral hearing loss is relatively common in the early stages. and develop a nodular texture. Reactive hypertrophy of adjacent bone
Consider screening with annual auditory brainstem responses or brain and connective tissue may occur. Some children have the character-
MRI. istic neurological and radiographic features of SWS, yet have no skin
Other CNS tumors occur much less often than vestibular schwan- lesions. More frequently, the typical cutaneous and ophthalmic find-
nomas. The term MISME syndrome (multiple inherited schwannomas, ings are present without clinical or radiographic evidence of an intra-
meningiomas, and ependymomas) applies to this disorder. The clinical cranial lesion. Only 10%–20% of children with a port-wine nevus of
the forehead have a leptomeningeal angioma. Although the leptomen- Epilepsy eventually develops in 72%–80% of patients with SWS
ingeal angioma is typically ipsilateral to a unilateral facial nevus, bilat- with unilateral lesions and in 93% of patients with bihemispheric
eral brain lesions occur in at least 15% of patients, including some with involvement. Although some begin in adult life, 75% of seizures begin
a unilateral cutaneous nevus. during the first year, 86% by age 2, and 95% before age 5. Focal motor
seizures or generalized tonic-clonic seizures are the most typical sei-
Ocular Features zure type initially associated with SWS. Other initial seizure types are
Glaucoma is the main ophthalmological condition associated with infantile spasms, myoclonic seizures, and atonic seizures. The first few
SWS. The risk of developing glaucoma has two age peaks, the first in seizures are often focal, even in patients who later develop generalized
infancy and the second in late childhood. Amblyopia and buphthal- tonic-clonic seizures or infantile spasms. Seizures can be refractory or
mos (enlarged globe) are present in some newborns. In others, the may remain well controlled with medication for long intervals.
glaucoma becomes symptomatic later and, if untreated, causes pro- The neurological impairment caused by SWS depends in part on
gressive blindness. Periodic measurement of the intraocular pressure is the site of the intracranial vascular lesion. Because the occipital region
mandatory, particularly when the nevus is near the eye. Patients with frequently is involved, visual-field deficits are common. Hemiparesis
SWS also may develop choroid angiomas or heterochromasia of the often develops acutely in conjunction with the initial flurry of seizures.
iris ipsilateral to the nevus. Although often attributed to postictal weakness, hemiparesis may be
permanent or persist longer than typical of a postictal deficit. Some
Neurological Features children develop sudden weakness without seizures, either as repeated
Epilepsy, intellectual disability, and focal neurological deficits are the episodes of weakness similar to transient ischemic attacks or as a single
principal neurological abnormalities of SWS. Seizures often begin in stroke-like episode with persistent neurological deficit. Not all patients
conjunction with hemiparesis or other focal deficits. Seizure onset have permanent focal neurological signs.
before age 2 years increases the likelihood of future intellectual dis- Early developmental milestones may be normal, but mild to pro-
ability and refractory epilepsy. Intellectual disability is likely in chil- found mental deficiency eventually develops in approximately half
dren with refractory seizures, whereas children who never experience of patients. Only 8% of the patients with bilateral brain involve-
seizures usually have normal intelligence. Few children who have ment are intellectually normal. Behavioral concerns are frequent,
normal cognition at age 3 years will later develop severe intellectual even in patients who are not intellectually disabled. The clinical
impairment. condition eventually stabilizes, resulting in residual hemiparesis,
A B
Fig. 99.14 Two patients with the classic distribution of the port-wine nevus of Sturge-Weber syndrome on
the face and eyelid. A, The nevus has developed a nodular texture. B, Episcleral or conjunctival angiomas can
occur on the affected side.
hemianopia, intellectual disability, and epilepsy, but without fur- than standard skull radiographs. Extensive cerebral atrophy is appar-
ther deterioration. ent even with CT, but MRI more readily shows subtle atrophy.
MRI with gadolinium contrast (Fig. 99.16) effectively demonstrates
Diagnostic Studies the abnormal intracranial vessels in most patients with SWS. Positron
Most children with a facial port-wine nevus do not have an intracranial emission tomography (PET) demonstrates reduced metabolism of the
angioma. Neuroimaging studies help distinguish children with SWS brain adjacent to the leptomeningeal lesion. However, patients with
from those with isolated cutaneous lesions. Although gyral calcification recent-onset seizures may have increased cerebral metabolism near
is a typical feature of SWS, the tram-track appearance first described the lesion. Single-photon emission computed tomography (SPECT)
on standard radiographs is uncommon and is almost never present in shows reduced perfusion of the affected brain. Both PET and SPECT
neonates. CT shows intracranial calcification much earlier (Fig. 99.15) often reveal vascular changes extending well beyond the area of abnor-
mality depicted by CT (Maria et al., 1998). Although functional imag-
ing is not necessary for all patients, it may help initially to establish a
diagnosis and may help characterize the extent of abnormality before
surgery.
Cerebral arteriography is no longer routine in the evaluation of
SWS but is sometimes useful in atypical patients or prior to surgery for
epilepsy. The veins are more abnormal than the arteries, with enlarged,
tortuous, subependymal, and medullary veins and sparse superficial
cortical veins. Failure of the sagittal sinus to opacify after ipsilateral
carotid injection may be due to obliteration of the superficial corti-
cal veins by thrombosis; the abnormal deep venous channels probably
have a similar origin as they form collateral conduits for nonfunction-
ing cortical veins. Microscopic hemorrhages are sometimes evident on
pathology specimens, although significant intracranial hemorrhage is
rare.
Treatment
Generally, the more extensive the intracranial lesion, the more diffi-
cult it is to control seizures with medication. Resection of a localized
brain vascular lesion or hemispherectomy can often improve seizure
control and may promote better intellectual development (Bourgeois
Fig. 99.15 Computed tomographic scan from a typical patient with
et al., 2007). Despite general agreement on the efficacy of surgical
Sturge-Weber syndrome; the occipital gyriform calcification pattern resection, debate remains concerning patient selection and the tim-
(arrow) is easily seen. (Reprinted with permission from Garcia, J.C., ing of surgery. Almost one patient in five has bilateral cerebral lesions,
Roach, E.S., McClean, W.T., 1981. Recurrent thrombotic deterioration limiting the surgical options unless one hemisphere is clearly respon-
in the Sturge-Weber syndrome. Childs Brain 8, 427–433.) sible for most of the seizures. Often the patient selected for surgery is
A B
Fig. 99.16 A, Magnetic resonance imaging study from a child with Sturge-Weber syndrome; this T1-weighted
axial view without contrast infusion is normal. B, Scan on the same child with gadolinium reveals leptomen-
ingeal and intraparenchymal angioma.
one with refractory seizures, clinical dysfunction (e.g., hemiparesis,

hemianopia) of the area selected for resection, and failure to respond
to an adequate trial of anticonvulsants. Patients with less extensive
lesions should have a limited resection rather than a complete hemi-
spherectomy. The limited resection preserves as much normal brain
as possible, even at the risk of having to do another operation later.
Corpus callosotomy is useful for patients with refractory tonic or
atonic seizures and extensive disease. In effect, the surgical consid-
erations in children with SWS are similar to those used with other
patients with epilepsy. Low-dose aspirin has been offered to patients
with SWS in an effort to minimize the burden of stroke-like episodes,
seizures, or cognitive impairment (Lance et al., 2013). Aspirin is gen-
erally well-tolerated, but its efficacy has not been established.
VON HIPPEL-LINDAU SYNDROME

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant inher-
ited disorder characterized by hemangioblastomas arising in the retina
and CNS, as well as visceral cysts and tumors. Hemangioblastomas
may occur sporadically but are usually multiple and more likely to
occur in young persons. Current prevalence estimates of this disorder
are approximately 1 in 40,000.
Hemangioblastomas are benign slow-growing vascular tumors that
cause symptoms from hemorrhage or local mass effect. Histologically,
hemangioblastomas are composed of endothelium-lined vascular Fig. 99.17 Magnetic resonance imaging showing multiple cerebellar
channels surrounded by stromal cells and pericytes. Mast cells are pres- hemangioblastomas in a patient with Von Hippel-Lindau syndrome.
ent and may produce erythropoietin.
The initial symptoms of VHL usually arise from effects of the vas- imaging of the entire spinal cord. Arteriography is not necessary
cular anomalies in the CNS, but some patients may present with pheo- for diagnosis but is valuable in demonstrating the feeding vessels if
chromocytoma or renal, pancreatic, hepatic, or epididymal tumors. surgical resection is planned.
One classification system categorizes patients according to whether Endolymphatic sac tumors occur in 10%–15% of these individu-
pheochromocytoma is present. The most common pattern of VHL als. Sometimes they are bilateral. Presenting symptoms can be abrupt
findings includes retinal and CNS hemangioblastomas and pancreatic change in hearing accompanying hemorrhage or vertigo and tinnitus
cysts (Lonser et al., 2003). (Butman et al., 2008).
Neurological Features Ocular Features

In the CNS, the most common site of hemangioblastomas is the cer- Childhood onset of symptoms is unusual, but retinal hemangioblasto-
ebellum in approximately half of patients (Fig. 99.17), followed by mas may occur in children as young as 1 year. Retinal hemangioblasto-
spinal and medullary sites. Cerebral hemangioblastomas are present mas may be asymptomatic, especially if they occur in the periphery of
in less than 5% of patients with VHL. The cerebellar hemispheres are the retina. Vision loss occurs when the lesions are large and centrally
affected far more frequently than the cerebellar vermis. Cerebellar located, even in the absence of hemorrhage. Arteriovenous shunting
hemangioblastomas typically present in the second decade of life. leads to fluid extravasation. Hemorrhage may lead to retinal injury
Early symptoms of cerebellar and brainstem hemangioblastomas and detachment, glaucoma, uveitis, macular edema, and sympathetic
include headache, the most common symptom, followed by ataxia, ophthalmitis.
nausea and vomiting, and nystagmus. Symptoms are often intermit-
tent or slowly progressive, but up to 20% of patients have an acute Systemic Features
onset of symptoms following mild head trauma. Spinal hemangio- Renal cysts are present in more than half of individuals with
blastomas typically present with focal back or neck pain and sensory VHL, although, as with CNS and retinal hemangioblastomas, the
loss or weakness. Because of their typical intramedullary location, spi- patients may be asymptomatic. Extensive renal cysts rarely lead
nal hemangioblastomas frequently lead to syringomyelia. The conus to renal failure. Of greater concern is renal cell carcinoma, which
medullaris and the cervicomedullary junction are the most common develops in more than 70% of patients and is the leading cause
sites. Brainstem hemangioblastomas tend to arise in the area post- of death. These tumors are usually multiple and tend to occur at
rema in the medulla, where they may be associated with syringobulbia. a younger age than sporadic renal cell carcinoma (Ashouri et al.,
Occasionally, hemangioblastomas occur in the cerebral hemispheres 2015). Simple renal cysts arise from distal tubular epithelium,
or sites near the third ventricle, such as the pituitary gland or its stalk, whereas renal cell carcinoma tumors arise from proximal tubular
the hypothalamus, or optic nerve. The incidence of cerebellar heman- epithelium.
gioblastomas increases with age, and 84% of patients with VHL will Pheochromocytomas occur in 7%–19% of patients and may be the
develop at least one such tumor by age 60 years (Maher et al., 1990). only clinical manifestation of VHL, even in carefully screened individ-
Hemangioblastomas are best visualized using contrast-en- uals. Tumors may be bilateral and occur outside the adrenal glands.
hanced MRI. Routine screening of the brain and spinal cord should Symptoms of pheochromocytoma include episodic or sustained
include precontrast and postcontrast T1-weighted images with thin hypertension, severe headache, and flushing with profuse sweating—
sections through the posterior fossa and spinal cord and surface coil or even hypertensive crises, stroke, myocardial infarction, and heart
failure. Diagnostic laboratory investigation demonstrates excessive

BOX 99.3 Cambridge Screening Protocol
catecholamine concentrations in serum and urine.
Cysts and tumors of the pancreas and epididymis are also features
for von Hippel-Lindau Disease
of VHL. Pancreatic tumors include nonsecretory islet cell tumors, Affected Patient
simple cysts, serous microcystic adenomas, and adenocarcinomas. Annual physical examination and urine testing
Pancreatic cysts are the most common of these lesions and are asymp- Annual direct and indirect ophthalmoscopy with fluorescein angioscopy or
tomatic unless they obstruct the bile duct or become numerous enough angiography
to cause pancreatic insufficiency. Islet cell tumors coincide frequently Cranial magnetic resonance imaging (MRI) or computed tomography (CT) every
with pheochromocytomas, possibly because both tumors derive from 3 years to age 50 and every 5 years thereafter
neural crest cells. Epididymal cystadenomas also may be asymptomatic Annual renal ultrasound, with abdominal CT scan every 3 years (more fre-
but palpable and cause discomfort. quently if multiple renal cysts are discovered)
Annual 24-h urine collection for vanillylmandelic acid
Molecular Genetics
Confirming initial suspicions, the VHL gene is a tumor-suppressor At-Risk Relative
gene located on chromosome 3p25–26. A mutation in the VHL gene Annual physical examination and urine testing
also occurs in many sporadic clear-cell renal carcinomas that present Annual direct and indirect ophthalmoscopy from age 5 years
later in life, as compared with those with VHL disease. This gene plays a Annual fluorescein angioscopy or angiography from age 10 years until age 60
role in the function of hypoxia-induced factor HIF2α. This regulation Cranial MRI or CT every 3 years from age 15 to 40 and every 5 years until
contributes to increased vascularization and upregulation of proan- age 60
giogenic genes and other oxygen-sensitive genes via hypoxia response Annual renal ultrasound, with abdominal CT scan every 3 years from age 20
elements (HREs). These genes include vascular endothelial growth to 65 years
factor (VEGF), platelet-derived growth factor (PDGF), transforming Annual 24-h urine collection for vanillylmandelic acid
growth factor alpha (TGF-α), glucose transporter-1 (GLUT1), car-
bonic anhydrase IX, and erythropoietin (EPO), among others. In par-
ticular, VEGF is important in angiogenesis; its level in ocular fluid of polyposis and HHT. Up to 30% of cases arise from spontaneous muta-
patients is significantly higher than in unaffected subjects. Recognition tions. The clinical features and the age at presentation are highly variable.
of these affected genes has focused trials of certain therapies (Clark & Diagnostic criteria known as the Curacao criteria include spontaneous
Cookson, 2008). recurrent epistaxis, visceral manifestation, and an affected first-degree
Hundreds of known mutations exist. Despite complex geno- relative; these were formulated in 2000 (Shovlin, 2000). Consensus
type-phenotype relationships, some clinical correlations are possible. guidelines regarding surveillance in 2009 recommend sequence analysis
Missense mutations in this gene are associated with pheochromocy- of ENG and ACVRL1 in index cases to guide testing at-risk family mem-
toma, whereas nonsense, frameshift, and splice-site mutations as well bers or to assist diagnosis in individuals who do not meet the requisite
as deletions predominate in families without pheochromocytomas. three of the four clinical criteria (Faughnan et al., 2011)
Microdeletions and microinsertions, nonsense mutations, or dele- Cutaneous telangiectasias most often occur on the face, lips, and
tions appear in 56% of families with VHL type 1, whereas missense hands and are less common on the trunk. Telangiectasias of the nasal
mutations account for 96% of those responsible for VHL type 2 (Chen mucosa often cause epistaxis well before other complications of the
et al., 1995). Specific mutations in codon 238 account for 43% of the disease occur and can be severe enough to contribute to iron-defi-
mutations responsible for VHL type 2, and one group of patients ciency anemia. Approximately one-third of patients have conjunctival
(type 2C) appears to be at low risk for any feature of VHL except telangiectasias, and 10% have retinal vascular malformations, although
pheochromocytoma. vision loss from these lesions is uncommon. Telangiectasias are not
prominent during the first decade, but they tend to enlarge and mul-
Treatment tiply thereafter.
Careful screening (Box 99.3) is the most important aspect of man- Widespread vascular dysplasia of the lungs, gastrointestinal tract,
agement of VHL. Screening is mandatory for all first-degree relatives or genitourinary system, depending on which site is predominantly
in a family with VHL or pheochromocytoma. Other indications for affected, can produce hemoptysis, hematemesis, melena, or hematuria.
clinical screening include pancreatic cysts, multiple or bilateral renal Other involved organs and tissues can include the thyroid, diaphragm,
cell tumors, retinal hemangiomas, and cerebellar hemangioblastomas. liver, pancreas, spleen, vertebrae, or aorta. Pulmonary arteriovenous
Availability of molecular analysis for the VHL gene reduces the num- malformations (AVMs) occur in 15%–20% of patients, and 60%–90%
ber of asymptomatic relatives requiring surveillance; only relatives of all pulmonary AVMs are associated with HHT. Screening includes
who have inherited the VHL mutation need annual screening. chest radiograph, arterial blood gas on oxygen, and bubble contrast
echocardiogram to evaluate for pulmonary shunting. Repeat screening
is helpful every 5 years or at times when the number and size of AVMs
HEREDITARY HEMORRHAGIC TELANGIECTASIA increase, such as during puberty or pregnancy. Other tests include
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu- chest CT and pulmonary angiography.
Osler-Weber syndrome or Osler-Weber-Rendu syndrome, is a highly
penetrant autosomal dominant disorder characterized by telangiec- Neurological Features
tasias of the skin, mucous membranes, and various internal organs. Neurological complications are common. Frequent complaints include
The prevalence is 1 in 10,000. Two different genes are responsible for headache, dizziness, and seizures. Less common complications include
most cases. One gene on chromosome 9q33–34 (HHT1) encodes for paradoxical embolism with stroke, intraparenchymal or subarachnoid
endoglin (ENG), a TGF-β binding protein. The other gene, on chro- hemorrhage, and meningitis or brain abscess.
mosome 12q13 (HHT2), encodes for activin A receptor type II-like 1 Paradoxical embolism via a pulmonary arteriovenous fistula
kinase, or ACVRL1. In some, a SMAD4 gene mutation leads to juvenile (AVF) leads to cerebral infarction. Rarely, a clot may form within the
fistula itself before migrating into the arterial circulation. Intermittent Many different cytogenetic anomalies occur in HI. Most patients
symptoms with subsequent improvement result from repeated small are mosaic for aneuploidy or unbalanced translocations, with two or
emboli. The cause of transient ischemic attacks during hemoptysis is more chromosomally distinct cell lines either within the same tissue or
air embolism from a bleeding pulmonary AVF. Approximately 1% between tissues. Genetic alterations in HI include ring chromosome
develop cerebral abscess or meningitis, probably because septic micro- 22, mosaic trisomy 18, 18/X translocation, and others. Mosaicism
emboli bypass the normal filtration of the pulmonary circulation via a for sex chromosome aneuploidy also occurs. Many individuals have
pulmonary AVF. normal lymphocyte karyotypes, but it is important to recognize that
Vascular anomalies may be found anywhere in the brain, spinal mosaicism may be tissue specific, so karyotype abnormalities may be
cord, or meninges, and more than one type of lesion may be present demonstrable in fibroblasts but not in lymphocytes.
in the same patient—making this a diagnosis for consideration in
patients with multiple cerebrovascular malformations. Approximately Neurological Features
one-fourth of HHT patients are likely to have a cerebral vascular mal- The frequency of neurological abnormalities in patients with typical
formation. AVMs, high-flow pial fistulae, and telangiectasias are most skin lesions ranges from 50% to 80% (Nehal et al., 1996). Epilepsy and
common; cavernous malformations, venous angiomas, and vein of intellectual disability are the most common neurological abnormali-
Galen malformations also occur, but less commonly. ties. Approximately half of patients with HI have seizures, usually with
Screening should begin with MRI and MR angiography (MRA) of onset in the first year of life. Focal seizures are most common.
the brain, although cerebral angiography is most sensitive. Angiography Macrocephaly is more common than microcephaly. Generalized
every 5 years with interim surveillance is recommended. MRI is the cerebral or cerebellar hypoplasia is the most common abnormality
best procedure for patients with known AVMs. on imaging. Severe cortical neuronal migration anomalies, hemimeg-
alencephaly, and lissencephaly occur as well. Hemimegalencephaly
Treatment may be ipsilateral or contralateral to the cutaneous hypopigmentation.
As with most of the neurocutaneous syndromes, treatment of HHT is Extensive periventricular white-matter lesions are another common
limited to the management of complications. Because many of the neu- finding. Small periventricular cysts and gray-matter heterotopias occur
rological complications of the disease arise secondary to a pulmonary as well. About a third of patients with HI have normal cranial MRI
AVF, resection or embolization of the fistula is essential. Treatment studies.
of cerebral AVMs is embolization, excision, or radiosurgery. Periodic
transfusion and chronic iron administration may be necessary. To Systemic Features
reduce risk of brain abscess in cases of undiagnosed pulmonary AVM, Some 50%–70% of patients with HI have noncutaneous defects. Ocular
antibiotic prophylaxis is a recommendation prior to dental procedures findings include microphthalmia, heterochromia iridis, dacryosteno-
(Faughnan et al., 2011). sis, pannus, corneal opacities, cataract, optic atrophy, retinal detach-
ment, and pigmentation anomalies of the retina. The most common
musculoskeletal anomaly is hemihypertrophy, but other anomalies
HYPOMELANOSIS OF ITO include short stature, pectus carinatum and excavatum, cleft palate,
Hypomelanosis of Ito (HI) is a heterogeneous and complex neuro- butterfly vertebrae, scoliosis, and clinodactyly and polysyndactyly.
cutaneous disorder affecting the skin, brain, eye, skeleton, and other Dental anomalies are frequent, including conical or hypoplastic teeth,
organs. Ito named the disorder incontinentia pigmenti achromians, but hypoplastic dental enamel, and cleft lip and palate. Cardiac defects
the present name is hypomelanosis of Ito to avoid confusion with incon- include tetralogy of Fallot, pulmonary stenosis, and septal defects.
tinentia pigmenti. It is the third most frequent neurocutaneous disease Disorders of endocrine and renal development occur infrequently.
after NF1 and the TSC. HI is usually a sporadic disorder with minimal
recurrence risk.
INCONTINENTIA PIGMENTI
Cutaneous Features Incontinentia pigmenti (IP) is a rare X-linked dominant condition
The skin findings are distinctive and in fact are the only constant affecting the skin, eyes, and CNS. Skeletal and dental anomalies are
feature of HI. Hypopigmented whorls, streaks, and patches are pres- common and variable. A transitory leukocytosis (predominantly
ent at birth and tend to follow Blaschko lines, pathways demarcating eosinophilic) of uncertain clinical significance can occur. Skin biopsy
embryonic skin development. In HI, the hypopigmented skin lesions was instrumental in making the diagnosis in the past, but now gene
are usually multiple, involve several body segments, and may be uni- testing is widely available. Skin biopsy from hyperpigmented regions
lateral or bilateral. They may be observable at birth but commonly shows free melanin granules in the dermis.
develop in infancy, depending on the degree of skin pigmentation.
Wood’s lamp examination may enable detection of hypopigmented Cutaneous Features
lesions. The degree or distribution of skin depigmentation does not The skin manifestations are characteristic. Skin abnormalities progress
appear to correlate with either the severity of neurological symp- in stages any time from the newborn period to adulthood. The duration
toms or associated organ pathology. The hypopigmented lesions of each stage is variable and may overlap with other stages. The lesions
follow Blaschko lines in two-thirds of patients and are patchy in typically evolve from blister (stage 1) to verrucous (stage 2) to linear
others. Other skin findings in patients with HI include café-au-lait and pigmented (stage 3) and finally to atrophic and hypopigmented
spots, cutis marmorata, aplasia cutis, nevus of Ota, trichorrhexis, (stage 4) (Fig. 99.18). Skin lesions develop along Blaschko lines. The
focal hypertrichosis, and nail dystrophy. Electron microscopy of the blister or bullous stage often presents in the neonatal period and is
hypopigmented lesions consistently shows a marked reduction of often evaluated as an infectious process. Verrucous transformation is
melanocytes (Cavallari et al., 1996). In the proximity of preserved most typical during infancy, and abnormalities of the nails and teeth
melanocytes, the basal keratinocytes contain a nearly normal content as they erupt become notable. The hyperpigmented stage is prominent
of melanosomes. Depigmented areas contain an increased number of in childhood and adulthood but begins to fade in the second or third
Langerhans cells. decade. The hypopigmented or atretic stage may demonstrate loss of
A B
Fig. 99.18 Features of incontinentia pigmenti change over time from blister-like and verrucous in the infant
(A) to hyperpigmented in an older individual (B).
normal hair and subcutaneous structures in addition to changes in col- to occur in individuals with ocular abnormalities. Some demonstrate
oration. Not all stages occur in all individuals, especially the hypopig- cerebral or cerebellar atrophy.
mented stage.
Abnormalities of hair include alopecia in areas that may have been Genetics
previously affected or unaffected by skin pigmentation changes. Scalp Transmission is X-linked dominant, and nuclear factor kappa B
hair may be thin or coarse. Abnormalities of eyebrows may be present (NF-κB) essential modulator (NEMO) is the causative gene—more
as well. Nails may be brittle or demonstrate pits; these findings may recently termed IKBKG (Greene-Roethke, 2017). Deletion in exons
wax and wane and raise concern for fungal infection. Tooth abnormal- 4–10 is the responsible mutation in 80%–90% of patients (Nelson,
ities may include abnormal shape or malpositioning. 2006). This protein is involved in prevention of apoptosis. The muta-
IP carries an increased risk of retinal detachment. This is most likely tion is expected to be lethal in males; however, males with somatic
to occur in early childhood and is rare after 6 years of age. Dilated mosaicism or an additional X chromosome, as in Klinefelter syn-
funduscopic examination demonstrates retinal neovascularization as drome, have survived. These individuals demonstrate immunodefi-
a precursor to detachment. Frequent surveillance ophthalmological ciency and ectodermal dysplasia rather than the characteristic skin
examination is important, especially early in life, and may be help- findings described.
ful in making the diagnosis in at-risk family members not otherwise
symptomatic.
ATAXIA-TELANGIECTASIA
Neurological Features Ataxia-telangiectasia (AT) is a neurodegenerative disorder that begins
Neurological abnormalities have been overestimated in the past, and in early childhood as a slowly progressive ataxia. Telangiectasias
the incidence appears less with laboratory confirmation available. (dilated small blood vessels), immunodeficiency, and cellular sensi-
Seizures occur more frequently in this population. Most affected tivity to ionizing radiation develop later. The distinctive skin lesions
females have normal intelligence. Affected males are more likely to predominantly involve the sclerae, earlobes, and bridge of the nose,
have developmental delay. Neurological abnormalities are more likely with less common involvement of the eyelids, neck, and antecubital
and popliteal fossae. The combination of these telangiectasias in a child Immunodeficiency and Cancer Risk
with progressive ataxia is pathognomonic for AT. The most striking Approximately 10%–15% of patients with AT develop a lymphoid
non-neurological feature of AT is an increased frequency of sinopul- malignancy by early adulthood (Taylor et al., 1996). T-cell malignan-
monary infections and a dramatically increased risk for malignancy of cies are more common than B-cell tumors, although both are more
the lymphoreticular system, especially leukemia and lymphoma. The frequent than in the general population. This increased risk of T-cell
estimated prevalence of AT, an autosomal recessive disorder, ranges tumors may be due to the increase in chromosomal rearrangement
from 1 in 40,000 to 1 in 100,000. The gene frequency is as high as 1% observed in T lymphocytes from patients with AT. T-cell tumors may
in the general population. occur at any age, whereas B-cell lymphomas tend to arise in older
children. AT is in a family of disorders (including Nijmegen breakage
Cutaneous Features syndrome, Bloom syndrome, and Fanconi anemia) characterized by
Telangiectasias typically do not develop until age 3–6 years, well specific cellular defects in response to deoxyribonucleic acid (DNA)-
after the onset of ataxia. Two other dermatological features of AT damaging agents.
that may be overlooked are hypertrichosis and occasional gray Other tumor types reported in association with AT include dys-
hairs. Hypertrichosis is noticeable particularly over the forearms. germinoma, gastric carcinoma, liver carcinoma, retinoblastoma, and
These often-overlooked features in the context of a child with slowly pancreatic carcinoma. In fact, nonlymphoid tumors, primarily carci-
progressive ataxia provide clues to the correct diagnosis. Progeric nomas, represent approximately 20% of all malignancies in patients
changes such as poikiloderma, loss of subcutaneous fat, and sclerosis with AT. Cerebellar astrocytoma, medulloblastoma, and glioma also
also have been associated. Abnormal radiosensitivity may underlie have been linked to AT in case reports.
reports of basal cell carcinomas in young adults. Cutaneous granu- Frequent sinopulmonary infections are another characteristic of
lomas, commonly associated with immunodeficiency states such as AT. A third of patients have a potentially severe immune deficiency.
severe combined immunodeficiency and X-linked hypogammaglob- Recurrent or chronic sinusitis, bronchitis, pneumonia, and chronic
ulinemia, may appear as the initial cutaneous manifestation of AT progressive bronchiectasis were frequent causes of death in previous
(Chiam et al., 2011). years but now usually respond to antibiotic treatment. The thymus
gland is often small or absent on chest radiography, and at autopsy
Neurological Features may be only rudimentary.
Ataxia, the first manifestation of AT, appears when the child learns to
walk in the second year of life. Truncal ataxia predominates early in Laboratory Diagnosis
the course of the disorder, affecting sitting, balance, and gait. Muscle Useful laboratory tests in the diagnosis of AT include serum α-fetopro-
strength is normal, and attainment of early gross motor milestones is tein, immunoglobulins (Igs), and cellular radiosensitivity tests. Nearly
usually on time. The ataxia is slowly progressive, and children typi- all patients with AT have an elevated α-fetoprotein level, which is uti-
cally require a wheelchair by the age of 12 years. As the child matures, lized as a screening diagnostic test. Approximately 80% have decreased
limb ataxia, intention tremor, and segmental myoclonus become serum immunoglobulin—IgA, IgE, or IgG, especially the IgG2 sub-
apparent. Choreoathetosis may be difficult to distinguish from dysme- class. Characteristic cellular features are reduced life span in culture,
tria and intention tremor, but it may dominate the clinical picture in cytoskeletal abnormalities, chromosomal instability, hypersensitivity
older children. At times, the choreoathetosis may resemble segmental to ionizing radiation and radiomimetic agents, defective radiation-
myoclonus of the limbs or trunk. Progressive dystonia of the fingers induced checkpoints at the G1, S, and G2 phases of the cell cycle, and
may appear in the second and third decades of life. Axial muscles are defects in signal transduction pathways (Rotman & Shiloh, 1997).
affected, and a stooped posture gradually develops. Progressive dysar- The gene associated with AT, ataxia telangiectasia mutated (ATM),
thria is present. is a large gene located at chromosome 11q22–23, and more than
Abnormal eye movements are nearly universal in children with 100 ATM mutations occur widespread throughout the ATM gene.
AT. Voluntary ocular motility is impaired; nystagmus and apraxias of Although the function of the ATM gene product is not clear, it belongs
voluntary gaze such as disorders of smooth pursuit and limitation of to a family of large proteins involved in cell cycle progression and
upgaze are the most common abnormalities. Oculomotor apraxia may checkpoint response to DNA damage. One postulation is that oxida-
precede appearance of the telangiectasias but is often misidentified as tive stress specifically activates ATM by initiating signal transduction
an attention-seeking behavior. Strabismus is seen in many young chil- pathways responsible for protecting cells from such insults (Savitsky
dren with AT, but it is often transitory and does not warrant corrective et al., 1995). Thus, the production of reactive oxygen species by ioniz-
surgery. ing radiation may play an important role in mutagenesis in cells with
In adult patients with AT, the neurological features include progres- absent or abnormal ATM.
sive distal muscular atrophy and fasciculations, with relative preserva- The high risk of malignancy in AT underscores the importance of
tion of proximal strength. The gradual loss of vibration and position early diagnosis in affected individuals and subsequent routine surveil-
sense indicates involvement of the spinal cord dorsal columns, and lance for leukemia and lymphoma. Treatment of the neurological defi-
neuropathological and electrophysiological studies reveal a primarily cits is symptomatic at present. Whether neuroprotective medications
axonal peripheral polyneuropathy (Verhagen et al., 2007). or medications that modulate neuronal growth factors can slow neu-
Serial brain imaging in older children and adults shows non- rodegeneration in AT is unknown. Treatment options include vitamin
progressive cerebellar atrophy. Autopsy studies confirm the E, α-lipoic acid, and folic acid for their theoretical role in reduction
radiographic impression of cerebellar degeneration, with reduced in chromosomal breaks and subsequent translocations or inversions.
numbers of Purkinje cells, granular and basket cells of the cortex, Genetic counseling and prenatal diagnosis are available.
and neurons in the nuclei of the vermis. Degenerative changes are
more extensive in adults, involving the substantia nigra, brain-
EPIDERMAL NEVUS SYNDROME
stem nuclei, and spinal cord. Relative sparing of the cerebral cor-
tex is associated with fewer significant neuropsychological deficits The term epidermal nevus syndrome (ENS) encompasses several dis-
(Hoche et al., 2014). orders that have in common an epidermal nevus and neurological
manifestations such as epilepsy or hemimegalencephaly. The syn- Approximately 10% of patients with ENS have cardiovascular
drome name represents the predominant cell type of the nevus; for and genitourinary malformations. Single reports describe hypoplas-
example, nevus verrucosus (keratinocytes), nevus comedonicus (hair tic left-sided heart, ventricular septal defect, coarctation of the aorta,
follicles), and nevus sebaceous (sebaceous glands). Several subtypes pulmonic stenosis, patent ductus arteriosus, and dilated pulmonary
of ENS exist and should be differentiated from one another: nevus artery. Horseshoe kidney, cystic kidneys, duplicated collecting system,
sebaceous syndrome (Schimmelpenning-Feuerstein-Mims syndrome), and ureteropelvic junction obstruction also occur.
Proteus syndrome, CHILD (congenital hemidysplasia with ichthyosi-
form nevus and limb defects) syndrome, Becker nevus associated with Neuroimaging
extracutaneous involvement (pigmented hairy ENS), nevus comedonicus Megalencephaly ipsilateral to the epidermal nevus is the most
syndrome, and phakomatosis pigmentokeratotica (Happle, 1995). Terms frequent finding on neuroimaging, but bilateral involvement is
such as Schimmelpenning syndrome, organoid nevus syndrome, and common also. In some patients, megalencephaly results from
Jadassohn nevus phakomatosis describe combinations of neurological asymmetrical growth of the skull, with the brain being of normal
findings and sebaceous nevi. It is probably best to consider ENS a het- size. MRI of the skull may show a widened diploic space. Often,
erogeneous group of disorders characterized by epidermal and adnexal enlargement of the calvarium and the ipsilateral cerebral hemi-
hamartomas and other organ system involvement. sphere are present together. In addition, several types of cerebral
dysplasia are associated with ENS, also primarily ipsilateral to the
Cutaneous Features epidermal nevus. Focal pachygyria is the most common type of cor-
Epidermal nevi are linear or patchy slightly raised lesions that typi- tical dysplasia in ENS. The surface of the affected hemisphere may
cally present at birth but may appear first in early childhood. The most be smooth, the cortical mantle thickened, and the adjacent white
common location is on the head or neck. Only 16% of congenital nevi matter abnormal.
subsequently enlarge, compared with 65% of nevi arising after birth.
Nevi on the head and neck rarely enlarge, whereas more than half of
NEUROCUTANEOUS MELANOSIS
lesions elsewhere extend beyond their original boundaries.
Most nevi contain more than one tissue type, complicating derma- Neurocutaneous melanosis (NCM) is a congenital disorder of mela-
tological classification; the nevus name typically reflects the predomi- notic cell development that involves the CNS, especially the leptome-
nant tissue. Verrucous nevi are the most common type. ninges (Agero et al., 2005). Congenital melanocytic nevi may occur
without CNS involvement, and, conversely, melanin is found normally
Neurological Features in the CNS in the absence of congenital nevi. NCM is apparently not
Neurological involvement is variable but more likely when other hereditary and affects male and female subjects with equal frequency.
extracutaneous disease is present. The location of the nevus appears The incidence of NCM is unknown, but it is very uncommon, with
to correlate with the likelihood of neurological symptoms, with neu- only 100–200 cases reported in the literature.
rological complications of ENS most often occurring in the setting of Although the precise pathogenesis is not well understood, a
an epidermal nevus on the face or scalp (Asch & Sugarman, 2018). disorder involving neural crest cell differentiation and melano-
Cognitive deficits are common, and seizures occur in more than half cyte embryogenesis is suspected. The prominent involvement of
of those affected. Usually ipsilateral to the nevus, focal epileptiform the leptomeninges and skin over the spine supports the suggestion
discharges and focal slowing are the most common EEG abnormali- that the primary defect is abnormal migration of nevus cell pre-
ties. Infantile spasms with hypsarrhythmia may occur. Other neuro- cursors, although the embryological origin of nevus cells has not
logical symptoms include cranial nerve palsies, hemiparesis (especially been determined. Alternatively, melanin-producing cells may be
in patients with hemimegalencephaly), microcephaly, and behavior produced in excessive numbers. It has also been speculated that
problems. Spina bifida and encephaloceles rarely occur. nevi located over the spine result from an error early in nevus
Cerebrovascular anomalies occur in approximately 10% of patients cell migration or differentiation, whereas nevi are restricted to the
with ENS. Intracranial blood vessels may be dysplastic, dilated, or extremities if the error occurs later in development (Pavlidou et
occluded. A few patients have had AVMs and aneurysms. Ischemia al., 2008).
or hemorrhage from intracranial blood vessel anomalies may result in
porencephaly, infarctions, and dystrophic calcification. Cutaneous Features
The characteristic lesions are dark to light brown hairy nevi present
Other Features at birth (Fig. 99.19). Multiple small nevi (satellite nevi) usually are
Tumors occur with moderate frequency in association with ENS. The present around one giant nevus that most commonly appears on the
nevus itself may undergo malignant transformation, often into a basal lower trunk and perineal area (swimming trunk nevus). A giant nevus
cell carcinoma. Extracutaneous tumors have included astrocytomas, is absent in 34% of patients with NCM. Approximately one-third of
Wilms tumors, rhabdomyosarcomas, and gastrointestinal carcinomas, patients have a large nevus over the upper back (cape nevus). The giant
among others. nevi may fade over time, but satellite nevi continue to appear during
Skeletal abnormalities are quite frequent but often secondary to the first few years of life.
neurological dysfunction that alters skeletal development. Certain Diagnostic criteria for NCM have been suggested: (1) large or mul-
skeletal anomalies may be a primary part of ENS, such as abnor- tiple (three or more) congenital nevi (large is ≥20 cm in an adult, 9
mal vertebrae. Limb anomalies include clinodactyly, limb reduction cm on the scalp of an infant, or 6 cm on the body of an infant); (2)
defects, syndactyly, polydactyly, bifid thumbs, and talipes equinovarus. no evidence of cutaneous melanoma, except in patients in whom the
Half of patients with ENS have ocular abnormalities such as colo- examined portions of the meningeal lesions are benign; and (3) no evi-
bomas. Disorders of globe growth include either microphthalmia or dence of meningeal melanoma, except in patients in whom the exam-
macrophthalmia. Retinal lesions such as scarring, degeneration, and ined areas of the cutaneous lesions are benign (Marghoob et al., 2004).
detachment may occur. Strabismus and lipodermoid lesions of the Some authors argue that a definitive diagnosis of NCM requires histo-
conjunctivae are more frequent but less serious findings. logical confirmation of the CNS lesions. However, in the context of the
Fig. 99.20 Leptomeningeal Melanosis at Autopsy in a Patient With

Neurocutaneous Melanosis. (Photo courtesy Dr. John Bodensteiner.
Reprinted with permission from Miller V.S. 2004. Neurocutaneous mel-
anosis, In: Roach E.S., Miller V.S. (Eds.), Neurocutaneous Disorders.
Cambridge University Press, Cambridge, pp. 71–76.)
papilledema. In infants, symptoms may include rapidly increas-

ing head circumference or tense anterior fontanelle. Cranial nerve
deficits such as limitation of upgaze and lateral gaze are common.
Myelopathy occurs when leptomeningeal proliferation affects the
spinal cord or spinal nerves.
The likelihood of symptomatic neurological involvement correlates
with location of large nevi. Large congenital melanocytic nevi occur
in a posterior and midline position in nearly 80% of affected patients
(Agero et al., 2005). In one series, all 33 patients with neurological
symptoms had a nevus over the back, whereas none of 26 patients with
Fig. 99.19 Large, Dark, Hairy Nevus Covering most of the back of an nevi restricted to the limbs had neurological abnormalities. Patients
Infant with Neurocutaneous Melanosis. occur with leptomeningeal melanosis confirmed by biopsy and CNS
involvement but without skin lesions.
typical melanocytic cutaneous nevi and characteristic neuroimaging Laboratory Findings

findings, leptomeningeal or brain biopsy is unnecessary. CSF from patients with neurological symptoms may show a mild pleo-
Biopsy of a congenital nevus reveals extension of the nevus cells cytosis and elevated pressure and protein. CSF cytopathology shows
into the deep dermis or even the subcutis between collagen bundles numerous round cells with abundant cytoplasm and ovoid nuclei, and
and around nerves, hair follicles, and blood vessels. Nevus cells tend light brown cytoplasmic granules (presumably melanin) may be seen.
to form cords or nests. Sheets of nevomelanocytes in the dermis may The most characteristic histological feature is the presence of numer-
display a few mitoses and large atypical cells positive for S100 and ous irregular fingers projecting from the cell body, which may aid in
HMB45 antibodies and formaldehyde-induced green-specific fluores- diagnosis of NCM.
cence. The occurrence of atypical mitoses in the dermis may constitute
an early stage of malignant melanoma. The greatest risks in NCM are Neuroimaging
the high incidence of malignant transformation of melanotic cells and Approximately half of neurologically asymptomatic children
spinal and intracranial pathology. with NCM have abnormal cranial neuroimaging study results.
Cranial MRI demonstrates lesions with T1 shortening in the cer-
Neurological Features ebellum, in the anterior temporal lobe (especially the amygdala),
Neurological symptoms may result from leptomeningeal mela- and along the basilar meninges (Fig. 99.21). Some of these lesions
nosis, intracranial melanoma, or intracerebral or subarachnoid also show T2 shortening. The pons, medulla, thalami, and base
hemorrhage. Malformations of the vertebral column, spine, and of the frontal lobe often are affected (Ramaswamy et al., 2012).
brain also may impair neurological function. The median age of Gadolinium-enhanced MRIs rarely may show enhancement of the
neurological complications is 2 years, but infants may be affected pia-arachnoid. In one study, five of six children with neurological
(DeDavid et al., 1996). Leptomeningeal melanosis is probably the symptoms of increased intracranial pressure showed leptomenin-
most common cause of neurological symptoms, especially in chil- geal thickening and enhancement. Conversely, asymptomatic chil-
dren. This tends to occur at the base of the brain along the interpe- dren never showed leptomeningeal thickening. Inferior vermian
duncular fossa, ventral brainstem, upper cervical cord, and ventral hypoplasia and Dandy-Walker malformation have been reported.
surface of the lumbosacral cord. Marked leptomeningeal mela- Spinal MRI study results are usually normal.
nosis (Fig. 99.20) is present in the vast majority of patients with It may be difficult to distinguish radiological evidence of CNS
NCM and associated with interruption of cerebrospinal fluid (CSF) melanoma from benign melanin deposits. Serial imaging studies are
flow. This leads to hydrocephalus and increased intracranial pres- the best way to follow clinically suspect MRI lesions. Certain neuro-
sure with typical symptoms of irritability, vomiting, seizures, and imaging findings help distinguish benign intracranial melanosis from
Fig. 99.22 Cutaneous hyperelasticity of the anterior chest in a patient

with Ehlers-Danlos syndrome without cerebrovascular disease.
Fig. 99.21 T1-weighted cranial magnetic resonance imaging scan

showing leptomeningeal melanosis over the cerebellum (arrow) and
focal melanosis or melanoma in the temporal lobe (arrowhead).
A B
Fig. 99.23 A, Computed tomographic scan with contrast from an 18-year-old patient with headache and a
family history of type IV Ehlers-Danlos syndrome reveals a giant aneurysm (arrow) of the right intracavernous
carotid artery. B, Right internal carotid angiogram confirms the giant aneurysm of the intracavernous carotid
artery. (Reprinted with permission from Roach, E.S., Zimmerman, C.F., 1995. Ehlers-Danlos syndrome, In:
Bogousslavsky, J., Caplan, L.R. (Eds.), Stroke Syndromes. Cambridge University Press, London, pp. 491–496.)
melanoma; necrosis, perilesional edema, contrast enhancement, and ligaments, and others may present with neonatal hypotonia or weak-
hemorrhage are features of melanoma. Unfortunately, melanoma may ness. Neuromuscular kyphoscoliosis can develop. However, vascular
not exhibit any of these findings until late in its course when metastasis lesions such as aneurysm (Fig. 99.23) and arterial dissection are the
is likely to have already occurred. most serious threat to the nervous system. (See also Chapter 65 and
104.)
More than 80% of EDS patients have type I, II, or III, and the
EHLERS-DANLOS SYNDROME other subtypes are individually uncommon. Type IV most often leads
At least 10 subtypes of Ehlers-Danlos syndrome (EDS) exist, to neurovascular complications, and its prevalence is 1 in 50,000 to
defined by the clinical features, inheritance pattern, and even spe- 500,000. Often, a delay in the diagnosis of type IV EDS occurs because
cific molecular defects. Together these syndromes are characterized of a decreased incidence of hyperelastic skin or hyperextensible joints
by fragile or hyperelastic skin (Fig. 99.22), hyperextensible joints, compared to other types. Transmission of all familial type IV EDS
vascular lesions, easy bruising, poor wound healing, and excessive cases with a documented abnormality of type III collagen is auto-
scarring. Some patients develop peripheral neuropathy caused by lax somal dominant. Various defects of the COL3A1 gene (which codes
for the α1 chain of type III collagen) on chromosome 2 have been

BOX 99.4 Clinical Features of
identified (Schwarze et al., 1997). Mutations of this gene are rare in
patients with aneurysm without type IV EDS (Hamano et al., 1998).
Cerebrotendinous Xanthomatosis
Neurological
Neurovascular Features Progressive dementia
There is a risk of aneurysms, and the most commonly affected intracra- Ataxia
nial vessel is the internal carotid artery, typically in or just beyond the Nystagmus
cavernous sinus. Rupture of the aneurysm can occur spontaneously Dysarthria
or during vigorous activity. Rupture within the cavernous sinus may Hyperreflexia
create a carotid-cavernous fistula. Less often, the aneurysm occurs in Bulbar symptoms
other intracranial arteries and presents with subarachnoid hemor- Palatal and pharyngeal myoclonus
rhage. Most individuals become symptomatic in early adulthood, but Peripheral neuropathy
some begin in childhood and adolescence. Electroencephalographic abnormalities
Some patients develop a fistula after minor head trauma, but most Parkinsonism
occur spontaneously and even without an aneurysm. Clinical features of Cerebral and cerebellar atrophy
carotid-cavernous fistula include proptosis, chemosis, diplopia, and pul- Cataracts
satile tinnitus. The vascular fragility of type IV EDS makes both standard
angiography and intravascular occlusion of the fistula difficult. Behavioral Abnormalities
Arterial dissection occurs in both intracranial and extracranial Personality changes
arteries, and the initial features depend primarily on which artery is Irritability
affected. One patient with a vertebral dissection developed a painful Agitation
pulsatile mass of the neck. Dissection of an intrathoracic artery sec- Aggressiveness
ondarily can occlude cervical vessels, and distal embolism from a Paranoid ideation
dissection can cause cerebral infarction. Surgery is difficult because Auditory hallucinations
the arteries are friable and difficult to suture, and handling the tissue Catatonia
leads to tears of the artery or separation of the arterial layers. Type IV
EDS should be considered in children and young adults with arterial Musculoskeletal
dissection. Xanthomas
Osteoporosis and bone fractures
Large paranasal sinuses
CEREBROTENDINOUS XANTHOMATOSIS
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive
disorder of bile acid synthesis characterized by tendon xanthomas, biopsy may show reduced densities of both myelinated and unmyelin-
cataracts, and progressive neurological deterioration (Box 99.4). The ated axons, and teased fibers show axonal regeneration and remyelin-
underlying defect consists of the enzyme, sterol 27-hydroxylase, whose ation. Large-diameter myelinated nerve fibers particularly are affected.
gene (CYP27A1) is located on chromosome 2q. The enzyme deficiency Schwann cells contain foamy macrophages and lipid droplets. Short-
leads to deposits of cholesterol and cholestanol, a metabolic derivative latency somatosensory evoked potentials may show prolonged central
of cholesterol, in virtually every tissue, particularly the Achilles ten- conduction times with tibial nerve stimulation, but normal conduction
dons, brain, and lungs. Bile acid production decreases markedly, which velocities with median nerve stimulation. Brainstem auditory evoked
leads to reduced chenodeoxycholic acid (CDCA) concentration in bile. potentials and visual evoked potentials are abnormal in approximately
Excretion of bile acid precursors increases in bile and urine. Serum half of patients studied. These electrophysiological parameters cor-
cholesterol levels are typically not elevated in CTX syndrome. relate with the ratio of serum cholestanol to cholesterol concentration
and may improve with treatment with CDCA.
Neurological Features
Personality changes and decline in school performance may be the Xanthomas
earliest neurological manifestations of this syndrome. Progressive loss The Achilles tendon is the most common site of tendon xanthomas,
of cognitive function typically begins in childhood, but some patients but the quadriceps, triceps, and finger extensor tendons also show xan-
remain intellectually normal for many years. EEG shows nonspecific thomatous involvement. Tendon xanthomas usually appear after the
characteristics of metabolic encephalopathy such as slowing. Seizures age of 20 years but may occur earlier. A substantial number of patients
may occur. Ataxia with gait disturbance, dysmetria, nystagmus, and never develop xanthomas. Compared with xanthomas found in
dysarthria are common. Psychosis with auditory hallucinations, par- patients with familial hypercholesterolemia or hyperlipoproteinemia,
anoid ideation, and catatonia occur rarely, but examination for cata- these xanthomas appear similar grossly but contain high amounts of
racts and tendon xanthomas should be included in the evaluation of cholestanol and little cholesterol. The presence of early-onset cata-
patients with new-onset psychosis. Parkinsonism may be the only neu- racts, progressive dementia, and tendon xanthomas is pathognomonic
rological symptom. Cranial MRI typically shows involvement of the of CTX syndrome (Salen & Steiner, 2017). The differential diagnosis
dentate nuclei (Gallus et al., 2006). Other findings include cerebral and includes Marinesco-Sjögren syndrome multiple sclerosis, hereditary
cerebellar atrophy and diffusely abnormal white matter, presumably spastic paraparesis, olivopontocerebellar atrophy, and spinocerebellar
reflecting sterol infiltration with demyelination. Focal lesions of the degeneration.
cerebral white matter and globus pallidus are sometimes demonstrable
on MRI. Other Clinical Features
Peripheral neuropathy is a prominent feature of CTX, with signs Onset of cataracts by age 10 years and chronic diarrhea are a character-
of pes cavus, areflexia, and loss of vibration perception. Sural nerve istic combination in CTX. Cataracts can be bilateral and asymptomatic.
Osteoporosis may lead to an increased risk of skeletal and vertebral

fractures. Large paranasal sinuses occur in association with CTX. Renal
disorders reported in patients with CTX include nephrolithiasis, neph-
rocalcinosis, and renal tubular acidosis.
Treatment
Treatment of CTX focuses on lowering cholestanol levels, primarily
with CDCA. Other lipid-lowering agents such as cholestyramine or
β-hydroxymethylglutarate-CoA inhibitors are not as effective alone,
but the latter in combination with CDCA constitutes the most effec-
tive treatment. Long-term therapy can lead to striking improvement
in neurological function, resolution of peripheral and intracranial
xanthomas, and improvement of EEG and peripheral nerve conduc-
tion abnormalities as well as visual and somatosensory evoked poten-
tials. It may be that early treatment is required, which ideally would
begin before onset of clinical symptoms in individuals with a family
history of CTX. The possibility that early treatment may improve the
neurological symptoms of CTX underscores the importance of careful
screening and genetic counseling of asymptomatic relatives of patients
with this disorder. Treatment with cholic acid is also an option and
may produce fewer side effects (Mandia et al., 2019).
PROGRESSIVE FACIAL HEMIATROPHY

Progressive facial hemiatrophy (Parry-Romberg syndrome) occurs
Fig. 99.24 Unilateral atrophy of the skin and subcutaneous tissue
sporadically. The relationship of this disorder to en coup de sabre, mor- (arrows) in a young boy with progressive hemifacial atrophy.
phea, and linear scleroderma is still debated (Peterson et al., 1995).
Traditionally, progressive facial hemiatrophy involves the upper cra-
nium, whereas en coup de sabre tends to affect the lower face as well.
Scleroderma and morphea affect other parts of the body. However,
understanding of pathogenesis is poor, and they may prove to have a sim-
ilar origin. An arbitrary distinction based on the anatomical distribution
does have at least one practical use: as a rule, only patients whose upper
face and head are affected are likely to develop cerebral complications.
Clinical Features
Progressive facial hemiatrophy is characterized by unilateral atrophy of
the skin, subcutaneous tissue, and adjacent bone (Fig. 99.24). The atro-
phic area is characteristically oblong or linear and sometimes begins
as a raised erythematous lesion. The lesion sometimes begins after
trauma to the area. The atrophy eventually stabilizes, leaving facial
disfigurement.
Epilepsy is probably the most common neurological problem asso-
ciated with progressive facial hemiatrophy. Some patients develop a
usually mild hemiparesis. Less common neurological features include
cognitive impairment, cranial neuropathy, or even brainstem signs.
Cerebral calcifications and white-matter lesions are common neuro-
imaging findings (Fig. 99.25); abnormalities typically lie beneath the
cutaneous lesion (Fry et al., 1992).
Understanding of the cause of progressive facial hemiatrophy and
related disorders is poor. Proposed mechanisms (e.g., cortical dysgen-
Fig. 99.25 Computed tomographic scan revealing right frontal enceph-
esis, dysfunction of the sympathetic nervous system, chronic local- alomalacia and calcification in a patient with progressive facial hemi-
ized meningoencephalitis) are inadequate to explain all of the clinical atrophy.
features.
1 in 40,000 to 1 in 298,000 live births. In the classic form of kinky hair

KINKY HAIR SYNDROME (MENKES DISEASE) syndrome, the neurological symptoms begin in the first year of life, and
Kinky hair syndrome, also known as Menkes disease or trichopoliodys- the course is rapidly progressive, with death by the third year of life in
trophy, is an X-linked recessive disorder of connective tissue and more involved cases. Death is commonly due to infection, cerebrovas-
neuronal metabolism caused by inborn disorders of copper metabo- cular complications, or the neurodegenerative process. Documented
lism:namely, impaired cellular export of copper, leading to accumula- cases of late-onset cases and apparently asymptomatic individuals are
tion in all tissues except the liver and brain. The estimated frequency is in the literature. Clinical features in affected girls are similar to but
A B
Fig. 99.26 A, Brittle, light-colored hair seen in kinky hair syndrome. B, Hair shaft from a patient with kinky
hair syndrome.
milder than those seen in typical neonatal-onset cases; genetic analysis

BOX 99.5 Neurological and Systemic
reveals inactivation of the normal X chromosome.
Features of Infantile-Onset Kinky Hair
Cutaneous Features Syndrome
Connective tissue abnormalities are a major feature of kinky hair Premature birth, low birth weight
syndrome and include loose skin, hyperextensible joints, bladder Neonatal jaundice
diverticula, and skeletal anomalies. The enzyme lysyl oxidase has Hypothermia
copper-dependent steps that are impaired in the establishment of Decreased facial expression
elastin and collagen cross-linking. Keratin cross-linking and melanin Prominent forehead
production also depend on copper, and copper deficiency leads to Full cheeks
characteristic cutaneous features. The hair is light-colored and brit- Narrow palate
tle and on microscopic examination (Fig. 99.26) appears as pili torti Hypopigmented skin
(twisted hair) and trichorrhexis nodosa (complete or incomplete frac- Cutis laxa
tures of the hair shafts at regular intervals). Trichorrhexis nodosa is Pili torti
not pathognomonic of kinky hair syndrome; it also occurs in biotin- Inguinal hernia
idase deficiency and argininosuccinic aciduria. Skin may be diffusely Hepatomegaly
hypopigmented or normal. Deafness
Bladder diverticula
Other Clinical Features Joint laxity
Kinky hair syndrome covers a clinical continuum from nearly normal Skeletal anomalies:
to the severe classic infantile-onset form (Box 99.5). Newborns may be Pectus excavatum
more prone to cephalohematomas or spontaneous bone fractures and Wormian skull bones
develop temperature instability, diarrhea, and failure to thrive in early Metaphyseal spurring of long bones
infancy. Sympathetic adrenergic dysfunction, including hypotension, Ataxia
hypothermia, anorexia, and somnolence, is attributable to the impair- Seizures
ment of dopamine β-hydroxylase that requires copper for the synthesis Intracranial hemorrhage
of norepinephrine and other neurotransmitters. Neuroimaging findings:
One variant of kinky hair syndrome is the occipital horn syndrome Cerebellar and cerebral atrophy
in which connective tissue symptoms predominate, and cognitive and White-matter abnormalities
motor involvement is variable. This disorder is named for the charac- Subdural fluid collections
teristic exostoses (“orbital horns”) resulting from calcification of the Dilated and tortuous intracranial and extracranial blood vessels
trapezius and sternocleidomastoid muscles at their attachment to the Cerebral edema
occipital skull.
Neurological Features prominent in the cerebrum and cerebellum. Microscopic findings

In early-onset cases, hypotonia develops in the first few weeks to months include abnormal dendritic arborization in the cerebellar cortex.
and gradually develops into spastic quadriparesis with clenched fists,
opisthotonus, and scissoring. Seizures are a prominent feature of this Neuroimaging
disorder, appearing by age 2–3 months, and may be focal or general- Cranial MRI and CT studies show diffuse cerebral atrophy with sec-
ized. Myoclonic seizures are especially common. Developmental delay ondary subdural fluid collections, which may be large enough to cause
and regression appear between ages 4 and 6 months in the classic form. mild compression of the ventricular system. The presence of large sub-
Intracranial and extracranial blood vessels may be tortuous, kinked, dural fluid collections and metaphyseal fractures in an infant can lead
and dilated (Kim & Suh, 1997); the cause may be defective or deficient to the erroneous diagnosis of child abuse. In older children, MRI stud-
elastin fibers in the walls of these blood vessels. Neuropathological ies typically reveal diffuse white-matter signal abnormalities suggestive
studies show diffuse neuronal loss and gliosis that is particularly of demyelination and gliosis, whereas in infants the white matter may
be only focally affected. Diffuse brain atrophy, subdural effusions or XP and related syndromes such as Cockayne syndrome, trichothiodys-
hemorrhages, infarction, or edema also may be present. MRI shows trophy, and De Sanctis-Cacchione syndrome.
tortuous intracranial blood vessels, better seen by MRA or conven-
tional angiography. Skull radiographs may show wormian bones. Complementation Groups
Complementation analysis has been important in understanding the
Genetic Studies genetic basis of XP. If two particular cell types with different metabolic
A gene involved in transmembrane copper transport, ATP7A (also abnormalities are fused, the cell produced may function normally.
referred to as MNK), has been implicated in both kinky hair syndrome These two cell types have different complementation groups and pre-
and occipital horn syndrome. ATP7A maps to Xq13.3 and is highly sumably have a different genetic basis. In XP, eight complementation
homologous to the gene implicated in Wilson disease. ATP7A mRNA groups have been identified (XP-A through XP-G and a variant group).
is present in several cell types and organs except liver, which explains Although some general genotype–phenotype correlations among these
the clinical observations that liver does not accumulate excess copper complementation groups exist, considerable clinical overlap exists
and is largely unaffected in kinky hair syndrome. between them (Copeland et al., 1997). Complementation groups
Infantile-onset kinky hair syndrome results from extensive muta- XP-A, XP-C, and XP-D are the most common. Despite the few indi-
tions of ATP7A (e.g., large deletions, frameshift mutations), whereas viduals with XP-B available, cloning of the responsible gene (XPBC)
occipital horn syndrome is associated with promoter and splicing effi- was successful. The XPBC gene is located on chromosome 2q21 and
ciency mutations, possibly leading to reduced levels of an otherwise encodes a protein that is a component of the basal transcription factor
normal protein product. Mutations of the ATP7A gene in the patients TFIIH/BTF2. This protein helps regulate both DNA transcription ini-
with the occipital horn syndrome have been base pair substitutions tiation and nucleotide excision repair.
affecting normal messenger ribonucleic acid (mRNA) splicing (Tumer Mutations in the XPCC gene, located on chromosome 3p25.1,
& Horn, 1997). Copper deficiency impairs the function of multiple cause XP-C. Patients with XP-C generally do not have prominent neu-
enzymes that require copper as a cofactor: tyrosinase, cytochrome C rological dysfunction. The XPCC gene codes for a protein involved in
oxidase, dopamine β-hydroxylase, and Cu/Zn superoxide dismutase, global genome repair, but full understanding of its exact role is lacking.
among others. Complementation group D is the third most common complemen-
tation group. Characteristic of the abnormalities are mild to severe
Diagnosis and Treatment neurological dysfunction. The gene associated with XP-D is at chro-
When suspected clinically, low serum copper and ceruloplasmin sup- mosome 9q13. The gene product in XP-D is a component of TFFIIH/
port the diagnosis. Plasma catecholamine analysis to evaluate for dopa- BTF2, as is XP-B, and accordingly, XP-B and XP-D have similar clinical
mine β-hydroxylase deficiency also may be helpful. Specialized centers features. Complementation group E (XP-E) is uncommon and asso-
can determine intracellular accumulation of copper. The large size of the ciated with mild neurological and cutaneous symptoms. The precise
ATP7A gene and the variety of mutations make detection of a specific localization and function of the XP-E gene of its associated protein,
genetic defect difficult, unless previously established for a given family. XPEC, has not been determined. No neurological symptoms occur in
Carrier status is difficult to assess, although prenatal testing for copper patients from complementation groups F or G or the variant group.
content in chorionic villi or cultured amniotic-fluid cells is available.
The focus of treatment approaches is to restore copper to normal Related Syndromes
levels in brain and other tissues. Careful medical care is particularly De Sanctis-Cacchione syndrome is a variant of XP in which patients
important in extending the life span. Copper histidine administered have severe and progressive cognitive deficiency, dwarfism, and
parenterally (subcutaneously) is the most promising treatment, and gonadal hypoplasia. Trichothiodystrophy and similar syndromes link
substantial clinical improvement in a small number of patients has to XP complementation groups B and D. Patients with trichothiodys-
been reported. Undoubtedly, response to copper histidine treatment trophy have brittle hair and nails because of sulfur-deficient matrix
partly depends on the specific mutation of ATP7A involved. Such cor- proteins, ichthyosis, and intellectual disability. Patients with photosen-
relations are not yet well characterized. sitivity (P), ichthyosis (I), brittle hair (B), impaired intelligence (I), pos-
Aggressive copper replacement beginning in early infancy may sibly decreased fertility (D), and short stature (S) fit into the PIBI(D)
be necessary to significantly improve neurological outcome (Tang S syndrome. DNA repair studies of patients with trichothiodystrophy
et al., 2008). Replacement therapy does not appear to help the con- demonstrate reduced ultraviolet-induced DNA repair synthesis, and
nective tissue abnormalities in kinky hair syndrome. Preservation one patient assigned to XP-D. A variant of trichothiodystrophy is Tay
of some residual activity of adenosine triphosphatase (ATPase) may syndrome, in which dysplastic nails and lack of subcutaneous fatty tis-
be required for significant clinical efficacy from copper replacement sue are characteristic. Low birth weight, short stature, and intellectual
treatment, since it did not normalize neurological outcome in two disability are also features of this disorder.
children with the Q724H splicing mutation, which yields a nonfunc- Cockayne syndrome combines cutaneous sunlight sensitivity,
tioning ATPase. dwarfism, intellectual disability, microcephaly, dental caries, periph-
eral neuropathy, and sensorineural deafness. The combined features
of XP and Cockayne syndrome within complementation groups XP-B,
XERODERMA PIGMENTOSUM XP-D, and XP-G indicate that there is considerable clinical heteroge-
Xeroderma pigmentosum (XP) is a group of uncommon neurocuta- neity and phenotypical overlap within the subsets of these comple-
neous disorders characterized by susceptibility to sun-induced skin mentation groups. Trichothiodystrophy may present with congenital
disorders and variable (but typically progressive) neurological deteri- ichthyosis (collodion baby) but persistent ichthyosis of the scalp, trunk,
oration. Inheritance of XP is autosomal recessive, often in the setting palms, and soles is the main feature.
of parental consanguinity, and occurs in 1 in 30,000 to 1 in 250,000
or higher. It occurs more frequently in Japan and Egypt than in the Cutaneous and Ocular Features
United States and Europe. Several gene mutations involving nucleo- Cutaneous and ocular features of XP result primarily from ultraviolet
tide excision repair and DNA transcription have been associated with light exposure (Box 99.6). The onset of cutaneous symptoms in XP is
mutations within the XPAC gene, and presumably this is true in other
BOX 99.6 Cutaneous and Ocular Features
types of XP (Maeda et al., 1995). The principal neurological symptoms
of Xeroderma Pigmentosum in XP-A are progressive dementia, sensorineural hearing loss, tremor,
Cutaneous Features choreoathetosis, and ataxia. Progressive dementia begins in patients
Sunlight sensitivity with XP-A during the preschool years, and IQ scores after 10 years of
Freckling age are invariably less than 50. Sensorineural hearing loss has a later
Atrophy onset, but most patients older than 10 years have hearing impairment.
Xerosis and scaling Cerebellar signs develop at approximately the same time as the hearing
Telangiectasia loss. Microcephaly is present in about half of patients.
Actinic keratosis EEG studies most often show nonspecific generalized slowing,
Angioma but focal slow waves and focal spike discharges occasionally occur.
Keratoacanthoma Peripheral neuropathy is a prominent feature that may begin in
Fibroma the first decade of life. Deep tendon reflexes are absent in nearly all
Malignant tumors patients older than 6 years. Motor nerve conduction velocities are
Basal cell carcinoma normal during the first 3 years of life but slow by 6 years. Similarly,
Squamous cell carcinoma all patients older than 6 years had either absent or prolonged sensory
Melanoma nerve conduction velocities. Electromyography shows a neuropathic
Fibrosarcoma pattern with large, prolonged, polyphasic motor unit potentials and
incomplete recruitment of motor units. Nerve biopsy may show an
Ocular Features age-dependent decrease of myelinated fibers, which was associated
with rare acute axonal degeneration, sparse axonal regeneration, rare
Eyelids axonal atrophy, and few onion bulb formations, consistent with a neu-
Atrophy leading to loss of lashes, ectropion, entropion ropathic process.
Neoplasm Neural tissue lacks exposure to sun-induced DNA damage.
Therefore, the cause of neurodegeneration in patients with XP remains
Conjunctiva
unexplained. The high frequency of neurological symptoms in XP-B
Conjunctivitis
and XP-D but not in XP-C, XP-F, XP-G, and the variant group sup-
Inflammatory lesions such as pinguecula
ports the notion that one cause of the neurological dysfunction in XP
Pigmentation, telangiectases, dryness
is dysfunction of DNA transcription rather than nucleotide excision
Symblepharon, inflammatory nodules
repair. Deficits in excision repair may closely link to skin cancer sus-
Neoplasm
ceptibility. In addition, recent work suggests that in XP, the cause of
Cornea neurological injury is partly defective repair of lesions produced in
Exposure keratitis leading to corneal clouding, dryness, ulceration, scarring, nerve cells by reactive oxygen species generated as by-products of an
and vascularization active oxidative metabolism. Specifically, two major oxidative DNA
Neoplasm lesions, 8-oxoguanine and thymine glycol, are excised from DNA
in vitro by the same enzyme system responsible for removing pyrimi-
Iris dine dimers and other bulky DNA adducts.
Iritis, synechiae, atrophy
Treatment
Cancer surveillance and avoidance of precipitating factors is the most
important aspect of health screening of individuals with XP. There is
usually early; the median age of onset is 1–2 years, typically freckling hope that gene therapy will reduce cancer risk and perhaps improve
or erythema and bullae formation after sun exposure. Nearly half of neurological outcomes. In vitro studies offer hope that, eventually,
patients develop malignant skin lesions, with the median age of first recombinant retroviruses can transfer and stably express the human
skin neoplasm being only 8 years. The estimated incidence of non-mel- DNA repair genes in XP cells to correct defective DNA repair (Zeng
anoma skin cancer under the age of 20 years is 10,000-fold greater than et al., 1997). Using the recombinant retroviral vector LXSN, success-
that observed for the general US population (DiGiovanna & Kraemer, ful transfer of human XP-A, XP-B, and XP-C–complementary DNAs
2012). Light-skinned infants develop erythema and bullae after even (cDNAs) into primary and immortalized fibroblasts obtained from
brief sun exposure. Sun exposure also induces prominent macule for- patients with XP-A, XP-B, and XP-C occurred. After transduction,
mation (freckling or solar lentigenes), which over time enlarge and monitoring of the complete correction of DNA repair deficiency
coalesce. Telangiectasias and epidermal and dermal atrophy develop and functional expression of the transgenes included ultraviolet sur-
in later years, and the skin becomes dry. Actinic keratosis, angiomas, vival, unscheduled DNA synthesis, and recovery of RNA synthesis.
keratoacanthomas, and fibromas also occur. Ocular tissues are partic- In a similar study, XP-FR2 cells expressed a high level of XP-F pro-
ularly susceptible to ultraviolet damage. Keratitis and conjunctivitis tein and ERCC1 protein following the cloning of XP-F cDNA into a
with photophobia are common in patients with XP. Atrophy of the mammalian expression vector plasmid and introduction into group
eyelids leads to loss of lashes and ectropion or entropion. Neoplasms of F XP (XP-F) cells. The XP-FR2 cells expressed a high level of XP-F
the eyelid, conjunctiva, and cornea include squamous cell carcinoma, protein and ERCC1 protein. They showed ultraviolet resistance com-
epithelioma and basal cell carcinoma, and melanoma. The tip of the parable to that in normal human cells and had normal levels of ultra-
tongue, gingiva, and palate also are susceptible to sun exposure. violet-induced unscheduled DNA synthesis and normal capability to
Most of what is known about the neurological features in XP remove DNA adducts. This demonstrates that the nucleotide exci-
comes from studies of Japanese patients with XP-A. Research indicates sion repair defect in XP-F cells is fully corrected by overexpression
that the severity of neurological symptoms correlates with particular of XP-F cDNA alone.
OTHER NEUROLOGICAL CONDITIONS WITH syndromes remains of utmost importance. Regardless of which sign or
symptom manifests first, the pathophysiology arising from angiogenic
CUTANEOUS MANIFESTATIONS proliferation or loss of tumor suppression function has guided prog-
Many other conditions with cutaneous stigmata also manifest neuro- nosis across multiple body systems. Imaging technology has enabled
logical symptoms primarily or secondarily. Fabry disease is an X-linked surveillance of involvement at presymptomatic stages. Significantly,
lysosomal disorder with prominent cutaneous angiokeratoma corporis the understanding of affected genes and gene protein function has not
diffusum, sensory neuropathy, and risk of stroke (see Chapters 68 and only advanced the phenotypic breadth of clinical involvement but also
106). A connective tissue disorder known as pseudoxanthoma elasticum has begun to expand the availability of interventions that might slow or
demonstrates characteristic skin plaques, and vascular involvement halt progression across multiple systems and syndromes.
leads to cerebrovascular compromise (see Chapter 65). Wyburn-
Mason syndrome (or Bonnet-Dechaume-Blanc syndrome) is a rare The complete reference list is available online at https://expertconsult.
sporadic neurocutaneous syndrome characterized by retinal, facial, inkling.com/.
and intracranial AVMs.
CONCLUSIONS
Neurocutaneous syndromes long have been defined on the basis of
cutaneous features and neurological involvement guiding diagnosis of a
syndrome—and the awareness of clinical features accompanying these
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100
Epilepsies
Bassel W. Abou-Khalil, Martin J. Gallagher, Robert L. Macdonald
OUTLINE
Seizures and Epilepsy Definitions, 1614 Paroxysmal Movement Disorders, 1642
Ictal Phenomenology, 1614 Evaluation and Diagnosis, 1642
Glossary of Seizure Terminology and Other Definitions, 1614 Evaluation of Recent-Onset Seizures and Epilepsy, 1642
Classification of Seizures, 1615 Evaluation of Drug-Resistant Seizures and Epilepsy, 1644
Other Seizure Terminology, 1617 Evaluation of Patients for Epilepsy Surgery, 1645
Seizure Types, 1618 Medical Therapy, 1649
Focal Seizures (Partial Seizures), 1618 Initiating Therapy, 1649
Generalized Seizures, 1622 Antiseizure Medication Considerations Based on
Classification of Epilepsies and Epileptic Syndromes, 1623 Age and Gender, 1652
Select Epilepsies, Epileptic Syndromes, and Related Disorders, 1624 Pharmacoresistance, Tolerance, and Seizure Aggravation, 1652
Causes and Risk Factors, 1633 Medication Adverse Effects, 1655
Seizure Precipitants, 1636 Therapeutic Drug Monitoring, 1655
Epidemiology of Epilepsy and Seizures, 1636 Discontinuation of Antiseizure Medication Therapy, 1656
Descriptive Epidemiology, 1636 Surgical Therapy, 1656
Epidemiology of the First Unprovoked Seizure, 1636 Timing, 1656
Morbidity and Mortality, 1636 Presurgical Evaluation, 1657
Morbidity and Comorbidity, 1636 Surgical Approaches, 1657
Mortality in Epilepsy, 1637 Surgical Results and Predictors of Surgical Freedom, 1658
Pathophysiology and Mechanisms, 1638 Other Therapies, 1658
Typical Absence Seizures, 1638 Dietary Therapy, 1659
Hippocampal Focal-Onset Seizures, 1639 Vagus Nerve Stimulation, 1659
Differential Diagnosis, 1640 Other Stimulation Therapies, 1660
Psychogenic Nonepileptic Seizures, 1640 Radiosurgery, 1661
Syncope, 1641 Quality-of-Care Standards in the Management of Epilepsy, 1661
Migraine, 1642 Seizure Clusters and Status Epilepticus, 1661
Sleep Disorders, 1642

occurring over the next 10 years, or (3) diagnosis of an epilepsy syn-

SEIZURES AND EPILEPSY DEFINITIONS drome (Fisher et al., 2014).
Seizures are transient events that include symptoms and/or signs of A variety of seizure types exist, and epilepsy is not a single entity
abnormal excessive hypersynchronous activity in the brain (Fisher but rather a collection of disorders/diseases that have in common the
et al., 2005). The traditional definition of epilepsy required the occur- occurrence of seizures. Hence, a need exists for classification of seizures
rence of two unprovoked seizures. It is known that the risk of seizure and of epilepsies and epileptic syndromes. The classification is import-
recurrence after two unprovoked seizures is greater than 60% (Hauser ant for communication and diagnostic purposes, but also for evaluat-
et al., 1998), and treatment would normally be initiated with an anti- ing drug specificity and prescribing the most appropriate therapy. The
seizure medication (ASM) in that setting. There are situations where diagnosis of certain seizure types can predict response to therapy and
the risk of seizure recurrence after a single seizure is equally high, prognosis. The newest classification has three levels, starting with clas-
suggesting an enduring predisposition to have recurrence. Treatment sification of seizure types (Scheffer et al., 2017). The classification of
would normally be initiated in these situations, and there was a desire seizures requires a description of signs and symptoms during a seizure.
to include this in the definition of epilepsy. In 2014, the International
League Against Epilepsy (ILAE) revised the definition of epilepsy as a ICTAL PHENOMENOLOGY
disease of the brain with (1) at least two unprovoked (or reflex) sei-
zures occurring greater than 24 hours apart, or (2) one unprovoked Glossary of Seizure Terminology and Other Definitions
(or reflex) seizure and a probability of further seizures similar to the The terms frequently used in the description of seizures follow.
general recurrence risk (at least 60%) after two unprovoked seizures, Whenever possible, the definition is derived from the glossary of
1614
CHAPTER 100 Epilepsies 1615
descriptive terminology for ictal semiology, reported by the ILAE task automatisms have been described with the acronym RINCH (rhythmic
force on classification and terminology (Blume et al., 2001). The term ictal nonclonic hand) movements (Kuba et al., 2013; Lee et al., 2006;
ictal semiology means the signs and symptoms associated with seizures. Zaher et al., 2020). Hyperkinetic automatisms imply an inappropri-
Motor manifestations refer to involvement of the musculature, usu- ately rapid sequence of movements that predominantly involve axial
ally with an increase in muscle contraction that produces a movement. and proximal limb muscles. The resulting motion can be thrashing,
A motor manifestation can also be negative, associated with a decrease rocking, pelvic thrusting, kicking, or bicycling motions. Seizures with
in muscle contraction. The term positive motor can be used to specifi- hyperkinetic automatisms are often referred to as hypermotor (Video
cally indicate an increase in muscle contraction. 100.3). Gelastic refers to abrupt laughter or giggling (Video 100.4),
Several qualifiers for motor manifestation exist. Elementary motor while dacrystic refers to abrupt crying, both inappropriate.
refers to the contraction of a muscle or group of muscles that is usually Seizures may include a variety of subjective or sensory phenomena.
stereotyped and does not include multiple phases. Elementary motor Sensory phenomena are described as elementary if they involve a single
manifestations include tonic, which means a sustained increase in mus- primary sensory modality with unformed phenomena. This is applied
cle contraction lasting up to minutes. Tonic activity includes epileptic predominantly to visual or auditory hallucination. Elementary visual
spasms that are a sudden flexion and/or extension which is more sus- phenomena could consist of flickering or flashing lights and other sim-
tained than a myoclonic jerk but yet very short in duration, affecting pre- ple patterns such as spots, scotomata, or visual loss. Elementary audi-
dominantly proximal or truncal muscles. Postural manifestation suggests tory phenomena include buzzing, ringing, or humming sounds or single
tonic activity that results in a posture. This will usually involve contrac- tones, but may also be negative, with loss of hearing. Somatosensory
tion of more than one muscle. Versive manifestation indicates a sustained phenomena can include tingling and other paresthesias, shock-like sen-
or forced deviation of the eyes or the head to one side (Fig. 100.1). This sations, numbness, pain, or a sense of movement or a desire to move a
may be associated with a truncal rotation. Dystonic posturing is a sus- body part. Somatosensory phenomena can remain confined to the same
tained contraction that results in an abnormal posture with a rotating body part or could also have a Jacksonian march, in which case the sen-
or twisting motion (Fig. 100.2). A myoclonic jerk or myoclonus refers to a sation moves to adjacent body parts on the same side, reflecting spread
very brief involuntary contraction usually lasting less than 100 ms. This of the seizure discharge in the sensory cortex. Olfactory hallucinations are
can affect any distal or proximal body part and may also be generalized. most often disagreeable and usually difficult to characterize. A variety of
Negative myoclonus refers to an interruption of tonic muscle activity for gustatory hallucinations can occur, particularly with a metallic taste. A
less than 500 ms without prior positive contraction. Negative myoclonus cephalic sensation is a sensation in the head that can be described vari-
may produce a jerk-like motion in association with a transitory loss of ably, including tingling, fullness, pressure, or lightheadedness.
posture of that body part. Negative myoclonus would not be visible if the The category of experiential phenomena is wide and includes affec-
affected body part were resting. Clonic activity refers to a regularly repetitive experiences such as fear, sadness, elation; dysmnesic phenomena
tive jerking that is prolonged. Clonic activity is further described as being such as feelings of familiarity (déjà vu) or unfamiliarity (jamais vu);
without a march if it remains confined to the same body part from begin- and complex hallucination (such as seeing people or hearing music)
ning to end. Clonic activity has a Jacksonian march if it spreads through and illusions (alterations of perception). Dyscognitive describes events
contiguous body parts on the same side, reflecting horizontal spread of in which the predominant feature is alteration of cognition including
seizure activity over the motor strip. Tonic-clonic activity is a sequence of perception, attention, memory, or executive function. The most recent
initial tonic posturing that evolves to a clonic phase. Atonic activity refers classification of seizures reorganized experiential phenomena into cog-
to a sudden decrease or loss of muscle tone usually lasting more than nitive category and emotional or affective category (Fisher et al, 2017).
1 second. This can affect the head, trunk, or limbs, usually bilaterally. Autonomic phenomena are very common in seizures. They may be
However, focal atonic activity can also occur. Astatic refers to a loss of subjective, including an epigastric sensation, nausea, a feeling of palpi-
erect posture; an astatic seizure is synonymous with a drop attack. tation, or a feeling of flushing, or can be objective, including pupillary
Automatisms are repetitive motor activities that are more or less dilation, piloerection, pallor or flushing, vomiting, and even flatulence.
coordinated and resemble a voluntary movement but are not purpose-
ful. Automatisms usually occur in association with altered sensorium,
CLASSIFICATION OF SEIZURES
and the individual is usually amnestic to their occurrence. Automatisms
may be an inappropriate continuation of previously ongoing activity. Two classifications developed by the ILAE were used widely: the Clinical
This is referred to as perseverative automatisms. Automatisms that start and Electroencephalographic Classification of Epileptic Seizures pub-
after seizure onset are called de novo automatisms. Automatisms may lished in 1981 (Commission on Classification and Terminology of
be reactive—for example, fumbling with an object that was present or the International League Against Epilepsy, 1981; Box 100.1) and the
newly placed in the patient’s hand. Classification of Epilepsies and Epileptic Syndromes introduced in 1989
Automatisms can be described by the part of the body affected. Some (Commission on Classification and Terminologyof the International
of the most common are oroalimentary automatisms, which include League Against Epilepsy 1989; Box 100.2). These classifications were
lip smacking, chewing, swallowing, and other mouth movements recently revised based on advances made in the last three decades (Fisher
(Video 100.1). Ictal spitting and ictal drinking can be considered et al., 2017; Scheffer et al., 2017). The current chapter uses the newer
forms of oroalimentary automatisms. Automatisms affecting the distal terminology but offers the corresponding older established terminology.
extremities are manual or pedal. Manual or pedal automatisms can be The 1981 classification of seizures has a major dichotomy based
bilateral or unilateral. Gestural automatisms include extremity move- on whether seizures start in one part of one hemisphere or in both
ments such as those used to enhance speech. More recently, introduced hemispheres simultaneously. Seizures that start in one part of one
categories for upper extremity automatisms are manipulative and non- hemisphere are classified as partial (or partial-onset) seizures, whereas
manipulative (Kelemen et al., 2010). Manipulative automatisms involve those that start in both hemispheres simultaneously are classified as
picking and fumbling motions, typically reflecting interaction with generalized (or generalized-onset) seizures. Partial-onset seizures are
the environment (see Video 100.1). Nonmanipulative upper extremity subclassified as simple partial if there is no impairment of conscious-
automatisms tend to be rhythmic and do not involve interaction with the ness, complex partial if there is impairment or loss of consciousness
environment (Video 100.2). Distal nonmanipulative upper-extremity at any point in the seizure, and partial seizures evolving to generalized
CHAPTER 100 Epilepsies 1615.e1
Video 100.1 Focal impaired awareness seizure of right mesial tem- Video 100.3 Hyperkinetic automatisms in a hypermotor seizure of
poral origin. There are prominent oroalimentary automatisms and frontal lobe origin.
manipulative automatisms with picking and fumbling movements. https://www.kollaborate.tv/player?id=948152
https://www.kollaborate.tv/player?id=948150 Video 100.4 Gelastic seizure in a patient with hypothalamic
Video 100.2 Right hand rhythmic ictal nonclonic hand motions hamartoma.
during a left temporal ictal discharge. https://www.kollaborate.tv/player?id=948153
https://www.kollaborate.tv/player?id=948151
Fig. 100.1 Versive eye and head turning in transition to bilateral tonic posturing in a subject with right frontal
lobe seizures. Note the associated neck extension.
Fig. 100.2 Dystonic posturing (DP): variable pattern demonstrated in four patients with temporal lobe epi-
lepsy. Left to right: top, right arm DP, left arm DP; bottom, right arm DP, right arm DP.
tonic-clonic (GTC) convulsions. Simple partial seizures can have motor necessarily include the entire cortex (Fisher et al., 2017). The revised
signs, somatosensory or special sensory symptoms, autonomic symp- concepts acknowledge that generalized seizures can be asymmetrical
toms and signs, or psychic symptoms. Under the heading of gener- (Fisher et al., 2017). The category of focal-onset seizures underwent
alized seizures were included generalized absence (typical or atypical), major changes. The terms “simple partial” and “complex partial” were
myoclonic, clonic, tonic, tonic-clonic, and atonic seizures. Acknowledging abandoned. Level of consciousness during seizures can still be used to
that some seizures cannot be classified into partial or generalized onset, classify focal-onset seizures, if it is known, but it is no longer obligatory.
the classification also includes a category of unclassified seizures. The aspect of consciousness chosen for classification is the patient’s
One important criticism of the 1981 classification is that it requires awareness during a seizure. Focal seizures are focal aware seizures (FAS)
both clinical and electroencephalographic (EEG) information, and if awareness is totally preserved for the whole duration of the seizure
assumptions on correlation of clinical and EEG features may be incor- or focal impaired awareness seizures (FIAS) if there is any alteration
rect. A purely semiological classification of epileptic seizures was proof awareness during any part of the seizure. Secondarily generalized
posed, based solely on observed clinical features (Luders et al., 1998). seizures were renamed focal to bilateral tonic-clonic seizures (FBTCS).
The semiological seizure classification includes somatotopic modifi- The term “generalized” was reserved for seizures that are generalized
ers to define the somatotopic distribution of the manifestations and from onset. Another important level of classification for focal seizures
allows demonstration of evolution of ictal manifestations using arrows is by the first clinical manifestation at onset. Thus, focal seizures can be
to link sequential manifestations (Luders et al., 1998). Although this classified as motor or nonmotor, or if possible with the specific initial
classification was not adopted by the ILAE, it is considered an optional sign or symptom under these headings (Fig. 100.3). As an exception,
seizure classification system that is useful for localization purposes in for a seizure to be classified as behavior arrest seizure, behavior arrest
epilepsy surgery centers. has to be the dominant clinical feature for the whole duration of the
The latest ILAE revision of the seizure classification (Figure 100.3) seizure. The other major change in the classification is that it allows
has maintained the division of seizures based on generalized or focal some classification of unknown onset seizures. The new classification
onset but has recommended replacing the term partial with focal allows some seizure types such as tonic or myoclonic to be focal or gen-
(Fisher et al., 2017). The latest revision updated the definition of focal eralized. Table 100.1 summarizes some of the key terminology changes
seizures as “originating within networks limited to one hemisphere,” between the old and the new classifications.
with the possibility of the seizures being discretely localized or more
widely distributed, and possibly originating in subcortical structures. Other Seizure Terminology
Generalized seizures were defined as “originating at some point within, Convulsion is an old term typically used to denote a GTC seizure.
and rapidly engaging, bilaterally distributed networks,” which do not It may also be used to indicate a seizure with prominent motor
BOX 100.1 1981 International League BOX 100.2 1989 International League
Against Epilepsy Classification of Epileptic Against Epilepsy Classification of Epilepsies
Seizures and Epileptic Syndromes
I. Partial (Focal, Local) Seizures 1. Localization-related (focal, local, partial) epilepsies and syndromes
A. Simple partial seizures (consciousness not impaired) 1.1. Idiopathic (with age-related onset)
1. With motor symptoms 1.2. Symptomatic
2. With somatosensory or special sensory symptoms 1.3. Cryptogenic
3. With autonomic symptoms 2. Generalized epilepsies and syndromes
4. With psychic symptoms 2.1. Idiopathic (with age-related onset, listed in order of age appear-
B. Complex partial seizures (with impairment of consciousness) ance)
1. With simple partial onset followed by impairment of conscious- 2.2. Cryptogenic or symptomatic (in order of age)
ness 2.3. Symptomatic
2. With impairment of consciousness at onset 2.3.1. Nonspecific etiology
C. Partial seizures evolving to secondarily generalized seizures 2.3.2. Specific syndromes
1. Simple partial seizures evolving to generalized seizures 3. Epilepsies and syndromes undetermined as to whether they are focal or
2. Complex partial seizures evolving to generalized seizures generalized
3. Simple partial seizures evolving to complex partial seizures evolv- 3.1. With both generalized and focal seizures
ing to generalized seizures 3.2. Without unequivocal generalized or focal features
II. Generalized Seizures (Convulsive or Nonconvulsive) 4. Special syndromes
A. Absence seizures 4.1. Situation-related seizures (Gelegenheitsanfälle)
1. Typical absence seizures 4.1.1. Febrile convulsions
2. Atypical absence seizures 4.1.2. Isolated seizures or isolated status epilepticus
B. Myoclonic seizures 4.1.3. Seizures occurring only when there is an acute metabolic
C. Clonic seizures or toxic event
D. Tonic seizures
E. Tonic-clonic seizures From Commission on Classification and Terminology of the Interna-
F. Atonic seizures tional League Against Epilepsy, 1989. Proposal for revised classifica-
III. Unclassified Epileptic Seizures tion of epilepsies and epileptic syndromes. Epilepsia 30, 389–399.
From Commission on Classification and Terminology of the Interna-

tional League Against Epilepsy, 1981. Proposal for revised clinical and SEIZURE TYPES
electroencephalographic classification of epileptic seizures. Epilepsia
22, 489–501. Focal Seizures (Partial Seizures)
Focal Aware Seizures (Simple Partial Seizures)
FAS are seizures in which awareness is not altered at any point in the
course of the seizure. FAS of purely subjective nature are often referred
activity. Convulsive is an adjective indicating the presence of prom- to as auras or isolated auras. The manifestations of FAS depend on the
inent motor activity such as tonic or clonic or both. Nonconvulsive brain region involved in the ictal discharge. However, it is important
refers to a seizure or status epilepticus without prominent clonic to recognize that the seizure activity may originate in silent areas, and
or tonic motor activity. The term is most commonly used with the first clinical manifestations may reflect seizure spread to other
status epilepticus to indicate that seizure activity is predominantly brain regions. Nevertheless, FAS and auras may have important later-
affecting consciousness or behavior, with minimal or no motor alizing and localizing value. For example, focal clonic or tonic activity
activity. The term grand mal is also an old term that is usually syn- is usually contralateral to the hemisphere involved in seizure activity.
onymous with GTC seizure. The term is discouraged in scientific Somatosensory auras, visual auras, and auditory auras are often useful
writing because it does not specify whether the onset is focal or in suggesting localization and lateralization of the epileptogenic zone.
generalized. Patients may use the term grand mal simply to indi- However, some auras are nonspecific and may be seen with a variety
cate a big seizure, and the neurologist has to convert this term of localizations.
into official terminology. The term petit mal is an old synonym Auras are typically short in duration, lasting seconds to minutes.
for childhood absence epilepsy (CAE) but is also used to describe Some patients may experience a prodrome, a difficult-to-describe feel-
absence seizures. Again, the term is commonly used by patients ing that a seizure may occur. Prodromes may last hours or even days
to indicate a small seizure, which may actually be a focal seizure. and have to be distinguished from auras. On the other hand, auras
A primary generalized seizure or primarily generalized seizure is a may occasionally be prolonged, in which case they are called aura con-
synonym for generalized-onset seizure. Primary generalized epilepsy tinua, which is a form of focal nonconvulsive status epilepticus without
is a synonym for idiopathic generalized epilepsy (IGE). Secondarily impairment of consciousness.
generalized seizure is an old term for a focal seizure that evolves
to bilateral tonic-clonic activity. This is to be distinguished from Focal Impaired Awareness Seizures (Complex Partial Seizures)
secondary generalized epilepsy, which is a synonym of symptom- FIAS are characterized by altered awareness during the seizure.
atic generalized epilepsy, an old term for generalized epilepsy of Impairment may be very subtle, manifesting with slight confusion,
structural/metabolic etiology, where most seizures are usually of fuzziness, or slowing of responses. A patient may have some recol-
generalized onset. The term secondary generalized epilepsy should lection of events or total amnesia for the event. FIAS may start with
be discouraged because of confusion with secondarily generalized an aura or may start with loss of awareness. It is sometimes difficult
seizure. to determine if awareness was impaired. The patient may be totally
Video 100.5 Focal to bilateral tonic-clonic seizure in a patient with

left temporal seizure origin.
ILAE 2017 classification of seizure types: basic version

Focal onset Generalized onset Unknown onset
Impaired Motor Motor

Aware Tonic-clonic Tonic-clonic
awareness
Other motor Other motor
Nonmotor (absence) Nonmotor
Motor onset
nonmotor onset
focal to bilateral tonic-clonic Unclassified
ILAE 2017 classification of seizure types: expanded version

Focal onset Generalized onset Unknown onset
Impaired Motor Motor

Aware tonic-clonic
awareness tonic-clonic
clonic epileptic spasms
tonic NonMotor
Motor onset myoclonic behavior arrest
automatisms myoclonic-tonic-clonic
atonic myoclonic-atonic
clonic atonic
epileptic spasms epileptic spasms
hyperkinetic Unclassified
Nonmotor (absence)
myoclonic typical
tonic atypical
Nonmotor onset myoclonic
autonomic eyelid myoclonia
behavior arrest
cognitive
emotional
sensory
focal to bilateral tonic-clonic
Fig. 100.3 The 2017 ILAE Operational Classification of Seizure Types.
TABLE 100.1 Select Terminology in conscious but unable to respond verbally because of aphasia or unable
New Versus Old Seizure and Epilepsy to respond or react because of motor inhibition.
Classifications Impaired awareness seizures may arise from any lobe but most
1981 Terminology 2017 Terminology commonly arise from the temporal lobe; the frontal lobe is the second
most common site of seizure origin. The most common type of motor
Seizure Classification
activity in this seizure type is automatism, described earlier. The differ-
Partial seizure Focal seizure
ent seizure manifestations in seizures arising from different lobes of the
Simple partial seizure Focal aware seizure
brain are discussed in the next section.
Complex partial seizure Focal impaired awareness seizure
Secondarily generalized seizure Focal to bilateral tonic-clonic seizure Focal to Bilateral Tonic-Clonic Seizures (Partial Seizures
Epilepsy Classification Evolving to Generalized Tonic-Clonic Activity)
Localization related epilepsy Focal epilepsy
These seizures may start as focal aware or FIAS. The transition to
Idiopathic generalized epilepsy Idiopathic generalized epilepsy or
bilateral tonic-clonic activity usually involves versive head turning in
genetic generalized epilepsy (both
a direction contralateral to the hemisphere of seizure onset (see Fig.
terms are acceptable)
100.1), and focal or lateralized tonic or clonic motor activity. The pat-
Cryptogenic epilepsies Epilepsies of unknown cause
tern of evolution may be clonic-tonic-clonic in some instances. The
Symptomatic epilepsies Structural/metabolic epilepsies second-
bilateral tonic phase may be asymmetrical, with flexion on one side
ary to specific structural or metabolic
and extension on the other. This has been called figure-of-four postur-
lesions or conditions, but which do not
ing (Kotagal et al., 2000; Fig. 100.4). Some asymmetry and asynchrony
fit a specific electroclinical pattern.
may also occur in the clonic phase, resulting in a slight degree of side-
Benign Self-limited or pharmacoresponsive
to-side head jerking (Niaz et al., 1999). The evolution from tonic to
Epilepsies undetermined as to (1) Combined generalized and focal (if
clonic activity is gradual and not always simultaneous in all affected
whether focal or generalized both seizure categories coexist) or
body parts. A phase of high-frequency tremor has been referred to as
(2) Unknown (if the seizure type cannot
the tremulous or vibratory phase of the seizure (Theodore et al., 1994).
be determined)
Clonic activity typically decreases in frequency over time, with longer
Fig. 100.4 A, Figure-of-four posturing, usually seen in transition from focal to generalized activity. The sign
lateralizes seizure activity contralaterally to the extended upper extremity (left hemisphere on the left, right
hemisphere on the right).
intervals between jerks toward the termination of the seizure. The Nonmanipulative automatisms typically consist of rhythmic move-
clonic activity may end on one side of the body first so that clonic activ- ments either distally or proximally. These tend to be contralateral, often
ity may then appear lateralized to one side. In addition, there may be preceding overt dystonic posturing (Kuba et al., 2013; Lee et al., 2006;
a late head turn ipsilateral to the hemisphere of seizure origin (Wyllie Zaher et al., 2020). Head turning occurs commonly. Early head turning
et al., 1986). After the motor activity stops, the individual is usually is not usually forceful. It typically occurs at the same time as dystonic
limp and has a loud snoring respiration often referred to as stertorous posturing and is most often ipsilateral (Fakhoury and Abou-Khalil,
respiration (Video 100.5). During the course of recovery, there may be 1995; Williamson et al., 1998). Late head turning most often occurs
variable agitation. The speed of recovery is expected to be slower with during evolution to bilateral tonic-clonic activity (see Video 100.5).
longer and more severe seizures. This is usually contralateral to the side of seizure origin (Williamson
et al., 1998). Well-formed ictal speech may occur during seizures of
Focal Seizure Semiology in Relation to Localization nondominant temporal lobe origin (Gabr et al., 1989). Verbal output
Focal seizures of temporal lobe origin. Temporal lobe seizures may at times be tinged with a fearful tone. FIAS of temporal lobe origin
most often are of mesial temporal amygdalohippocampal origin, in usually last between 30 seconds and 3 minutes. Postictal manifesta-
association with the pathology of hippocampal sclerosis. Patients tions may be helpful in lateralizing the seizure onset. Postictal aphasia
commonly have isolated auras, and FIAS tend to start with an is commonly seen after dominant temporal lobe seizures (Gabr et al.,
aura. The most common aura is an epigastric sensation frequently 1989). In one study, patients with dominant left temporal seizure ori-
with a rising character (French et al., 1993). Other auras occur less gin were unable to read a test sentence correctly in the first minute
commonly and include fear, anxiety, and other emotions, déjà vu after seizure termination, but patients with nondominant right tem-
and jamais vu, nonspecific sensations, and autonomic changes such poral lobe origin were able to read the test sentence within 1 minute of
as palpitation and gooseflesh. Olfactory and gustatory auras are seizure termination (Privitera et al., 1991).
uncommon and are more likely with tumoral mesial temporal lobe Seizures of lateral temporal origin or neocortical temporal origin are
epilepsy (MTLE). much less common than those of mesial temporal origin. They cannot
FIAS may start with an aura or with altered consciousness. With be reliably distinguished based on their semiology, but certain features
nondominant temporal lobe seizures, the patient may remain respon- suggest lateral temporal origin. Auditory auras are the most common
sive and verbally interactive. However, recollection of conversations auras referable to the lateral temporal cortex, usually implying involve-
is unusual. Altered consciousness is often associated with an arrest ment of the Heschl gyrus. Other types of auras referable to the lateral
of motion and speech. Speech arrest is not synonymous with aphasia temporal cortex are vertigo and complex visual hallucinations (usually
and does not distinguish dominant and nondominant temporal lobe posterior temporal). Oroalimentary automatisms are less common, and
seizures. Automatisms are one of the most prominent manifestations, the pattern of contralateral dystonic posturing and ipsilateral extremity
and oroalimentary automatisms are the most prevalent. Extremity automatisms is also less common (Dupont et al., 1999). Early contralat-
automatisms also occur and are most commonly manipulative, with eral or bilateral facial twitching may be seen as a result of propagation to
picking or fumbling (see Video 100.1). This type of automatism is not the frontal operculum (Foldvary et al., 1997). Seizures of lateral tempo-
of direct lateralizing value. However, the contralateral upper extrem- ral origin tend to be shorter in duration and have a greater tendency to
ity is commonly involved in dystonic posturing (Kotagal et al., 1989) evolve to bilateral tonic-clonic activity than seizures of mesial temporal
or milder degrees of posturing and immobility (Fakhoury and Abou- origin. Seizures originating in the temporal lobe may have hypermotor
Khalil, 1995; Williamson et al., 1998). This reduces the availability semiology characteristic of frontal lobe origin, due to propagation to
of the contralateral arm for automatisms, so manipulative automa- the frontal lobe (Vaugier et al., 2009; Yu et al., 2013). This is commonly
tisms tend to be ipsilateral, involving the unaffected upper extremity. seen with seizure origin in the temporal pole (Wang et al., 2008).
Video 100.6 Frontal lobe seizure of right anterior cingulate origin.

Focal seizures of frontal lobe origin. Many different seizure area are less likely to have a march. Somatosensory auras tend to be
types can originate in the frontal lobe, depending on site of seizure contralateral to the hemisphere of seizure origin, but they may be
origin and propagation. FAS can be motor with focal clonic activity, bilateral or ipsilateral when arising from the second or supplementary
can originate in the motor cortex, or can be the result of spread to sensory regions. Other auras of parietal lobe origin are a sensation of
the motor cortex. These seizures may or may not have a Jacksonian movement in an extremity, a feeling of the body bending forward or
march. Asymmetrical tonic seizures or postural seizures are usually swaying or twisting or turning, or even a feeling of an extremity being
related to involvement of the supplementary motor area in the mesial absent (Salanova et al., 1995a, 1995b). Some patients may complain
frontal cortex anterior to the motor strip. The best-known posturing of inability to move a limb. Vertigo has been reported, as well as
pattern is the fencing posture in which the contralateral arm is extended visual illusions of objects going away or coming closer or looking
and the ipsilateral arm is flexed. Tonic posturing may involve all four larger (Siegel, 2003). Some patients may have initial auras suggesting
extremities and is occasionally symmetrical. When these seizures spread to the occipital or temporal lobe. Seizures involving the
originate in the supplementary motor area, consciousness is usually dominant parietal lobe may produce aphasic manifestations. Motor
preserved (Morris et al., 1988). Supplementary motor seizures are an manifestations tend to reflect seizure spread to the frontal lobe. These
important exception to the rule that bilateral motor activity during a include tonic posturing of the extremities, focal motor clonic activity,
seizure should be associated with loss of consciousness. Supplementary and version of the head and eyes (Cascino et al., 1993; Ho et al., 1994;
motor seizures are usually short in duration and frequently arise out of Williamson et al., 1992a). Negative motor manifestations may occur,
sleep. They tend to occur in clusters and may be preceded by a sensory with ictal paralysis (Abou-Khalil et al., 1995). Seizures may spread to
aura referable to the supplementary sensory cortex. The pattern of the temporal lobe, producing oroalimentary or extremity automatisms
posturing described with supplementary motor area seizures can occur (Siegel, 2003). In one study, motor manifestations were more likely
as a result of seizure spread to the supplementary motor area from with superior parietal epileptogenic foci, and oroalimentary and
other regions of the brain. In that case, consciousness is frequently extremity automatisms more likely with inferior parietal epileptogenic
impaired. Subjective FAS may also occur with frontal lobe origin, the foci (Salanova et al., 1995a). Visual manifestations seemed more likely
most common being a nonspecific cephalic aura. with posterior parietal lesions.
FIAS of frontal lobe origin tend to be very peculiar. They may be Focal seizures originating in the occipital lobe. The best-
preceded by a nonspecific aura (most commonly cephalic) or they may recognized occipital lobe seizure semiology is that of FAS with
start abruptly, often out of sleep. Their most characteristic features are visual manifestations (Salanova et al., 1992). The most common
hyperkinetic automatisms with frenzied behavior and agitation (Jobst are elementary visual hallucinations that are described as flashing
et al., 2000; Williamson et al., 1985). These are often referred to as colored lights or geometrical figures. These are usually contralateral
hypermotor seizures. There may be various vocalizations including but may move within the visual field. Complex visual hallucinations
expletives. The manifestations can be so bizarre as to suggest a psy- with familiar faces or people may also occur. Negative symptoms may
chiatric origin (Video 100.6). The seizure duration is short, often less be reported, with loss of vision in one hemifield. Ictal blindness may
than 30 seconds, and postictal manifestations are brief or nonexistent, occur, with loss of vision in the whole visual field. Objective seizure
further adding to the risk of misdiagnosis as psychogenic seizures. manifestations include blinking, nystagmoid eye movements, and
Frontal lobe FIAS arise predominantly from the orbitofrontal region versive eye and head deviation contralateral to the seizure focus. This
and from the mesial frontal cingulate region. However, they can arise version may occur while the patient is still conscious or could be a
from other parts of the frontal lobe. It may be difficult to determine component of impaired awareness seizures.
the region of origin in the frontal lobe based on the seizure manifes- Seizure manifestations that are related to seizure spread to the tem-
tations. It has been suggested that the presence of tonic posturing on poral or frontal lobe are very common. Oroalimentary automatisms
one side points to a mesial frontal origin, as does rotation along the are typical of seizures that spread to the temporal lobe, whereas asym-
body axis, which sometimes leads to turning prone during the seizure metrical tonic posturing typifies spread to the frontal lobe; both types
(Leung et al., 2008; Rheims et al., 2008). Ictal pouting, also known as of spread can be seen in the same patient (Williamson et al., 1992b).
“chapeau de gendarme,” tends to arise in the anterior cingulate region Spread to the temporal or frontal lobe is so common with occipital lobe
(Souirti et al., 2014). seizures that it is at times reported in most patients (Jobst et al., 2010b).
Seizures originating in the frontal operculum are associated with Ictal semiology cannot distinguish seizures originating from the mesial
profuse salivation, oral facial apraxia, and sometimes facial clonic versus lateral occipital region (Blume et al., 2005). Evolution of occipi-
activity (Williamson and Engel, 2008). Seizures originating in the dor- tal seizures to bilateral tonic-clonic activity is commonly reported.
solateral frontal lobe may involve tonic movements of the extremities
and versive deviation of the eyes and head. The head deviation preced- Focal Seizures Originating in the Insular Cortex
ing evolution to bilateral tonic-clonic activity is contralateral, but ear- Insular epilepsy is uncommon and frequently unrecognized because
lier head turning can be in either direction (Remi et al., 2011). Seizures of the inability to record directly from the insula with scalp electrodes.
may begin with forced thinking. Focal seizures of frontal origin may at Subjective symptoms that should suggest seizure origin in the insula
times resemble absence seizures (So, 1998). It is important to recog- include laryngeal discomfort, possibly preceded or followed by a sen-
nize that seizures originating in the frontal lobe can propagate to the sation in the chest or abdomen, shortness of breath, and paresthesias
temporal lobe and produce manifestations typical of mesial temporal around the mouth or also involving other contralateral body parts
lobe seizures. (Isnard et al., 2004). Objective seizure manifestations include dysar-
Focal seizures originating in the parietal lobe. The best- thria/dysphonia, sometimes evolving to complete muteness. With sei-
recognized seizure type that originates in the parietal lobe is focal zure progression in some patients, tonic spasm of the face and upper
seizure with somatosensory manifestations. The somatosensory limb, head and eye rotation, and at times generalized dystonia occur
experience can be described as tingling, pins and needles, numbness, (Isnard et al., 2004). Hypersalivation is also very common and can be
burning, or pain. The presence of a sensory march is most suggestive impressive. Insular-onset seizures may spread to other brain regions
of involvement of the primary sensory cortex. Sensory phenomena and can be disguised as temporal lobe, parietal lobe, or frontal lobe
arising from the second sensory area and the supplementary sensory epilepsy (Jobst et al., 2019; Ryvlin, 2006; Ryvlin et al., 2006).
Generalized Seizures Generalized myoclonic seizures may be immediately followed by

Generalized Absence Seizures a loss of tone. The seizure type is called myoclonicatonic. Historically
Typical absence seizures are characterized by a sudden blank stare it was called myoclonicastatic. The seizures are brief (1 second or less)
with motor arrest, usually lasting less than 15 seconds (Commission but may be associated with falls and injuries (Video 100.10). The EEG
on Classification and Terminology of the International League Against shows generalized spike-and-wave or polyspike-and-wave discharge.
Epilepsy, 1981). The individual is usually unresponsive and unaware. The slow wave is prolonged and associated with the electromyographic
The seizure ends as abruptly as it starts, and the patient returns imme- (EMG) silence characteristic of the atonic phase. Myoclonic seizures
diately to a baseline level of function with no postictal confusion may precede a more sustained tonic contraction, and the resultant sei-
but may have missed conversation and seems confused as a result zures may be referred to as myoclonic-tonic seizures (Berg et al., 2010).
(Video 100.7). If the only manifestation is altered responsiveness and Generalized myoclonic seizures may cluster just before a GTC seizure
awareness, with no associated motor component, the absence seizure occurrence (Video 100.11).
is classified as simple absence. Most often, generalized absence seizures
Generalized Clonic Seizures
include mild motor components and are classified as complex absence.
The most common motor components are automatisms such as lick- Unlike myoclonic seizures, which are single jerks (but may occur in
ing the lips or playing with an object that was held in the hand before arrhythmic clusters), each generalized clonic seizure consists of a series
the seizure. Other motor components include clonic, tonic, atonic, and of rhythmic jerks. Generalized clonic seizures are uncommon and par-
autonomic manifestations. Clonic activity may affect the eyelids or the ticularly rare in adults (Noachtar and Arnold, 2000). They are more
mouth. An atonic component may manifest with dropping an object or frequently seen in certain epileptic syndromes of infancy and child-
slight head drop or drooping of the shoulders or trunk. Tonic compo- hood. For example, clonic seizures are a common seizure type of severe
nents may manifest with slight increase in tone. myoclonic epilepsy of infancy (Dravet syndrome). Clonic seizures are
The EEG hallmark of a typical generalized absence seizure is general- also noted in progressive myoclonic epilepsies.
ized 2.5- to 4-Hz spike-and-wave activity with a normal interictal back-
Generalized Tonic Seizures
ground (Fig. 100.5). Atypical absence seizures are diagnosed primarily
based on a slower (<2.5 Hz) frequency of the EEG spike-and-wave Generalized tonic seizures are typically brief seizures, lasting a few seconds
activity. Less important distinctions are that the onset and termination to 1 minute (Video 100.12). Their onset may be gradual or abrupt. They
of an atypical absence seizure may be less abrupt and the motor com- may be initiated with a myoclonic jerk. They can vary in severity from
ponents a bit more pronounced than seen with typical absence seizures. subtle, with slight increase in neck tone with upward deviation of the
Atypical absence seizures usually occur in individuals with impaired eyes, to massive, with involvement of the axial muscles and extremities.
cognitive function. Affected individuals usually have associated seizure Proximal muscles are the most affected. Most commonly there is neck
types such as generalized tonic, generalized atonic, and GTC seizures. and trunk flexion as well as abduction of the shoulders and flexion of the
Additional generalized absence seizure types recently recognized by hips. However, extension may also occur. Tonic seizures may be asym-
the ILAE include myoclonic absences. The key manifestation of these metrical, which could result in turning to one side. The pattern of muscle
seizures is a prominent rhythmic myoclonus predominantly affect- involvement may change over time so that there may be a change in the
ing the limbs (Bureau and Tassinari, 2005b). Otherwise, myoclonic position of the limbs over the course of the seizure. Autonomic changes
absences resemble typical absence seizures with respect to impairment may occur, with tachycardia, pupil dilation, and flushing. Involvement of
of consciousness. Another related seizure type recently recognized is respiratory muscles could cause apnea and cyanosis. The tonic contrac-
eyelid myoclonia with absence. The eyelid myoclonia consists of pro- tion may end with one or more pauses that result in a few clonic jerks. A
nounced rhythmic jerking of the eyelids, usually associated with an postictal state with confusion may occur, but recovery is usually rapid.
upward deviation of the eyes and retropulsion of the head (Caraballo However, tonic seizures may be followed by atypical absence, resulting
et al., 2009). There may or may not be associated generalized spike- in what appears to be a more prolonged postictal state. This has been
and-wave activity on EEG. Absence seizures may evolve to GTC activ- referred to as tonic-absence seizure (Shih and Hirsch, 2003). Generalized
ity (Mayville et al., 2000; Video 100.8). tonic seizures occur most often out of sleep and drowsiness.
Epileptic Spasms
Generalized Myoclonic Seizures Epileptic spasms have similarities to generalized tonic seizures but a
Myoclonic seizures are muscle contractions lasting a fraction of a sec- shorter duration that is intermediate between generalized myoclonic
ond (<250 ms), in association with an ictal EEG discharge (Blume and generalized tonic seizures (Blume et al., 2001), with a typical dura-
et al., 2001). The myoclonic jerk can be generalized, affecting the whole tion of 0.5–2 seconds. The pattern of contraction is “diamond-shaped,”
body, or could affect just the upper extremities or (rarely) the head with intensity of contraction maximal in the middle of the spasm and
or trunk, or even the diaphragm. The myoclonic jerks may affect one less at the beginning and end. Epileptic spasms were also called infantile
side of the body at one time, but typically the other side is affected at spasms and salaam attacks. Because their occurrence is not restricted
other times. The jerks can be single or could occur in an arrhythmic to infants, the preferred current term is epileptic spasms. The classic
cluster ( Video 100.9). It should be noted that myoclonus is not always epileptic spasm involves neck and trunk flexion and arm abduction
epileptic (Faught, 2003). Myoclonus can be generated anywhere along with a jackknife pattern, but extension may be seen. Epileptic spasms
the central nervous system (CNS). Epileptic myoclonus is generated in typically occur in clusters recurring every 5–40 seconds. In a cluster,
the cerebral cortex and is usually associated with a single or brief serial the initial spasms may be subtle or mild, increase in intensity as the
spike-and-wave or polyspike-and-wave activity. cluster progresses, and decrease in intensity again toward the end of
Negative myoclonic seizures consist of a very brief pause in muscle the cluster (Bleasel and Lüders, 2000).
activity rather than a brief muscle contraction (Rubboli and Tassinari,
2006). Just as with positive myoclonus, negative myoclonus can be Generalized Tonic-Clonic Seizures
generalized, bilateral with limited distribution, or even focal, typically GTC seizures are dramatic and the best recognized form of seizures.
with shifting lateralization. They are commonly referred to as grand mal, but this term is archaic
Video 100.7 Generalized absence seizure with immediate return of Video 100.9 Myoclonic seizures in a patient with juvenile myo
responsiveness postictally. clonic epilepsy.
https://www.kollaborate.tv/player?id=948156 https://www.kollaborate.tv/player?id=948157
Video 100.8 Generalized absence seizure evolving to bilateral ton- Video 100.10 Myoclonic atonic seizure.
ic-clonic seizure. https://www.kollaborate.tv/player?id=948158
Fp1-LE
Fp2-LE
F3-LE
F4-LE
C3-LE
C4-LE
P3-LE
P4-LE
O1-LE
O2-LE
F7-LE
F8-LE
T7-LE
T8-LE
P7-LE
P8-LE
Fz-LE
Cz-LE
Pz-LE
ECG 250uv
1s
Fig. 100.5 Generalized absence seizure displayed with referential montage using linked ear reference. Spike-
and-wave discharges are bifrontally predominant.
and does not distinguish seizures of focal onset from those with a is a very brief loss of consciousness and brief postictal confusion. Seizures
generalized onset. GTC seizures do not have an aura, but they may are usually very brief, lasting 1 second to a few seconds. They may be pre-
be preceded by a prodrome—the vague sense a seizure will occur— ceded by a brief myoclonic jerk, in which case the seizure type is called
lasting up to hours. Seizure onset is abrupt, most often with loss of myoclonic-atonic (see Video 100.10). Very brief myoclonic-atonic seizures
consciousness and a generalized tonic contraction, but some seizures are typical of the syndrome of myoclonic-astatic epilepsy (Doose syn-
may be initiated with a series of myoclonic jerks, leading to the term drome) (Oguni et al., 2001). More prolonged atonic seizures can be seen
myoclonic-tonic-clonic seizure (see Video 100.11). The tonic phase may with Lennox-Gastaut syndrome or other symptomatic generalized epilep-
have asymmetrical movements, and these often change from seizure to sies. Despite their brief duration, generalized atonic seizures can result in
seizure. One such commonly encountered asymmetry is versive head serious injury and are an important cause of morbidity in epilepsy.
turning, which is not evidence of a focal onset (Chin and Miller, 2004;
Niaz et al., 1999). The tonic phase includes an upward eye deviation Generalized-Onset Seizures with Focal Evolution
with eyes half open and the mouth open. Involvement of the respira- Generalized-onset seizures rarely may evolve to focal seizures (Deng
tory muscles usually produces a forced expiration that produces a loud et al., 2007; Linane et al., 2016; Williamson et al., 2009). This seems
guttural vocalization, often referred to as the epileptic cry. Cyanosis to occur with either myoclonic or absence seizures. The clinical man-
may occur during the tonic phase in association with apnea. The tonic ifestations most often are behavioral arrest and staring, with minor
phase gradually evolves to clonic activity. The transition can be with automatisms. However, focal motor manifestations may also occur.
initially high-frequency and low-amplitude motion, often referred This type of seizure tends to be prolonged and may be associated with
to as a vibratory phase. With seizure progression, the frequency of postictal confusion (Linane et al., 2016; Williamson et al., 2009).
clonic jerks decreases, and the amplitude may initially increase but
later decreases just before the seizure stops. In the immediate postictal
state the individual is limp and unresponsive. Respiration is loud and
CLASSIFICATION OF EPILEPSIES AND EPILEPTIC
snoring in character (stertorous). The postictal state is often followed SYNDROMES
by sleep, although the individual may awaken briefly with postictal The classification of seizures addresses single seizure events and not epi-
confusion. Tongue biting commonly occurs and most often affects lepsy as a condition. The 1989 classification of epilepsies and epileptic
the side of the tongue. Incontinence of urine is common, and inconti- syndromes tried to organize epilepsies and epilepsy syndromes (com-
nence of stool may also occur. After awakening, patients often have a mission on classification and terminology of the International League
pronounced headache and generalized muscle soreness. GTC seizures Against Epilepsy, 1989). It defined an epileptic syndrome as “an epileptic
rarely last more than 2 minutes. The severity may vary. The postictal disorder characterized by a cluster of signs and symptoms customarily
state seems to correlate with severity and duration. occurring together; these include such items as type of seizure, etiology,
anatomy, precipitating factors, age of onset, severity, chronicity, diur-
Generalized Atonic Seizures
nal and circadian cycling, and sometimes prognosis.” A syndrome does
Generalized atonic seizures are associated with very brief, sudden loss of not necessarily have a common etiology and prognosis. Two important
tone and vary from extremely subtle, manifesting with only a head drop, to divisions were used in the classification. The first separated epilepsies
generalized loss of tone and falling. Atonic seizures may result in falling if with generalized-onset seizures, called generalized epilepsies, from epi-
the person is standing, called a drop attack. However, drop attacks may be lepsies with focal-onset seizures, referred to as localization-related, par-
the result of both generalized atonic and generalized tonic seizures. There tial, or focal epilepsies. The other division separated epilepsies of known
Video 100.11 Cluster of myoclonic seizures leading to tonic-clonic

seizure.
Video 100.12 Brief tonic seizure.
etiology (named symptomatic epilepsies) from those of unknown etiol- be bilateral. The seizures remit within 2–6 months. There is a slight
ogy. Epilepsies of unknown etiology were named idiopathic if they were increase in the risk of later epilepsy (11%–15%).
pure epilepsy and “not preceded or occasioned by another condition.”
These epilepsies were considered to have no underlying cause other Early Myoclonic Encephalopathy and Ohtahara Syndrome
than a possible hereditary predisposition. Thus, they were presumed Early myoclonic encephalopathy and Ohtahara syndrome have much
genetic. The idiopathic epilepsies were also defined by an age-related in common, including age at onset in the neonatal period, severe sei-
onset and clinical and EEG characteristics. Epilepsies of unknown eti- zure manifestations, and an EEG pattern of burstsuppression, in which
ology were called cryptogenic if they were presumed symptomatic, but periods of high-voltage EEG activity are separated by periods of gen-
with an occult etiology. Although the term cryptogenic was widely used eralized attenuation (Aicardi and Ohtahara, 2005; Djukic et al., 2006;
in the epilepsy field, confusion existed concerning its exact meaning, Ohtahara and Yamatogi, 2006).
which resulted in a recommendation to replace it with the term prob- Early myoclonic encephalopathy is characterized by focal myo
ably symptomatic (Engel, 2001). The 1989 classification of epilepsies clonus involving limbs or face that is very frequent, sometime con-
and epileptic syndromes also subdivided symptomatic partial epilepsies tinuous, shifting from one region to another. Generalized massive
based on lobar anatomical localization of the epileptogenic zone into myoclonus may appear shortly thereafter, as will focal motor seizures.
temporal, frontal, parietal, and occipital lobe epilepsy. Temporal lobe Epileptic spasms typically develop later in the course of the disorder.
epilepsy was further subdivided into amygdalohippocampal and lateral Neurological status is abnormal, either at birth or with the develop-
temporal, and frontal lobe epilepsy into seven subgroups: supplemen- ment of clinical seizures. Most infants are hypotonic. The prognosis
tary motor, cingulate, anterior frontopolar, orbitofrontal, dorsolateral, is poor. There is increased mortality in the first few years of life, and
opercular, and motor cortex. The abbreviated classification is found in survivors have considerable developmental delay.
Box 100.2. Ohtahara syndrome is characterized by epileptic spasms as the pre-
The 1989 classification of epilepsies and epileptic syndromes dominant seizure type, but a third of affected infants also have other
merited updating based on new knowledge. In 2010 the ILAE com- seizure types, including focal motor seizures, hemiconvulsions, and
mission on classification suggested eliminating the division of local- generalized motor seizures. The epileptic spasms are associated with
ization-related and generalized epilepsies (Berg et al., 2010), and generalized attenuation on EEG. The prognosis is also poor, with
instead listing epilepsies by age of onset, distinctive constellations,
or underlying cause (Box 100.3). The list incorporated newly iden-
tified or characterized epileptic conditions. In 2017 the ILAE pub- BOX 100.3 ILAE Classification of Status
lished an updated classification of epilepsies (Scheffer et al., 2017). Epilepticus (SE) (Trinka et al., 2015)
The classification had three levels: seizure types (from the classifi-
(A) With Prominent Motor Symptoms
cation of epileptic seizures), epilepsy types, and epilepsy syndromes
A.1 Convulsive SE (CSE, synonym: tonic–clonic SE)
(Fig. 100.6). Although achieving all three levels of classification is
A.1.a. Generalized convulsive
desirable, it is not feasible for all patients. In some instances, classi-
A.1.b. Focal onset evolving into bilateral convulsive SE
fication of the seizure type(s) may be the only level achieved, partic-
A.1.c. Unknown whether focal or generalized
ularly where medical resources are limited. However, at every level
A.2 Myoclonic SE (prominent epileptic myoclonic jerks)
of classification physicians are encouraged to consider/investigate
A.2.a. With coma
the etiology of the epilepsy and address comorbidities. The epilepsy
A.2.b. Without coma
types maintained the two major categories of focal and generalized
A.3 Focal motor
epilepsies, but also added a category of combined generalized and
A.3.a. Repeated focal motor seizures (Jacksonian)
focal epilepsies to include patients who have both focal-onset and
A.3.b. Epilepsia partialis continua (EPC)
generalized-onset seizures. The list of etiology categories comprises
A.3.c. Adversive status
structural, genetic, infectious, metabolic, immune, and unknown
A.3.d. Oculoclonic status
etiology, with the possibility that more than one category may apply
A.3.e. Ictal paresis (i.e., focal inhibitory SE)
for some epilepsies.
A.4 Tonic status
Select Epilepsies, Epileptic Syndromes, and Related A.5 Hyperkinetic SE
Disorders
(B) Without Prominent Motor Symptoms (i.e.,
An epileptic syndrome was defined as a complex of signs and symptoms that Nonconvulsive SE, NCSE)
define a unique epilepsy condition with different etiologies. A syndrome B.1 NCSE with coma (including so-called “subtle” SE)
must involve more than just a seizure type (Engel, 2006). One common B.2 NCSE without coma
important attribute of syndromes is a characteristic age at onset. Below are B.2.a. Generalized
descriptions of select epileptic syndromes or constellations. B.2.a.a Typical absence status
B.2.a.b Atypical absence status
Benign Familial Neonatal Epilepsy
B.2.a.c Myoclonic absence status
Benign familial neonatal epilepsy was previously referred to as benign B.2.b. Focal
familial neonatal convulsions (Plouin and Anderson, 2005). This rare, B.2.b.a Without impairment of consciousness (aura continua,
dominantly inherited disorder is due to mutations affecting volt- with autonomic, sensory, visual, olfactory, gustatory,
age-gated potassium channel genes (KCNQ2, KCNQ3) (Biervert and emotional/psychic/experiential, or auditory symptoms)
Steinlein, 1999). Affected infants are usually full term and appear nor- B.2.b.b Aphasic status
mal at birth. In 80% of instances, seizures start on the second or third B.2.b.c With impaired consciousness
day of life, although some infants may develop seizures later in the B.2.c Unknown whether focal or generalized
first month of life. The seizures are typically clonic but often preceded B.2.c.a Autonomic SE
by a tonic component. They are more often unilateral but can also
SE, Status epilepticus.
Seizure types*
Etiology
Focal Generalized Unknown
Structural
Comorbidities Genetic
Epilepsy types Infectious
Combined
Focal Generalized generalized Unknown
Metabolic
and focal
Immune
Unknown
Epilepsy syndromes
Fig. 100.6 The International League Against Epilepsy (ILAE) 2017 Classification of the Epilepsies. *denotes
onset of seizure.
very high mortality in the first few years of life, and severe mental and account for about 95% of cases. It may also be due to a nonsense muta-
physical handicap in survivors. The EEG may evolve from the initial tion of the GABRG2 γ-aminobutyric acid A (GABAA) receptor sub-
suppression-burst pattern to a hypsarrhythmia pattern, typical of West unit (Huang et al., 2012). Dravet syndrome and related epileptic or
syndrome. developmental encephalopathies may be caused by a number of other
genetic mutations (Steel et al., 2017). The typical clinical presentation
West Syndrome is that a previously normally developing infant has febrile status epi-
West syndrome has a later age at onset, with a peak onset between 3 and lepticus at around 6 months of age, and then recurrent generalized or
7 months of age. It is characterized by a clinical triad of epileptic spasms, shifting hemiclonic seizures are seen, often triggered by fever. After 1
arrest or deterioration of psychomotor development, and a characteris- year of age, other seizure types appear, including myoclonic seizures,
tic EEG pattern called hypsarrhythmia (Dulac and Tuxhorn, 2005). The absence seizures, and FIAS as well as atonic seizures at times. The sei-
disorder is heterogeneous in its etiology. Epileptic spasms are usually the zures are drug resistant and may be exacerbated by some sodium chan-
initial manifestation. They tend to occur in clusters, sometimes multi- nel blockers such as carbamazepine and lamotrigine. A delay or arrest
ple times a day. Approximately two-thirds of infants have brain lesions. in development may occur, and even regression may be seen, typically
Psychomotor development may be abnormal prior to onset, but there after episodes of prolonged seizure activity (Dravet et al., 2005; Scheffer
is a clear deterioration after onset. The spasms may have asymmetries, et al., 2009). The prognosis is poor; the majority of individuals develop
which are more likely when there is a focal brain lesion. The prognosis is intellectual disability and at times ataxia and spasticity.
variable, with a small proportion of patients recovering quickly without Borderline severe myoclonic epilepsy of infancy may include vari-
sequelae. This is more likely to happen in the absence of brain pathology. ations such as epilepsy with the absence of myoclonic seizures or even
Otherwise, more than 70% develop intellectual disability and other cog- other seizure types.
nitive disabilities. The treatment of infantile spasms has some important It has now become recognized that Dravet syndrome accounts for
differences from treatment of other seizure types. Steroids such as cor- a large proportion of individuals previously diagnosed with vaccine
ticotropin (adrenocorticotropic hormone [ACTH]) and prednisone are encephalopathy (Berkovic et al., 2006). The fever associated with vacci-
helpful, particularly in the absence of underlying known pathology. nation may cause an earlier age at onset of Dravet syndrome, but it does
Hypsarrhythmia is characterized by high-voltage disorganized not affect the eventual course of the condition (McIntosh et al., 2010).
EEG activity with slow waves and multifocal spikes and sharp waves
punctuated by periods of generalized attenuation (Fig. 100.7). When a Genetic Epilepsy with Febrile Seizures Plus
spasm occurs, it is usually during a period of attenuation. The attenu- Genetic epilepsy with febrile seizures plus (GEFS+) appears to be auto-
ation may have superimposed high-frequency, low-voltage EEG activ- somal dominant in inheritance, often due to a sodium channel muta-
ity. The periods of attenuation are typically very short in duration, tion, most often in the SCN1A or SCN1B gene (Escayg et al., 2001;
lasting 1–2 seconds. Wallace et al., 2002). It can also be due to a mutation in the γ2 sub-
unit of the GABAA receptor (Harkin et al., 2002). No mutation has
Dravet Syndrome been identified in the majority of families. The condition has a het-
Dravet syndrome, also called severe myoclonic epilepsy of infancy, is erogeneous phenotype in affected individuals, even within the same
usually due to a de novo mutation affecting the SCN1A gene encoding kindred (Scheffer and Berkovic, 1997; Singh et al., 1999; Fig. 100.8).
the α1 sodium channel subunit (Claes et al., 2001). De novo mutations Some individuals have only the typical febrile seizure phenotype, with
Fp1-Ave
Fp2-Ave
F3-Ave
F4-Ave
C3-Ave
C4-Ave
P3-Ave
P4-Ave
O1-Ave
O2-Ave
F7-Ave
F8-Ave
T7-Ave
T8-Ave
P7-Ave
P8-Ave
Fz-Ave
Cz-Ave
Pz-Ave
100 µV
1 sec
Fig. 100.7 Hypsarrhythmia pattern with disorganized high-voltage slow background activity, multifocal spikes
and sharp waves, and a period of attenuation.
febrile seizures disappearing by 6 years of age. Other individuals have disability. A worse prognosis is predicted by GTC seizures in the first 2
febrile seizures plus, which refers to febrile seizures persisting beyond years of life and early status epilepticus (Kelley and Kossoff, 2010).
6 years of age or febrile seizures intermixed with afebrile GTC sei-
Self-Limited Epilepsy with Centrotemporal Spikes
zures. Other individuals even have other seizure types such as gener-
alized absence or myoclonic seizures. Less common seizure types are Self-limited epilepsy with centrotemporal spikes, previously known as
myoclonic-atonic and focal seizures typical of temporal lobe origin benign epilepsy with centrotemporal spikes (BECTS) is also referred
(Abou-Khalil et al., 2001; Scheffer et al., 2007). to as benign rolandic epilepsy. This is the most common form of
idiopathic focal epilepsy in children (Dalla Bernardina et al., 2005).
Panayiotopoulos Syndrome Seizures begin between 3 and 13 years of age, with a peak between 5
The onset of seizures in Panayiotopoulos syndrome is typically and 8 years. Affected children will have had a normal development and
between 1 and 14 years of age, with a peak at 4–5 years (Covanis et al., normal cognitive function. Seizures typically start with paresthesias
2005). Seizures include autonomic manifestations, particularly ictal affecting one side of the face, particularly around the mouth, then con-
vomiting, altered responsiveness and arrest of activity, and deviation traction of that side of the face evolving into clonic activity of the face.
of the eyes to one side. Autonomic manifestations are particularly pro- Increased salivation and drooling occurs. Consciousness is preserved
nounced (Caraballo et al., 2007). Seizures can be very prolonged, last- in the vast majority of children if the seizure does not evolve to bilat-
ing longer than 30 minutes, qualifying for focal nonconvulsive status eral tonic-clonic activity. Seizures are typically nocturnal and generally
epilepticus. Seizures predominate during sleep. The EEG shows mul- have a low rate of recurrence, so treatment is not always necessary. The
tifocal spikes but with posterior predominance. Despite the alarming natural history is characterized by spontaneous remission around the
seizure manifestations, prognosis is generally good. Seizures are infre- time of puberty. Patients with BECTS may have cognitive and behav-
quent, with about a quarter of patients having only one seizure and ioral problems while the condition is active, but long-term prognosis
half having two to five at most. Remission typically occurs within 1–3 is excellent (Camfield and Camfield, 2014).
years of onset. BECTS has long been thought to have a genetic basis, but the con-
cordance in identical twins is low, suggesting that other mechanisms
Epilepsy with Myoclonic-Atonic Seizures (Myoclonic-Astatic may play a role (Vadlamudi et al., 2004). The diagnosis of BECTS
Epilepsy or Doose Syndrome) depends on the clinical presentation as well as the EEG. The typical
This presumed genetic epilepsy is characterized by seizure onset between EEG abnormality is high-voltage central-midtemporal blunt sharp
18 and 60 months of age (Guerrini et al., 2005). The characteristic sei- waves activated in sleep (Fig. 100.9). These can become bilateral inde-
zure types are myoclonic and myoclonic-atonic seizures, present in all pendent in deeper sleep. Atypical fields are common, particularly
affected children. Tonic-clonic seizures are also seen in a majority of chil- posterior temporal or parietal. The incidence of generalized spike-and-
dren. Atypical absence seizures are also common and frequently asso- wave discharges in affected individuals is increased (Beydoun et al.,
ciated with reduced muscle tone. Pure atonic seizures may also occur. 1992; Drury and Beydoun, 1991).
Generalized tonic seizures are less frequently seen. GTC seizures are most
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
often the seizure type that results in the diagnosis of epilepsy, with smaller
seizures noticed thereafter. Seizures can be easily precipitated by inap- Age at seizure onset in autosomal dominant nocturnal frontal lobe epi-
propriate treatment with carbamazepine. The course of the condition lepsy is highly variable but is most often younger than age 20, with a
is somewhat unpredictable. In more than half of affected children, the mean between 8 and 11 years. Seizures typically arise out of sleep. In
seizures go into remission. More than half of patients also have normal their most pronounced expression, they may be hypermotor with vig-
cognitive function, with less than half having mild to severe intellectual orous frenetic movements of the extremities such as thrashing, kicking,
Febrile seizures Febrile seizures, then epilepsy of unknown

only classification
Febrile seizures, Febrile seizures, then Febrile seizures, then
then TLE generalized epilepsy single afebrile convulsion
Febrile seizures, then epilepsy with generalized and focal seizures
Fig. 100.8 Pedigree of a family with autosomal dominant genetic epilepsy with febrile seizures plus, demon-
strating phenotypic heterogeneity in affected individuals. TLE, Temporal lobe epilepsy.
or bicycling. The seizures may be asymmetrical tonic, sometimes with is seen in typical absence seizures. Approximately two-thirds of patients
evolving posturing, or may have a mixture of hypermotor and tonic also have other seizure types, particularly GTC seizures. Seizures tend to
manifestations. The seizures are usually stereotyped. They are typically be resistant to monotherapy and often require dual therapy with valproate
short in duration, lasting less than 30 seconds. They can be so short and ethosuximide or one of these agents in combination with lamotrigine.
as to simply manifest with paroxysmal arousal (Provini et al., 1999). Myoclonic absences tend to disappear over time, but GTC seizures
The condition is often misdiagnosed as a sleep disorder or psychogenic may persist. Patients may have intellectual disability preceding the
seizures (Scheffer et al., 1995). onset of the seizures, and some may show decline over time, particu-
This disorder is genetically heterogeneous (De Marco et al., 2007) larly those with GTC seizures.
but typically due to mutations in the neuronal nicotinic acetylcholine
receptor (Steinlein et al., 1995). Carbamazepine appeared particularly Lennox-Gastaut Syndrome
effective in this condition. Interestingly, the mutated nicotinic recep- Lennox-Gastaut syndrome is defined by a triad of several seizure types
tors were found to be more sensitive to carbamazepine than to val- including generalized tonic, generalized atonic, and atypical absence
proate (Picard et al., 1999). seizures, a characteristic interictal EEG abnormality of generalized
slow spike-and-wave discharges (<2.5 Hz) in waking and bursts of par-
Late-Onset Childhood Occipital Epilepsy (Gastaut Type) oxysmal fast activity (≈10 Hz) in sleep (Fig. 100.10), and cognitive dys-
The age at onset of seizures in late-onset childhood occipital epilepsy function (Arzimanoglou et al., 2009; Beaumanoir and Blume, 2005).
ranges from 3 to 16 years, with a mean age of 8 (Covanis et al., 2005). The Drop attacks due to either generalized atonic or generalized tonic sei-
seizures are of occipital lobe onset and manifest with visual symptoms. zures tend to be the most debilitating seizure type because of associ-
The ictal phenomena include elementary visual hallucinations, complex ated injuries. The age of onset is between 3 and 10 years, with a peak
visual hallucinations and illusions, visual loss in one field or total blind- between 3 and 5 years. Lennox-Gastaut syndrome may start de novo
ness, eye deviation, and eye blinking. There may be progression of sei- or may evolve, for example from West syndrome. Seizures tend to be
zure manifestations with spread beyond the occipital lobe, particularly drug resistant. Lennox-Gastaut syndrome tends to be a chronic dis-
lateralized or GTC activity. Consciousness is usually preserved if seizure order even though epilepsy may become less active over time. Almost
activity does not spread beyond the occipital lobe. Postictal headache half of these patients may appear normal before onset of seizures, but
is a very common symptom, resulting in confusion with migraine. The deterioration occurs, and the cause is probably multifactorial.
interictal EEG is characterized by occipital spikes and sharp waves that
can be extremely frequent, and typically activated with eye closure. The Epileptic Encephalopathy with Continuous Spike-and-Wave
discharges can be so frequent as to raise concern for an ictal pattern. during Sleep and Landau-Kleffner Syndrome
The common features of the related conditions of epileptic enceph-
Epilepsy with Myoclonic Absences alopathy with continuous spike-and-wave during sleep (CSWS) and
Epilepsy with myoclonic absences is a syndrome with male predominance Landau-Kleffner syndrome (LKS) are a decline in cognitive function in
and starts between 1 and 12 years of age, with a mean of 7 years (Bureau association with an EEG pattern of continuous spike-and-wave activity
and Tassinari, 2005a). Its most distinctive seizure type is myoclonic during slow-wave sleep (Fig. 100.11). In both conditions the associated
absences. These seizures include impairment of consciousness of variable seizures are often easy to control, and the predominant clinical man-
degree and very prominent myoclonus involving primarily the upper ifestations are related to the EEG abnormality in sleep (Nickels and
extremities but also the legs. The duration varies from 10 to 60 seconds, Wirrell, 2008; Tassinari et al., 2005).
and seizures typically recur several times a day. The associated EEG usually In the case of LKS, the cognitive decline is specifically in the area of
shows 3-Hz generalized rhythmic spike-and-wave activity similar to what speech. The condition is often called acquired epileptic aphasia. This
Fp1-Ave
Fp2-Ave
F3-Ave
F4-Ave
C3-Ave
C4-Ave
P3-Ave
P4-Ave
O1-Ave
O2-Ave
F7-Ave
F8-Ave
T7-Ave
T8-Ave
P7-Ave
P8-Ave
Fz-Ave
Cz-Ave
Pz-Ave
ECG
9:23:53 AM Average, 30 mm/sec, 7 µV/mm, 70.0 Hz, 1.600Hz, Notch Off
Fig. 100.9 Characteristic sleep electroencephalographic recording in patient with benign epilepsy with
centrotemporal spikes, demonstrating frequent negative right midtemporal sharp waves (at T8) with field
extending to right posterior temporal (P8) and right central (C4) regions. Note simultaneous positivity in
bifrontal regions.
disorder typically appears between 2 and 8 years of age, with a peak instances, CAE evolves into juvenile myoclonic epilepsy (JME) in the
between 5 and 7 years. The most common initial manifestation is ver- second decade. This will be discussed later under that heading.
bal auditory agnosia. The language disturbance will usually progress CAE is thought to be genetically determined, with high concor-
despite good control of clinical seizures. In fact, clinical seizures may dance for monozygotic twins (Berkovic et al., 1998). However, the
not even occur in about a quarter of patients. The evolution is vari- exact mode of inheritance is unknown. Although some families had a
able. Spontaneous remissions may occur within the first year. Classical single gene mutation (including GABAA receptor and calcium channel
ASMs may be ineffective. Benefits have been reported with valproate, mutations), most are thought to have polygenic inheritance (Hughes,
levetiracetam, and benzodiazepines, which reduce the EEG abnormal- 2009; Wallace et al., 2001).
ity. Steroids and immunoglobulins have been reported to be helpful. For children with pure absence seizures, ethosuximide is the treat-
Surgical treatment with multiple subpial transections (MSTs) has been ment of choice (Glauser et al., 2010). Coexistence of other seizure types
advocated (Morrell et al., 1995). requires a broader-spectrum ASM. Absence seizures beginning before
CSWS differs from LKS in that a larger proportion of individuals 4 years of age could be due to glucose transporter 1 (GLUT1) defi-
have pre-existing neurological abnormalities, and the cognitive regres- ciency in 12% of patients (Arsov et al., 2012). This condition responds
sion is more likely to be global and associated with motor impairments. well to the ketogenic diet.
Childhood Absence Epilepsy Juvenile Absence Epilepsy
CAE syndrome, previously referred to as petit mal or pyknolepsy, typ- Juvenile absence epilepsy is very similar to CAE except that the age
ically starts between the ages of 4 and 10 years with a peak between 5 at onset is in the second decade, with a peak between ages 10 and 12
and 7 years (Hirsch and Panayiotopoulos, 2005). Affected children are (Wolf and Inoue, 2005). The absence seizures are not as frequent as
normal in their development and neurological status. The key seizure in CAE. In addition, the majority of patients also have GTC seizures.
type is generalized typical absence seizures occurring many times a day. This condition has a greater tendency for persistence of seizures into
In association with seizures, the EEG shows generalized synchronous adulthood than is the case with CAE.
and symmetrical spike-and-wave activity with a frequency around 3 Hz.
It is not unusual for the spike-and-wave frequency to be initially faster Juvenile Myoclonic Epilepsy
(up to 4 Hz) and drop by approximately 0.5–1 Hz by the end of the Juvenile myoclonic epilepsy (JME), also known as juvenile myoclonic
ictal discharge. Seizure duration is brief, usually less than 15 seconds. epilepsy of Janz or impulsive petit mal, is common (Thomas et al., 2005)
Seizure frequency is very high, with multiple daily seizures. In 2005 the and accounts for up to 10% of all cases of epilepsy. The age at onset is
ILAE proposed strict criteria to define the syndrome, which include the typically between 12 and 18, but epilepsy may start in the first decade
absence of GTC or myoclonic seizures prior to or during the active stage in a subgroup of patients who appear to have CAE early on. The defin-
of absence seizures. The criteria also exclude eyelid and perioral myoclo- ing seizure type is generalized myoclonic seizures, which occur in all
nia, high-amplitude rhythmic jerking of the limbs, and arrhythmic jerks patients by definition. Generalized myoclonic seizures typically occur
of the head, trunk, or limbs (Hirsch and Panayiotopoulos, 2005). With after awakening, particularly with sleep deprivation. They are typically
this strict definition of the syndrome, many patients with a predomi- mild, predominately affecting the upper extremities. Although they are
nance of absence seizures are excluded and cannot be classified as having the first seizure type to appear, they are often not recognized as seizures
CAE (Ma et al., 2011; Valentin et al., 2007), but a very favorable progno- and not brought to medical attention. Patients typically come to med-
sis is expected. Only 8% of patients fulfilling the strict criteria had GTC ical attention after a GTC seizure, which is most likely to occur after
seizures, compared to 30% of those who did not (Grosso et al., 2005), sleep deprivation or binge drinking of alcohol. The physician has to
and 65% of those satisfying the stricter criteria had a complete seizure ask about myoclonus in order to make the diagnosis. Approximately
remission, compared to 23% of those who did not. Persistence or relapse one-third of patients also have generalized absence seizures. JME is
of seizures tends to be predominately related to GTC seizures. In some clinically and genetically heterogeneous (Martinez-Juarez et al., 2006).
Fp1- LE
Fp2- LE
F3- LE
F4- LE
C3- LE
C4- LE
P3- LE
P4- LE
O1- LE
O2- LE
F7- LE
F8- LE
T7- LE
T8- LE
P7- LE
P8- LE
Fz- LE
Cz- LE
Pz- LE
50 µV
1 sec
ECG
Fp1- F3
F3- C3
C3- P3
P3- O1
Fp2- F4
F4- C4
C4- P4
P4- O2
Fp1- F7
F7- T7
T7- P7
P7- O2
Pp2- F8
F8- T8
T8- P8
P8- O2
Fz- Cz
Cz- Pz
50 µV
ECG 1 sec
Fig. 100.10 Typical electroencephalographic findings in Lennox-Gastaut syndrome, with slow spike-and-

wave activity in waking (top) and paroxysmal fast activity in sleep (bottom).
The most important group is classic JME, and the second largest is all three seizure types, but its teratogenicity and some adverse effects
CAE evolving to JME. The latter tends to be more treatment resistant. limit its use in women of childbearing age (Montouris and Abou-
The diagnosis of JME is based on the clinical history and EEG, Khalil, 2009). Seizures may be aggravated by several ASMs that are
which shows generalized irregular 4- to 6-Hz spike-and-wave activ- specific for focal epilepsy (Gelisse et al., 2004; Genton et al., 2000).
ity occurring in bursts. The EEG is most likely to record discharges JME is thought to have predominantly polygenic inheritance. It is
after awakening (Labate et al., 2007). JME is predominantly a lifelong genetically heterogeneous. There have also been some families with
condition, with less than 25% of patients seizure free off medication autosomal dominant inheritance and several identified mutations
in long-term follow-up (Camfield and Camfield, 2009; Geithner et al., (Delgado-Escueta et al., 2013), including a mutation of the GABAA
2012; Senf et al., 2013). However, the majority of patients can have receptor (Cossette et al., 2002).
seizure remission with medication therapy. The prognosis for seizure
freedom is lowest in individuals with CAE leading to JME and in indi- Epilepsy with Generalized Tonic-Clonic Seizures Alone
viduals who have all three seizure types: generalized myoclonic, GTC, Epilepsy with GTC seizures alone includes so-called epilepsy with
and generalized absence seizures (Gelisse et al., 2001; Martinez-Juarez grand mal on awakening as well as epilepsy with GTC seizures that are
et al., 2006). Valproate appears to be the most effective medication for random in timing. Although the onset is in the second decade in the
Fp1- F3
F3- C3
C3- P3
P3- O1
Fp2- F4
F4- C4
C4- P4
P4- O2
Fp1- F7
F7- T7
T7- P7
P7- O2
Fp2- F8
F8- T8
T8- P8
P8- O2
Fz- Cz
Cz- Pz
50 µV 200 µV
1 sec 1 sec
ECG
Fig. 100.11 Electroencephalogram in patient with epileptic encephalopathy with continuous spike-and-wave
during sleep with normal background in waking (left) and continuous spike-and-wave activity in deep sleep
(right).
majority of individuals, there is a very wide range. As noted with other Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
IGE syndromes, sleep deprivation is a frequent precipitant. Seizures MTLE with hippocampal sclerosis is one of the most common epi-
generally respond well to treatment, similarly to what has been noted lepsies in epilepsy referral centers. Mesial temporal or hippocampal
with JME. sclerosis is the most common pathology noted in surgical speci-
mens from patients undergoing temporal lobectomy for drug-re-
Autosomal Dominant Epilepsy with Auditory Features
sistant temporal lobe seizures. It is characterized by neuronal loss
Autosomal dominant epilepsy with auditory features (ADEAF) is and gliosis predominately affecting CA1 and CA3 sectors of the
usually related to a mutation in the leucine-rich glioma-inactivated-1 hippocampus, with relative sparing of CA2. Patients with MTLE
(LGI1) gene (Ottman et al., 2004), but may also be caused by reelin and hippocampal sclerosis frequently have a history of antecedent
mutations (Michelucci et al., 2017). Inheritance, as the name indi- febrile seizures (up to 80%) (French et al., 1993). The febrile sei-
cates, is autosomal dominant. Seizures typically begin in adolescence zures are usually complex, in particular prolonged. Even though
or adulthood, with a mean age at onset of 24. Affected subjects com- febrile status epilepticus is known to injure the hippocampus in
monly report an elementary auditory aura such as buzzing, ringing, some instances, it is not clear that this is the only factor at play
humming, or even loss of hearing. Seizures may start with aphasic (VanLandingham et al., 1998). Some studies have shown evidence
manifestations when the onset is in the dominant lateral temporal lobe of prior hippocampal malformation that may predispose to injury
(Gu et al., 2002). (Fernandez et al., 1998; Park et al., 2010a). In addition, hippocampal
sclerosis has been reported in familial MTLE without prior febrile
Familial Mesial Temporal Lobe Epilepsy
seizures (Kobayashi et al., 2003). The age at onset of habitual afe-
Familial MTLE is a heterogeneous condition. There is a benign syn- brile seizures is variable but most commonly is in late childhood or
drome, first identified in twins, in which the most prominent aura is adolescence. The presence of hippocampal sclerosis predicts poor
déjà vu with frequent FAS, infrequent FIAS, and rare FBTCS (Berkovic response to medical therapy (Semah et al., 1998). However, the
et al., 1996; Perucca et al., 2017). Prior febrile seizures are uncommon, exact percentage of individuals who are drug resistant has varied
and magnetic resonance imaging (MRI) is normal with no hippocam- between studies. It is not unusual for seizures to be drug responsive
pal sclerosis. The epilepsy is frequently not recognized when the only initially, with long remissions but later evolution to drug resistance
seizure type is subjective FAS, but when recognized is very responsive (Berg et al., 2006).
to medical therapy. The seizure pattern has already been described. The clinical seizure
Other familial MTLE may be associated with prior febrile convul- characteristics cannot reliably distinguish MTLE due to hippocampal
sions, hippocampal sclerosis on MRI, and less responsiveness to medi- sclerosis from that due to lesions (Wieser, 2004).
cal therapy, at times requiring surgical treatment (Cendes et al., 1998). The hippocampal sclerosis is usually identified on MRI showing
Familial MTLE is most probably polygenic in inheritance for most decreased volume and increased signal in the affected hippocampus
families, even though there are reports of autosomal dominant inheri- (Fig. 100.12). Positron emission tomography (PET) usually shows
tance (Chahine et al., 2013; Crompton et al., 2010; Hedera et al., 2007). temporal hypometabolism that is predominant in the mesial temporal
No gene mutation has yet been identified. region on the affected side (Fig. 100.13).
Neuropsychological evaluation commonly demonstrates memory

dysfunction which may be material specific, with greater involvement
of verbal memory when the left hemisphere is involved or visual-spa-
tial memory when the right hemisphere is involved. Memory impair-
ment tends to be greater with longer duration of uncontrolled seizures,
suggesting evidence of progression.
While drug resistance is common, the response rate for surgical
therapy is excellent. After temporal lobectomy or selective amygdalo-
hippocampectomy, 60%–80% of individuals are seizure free (Wieser,
2004).
Rasmussen Syndrome
Rasmussen syndrome is a chronic progressive disorder of unknown
etiology, and probably heterogeneous (Hart and Andermann, 2005).
Seizures most commonly start between 1 and 14 years of age with
focal-onset motor seizures. The seizures can remain focal aware or
evolve to focal impaired awareness or FBTCS. Seizures usually start
in the same hemisphere. They become progressively more frequent Fig. 100.12 Left hippocampal sclerosis identified on magnetic reso-
with episodes of status epilepticus. Progressive hemiparesis and other nance imaging T2-weighted oblique coronal image. Note hippocampal
deficits occur, depending on the affected hemisphere. General intellec- asymmetry, with relatively decreased volume and increased T2 signal in
tual decline occurs at the time of hemiparesis. Imaging shows progres- affected left hippocampus.
sive hemiatrophy, with lesser atrophy on the other side (Fig. 100.14).
An abnormal increased T2 signal is initially most pronounced in the
perisylvian region. PET reveals marked decreased metabolism in the 10.00
affected hemisphere.
An autoimmune etiology is suspected. In some patients, antibodies
to the GluR3 subunit of the glutamate receptor have been identified
(Rogers et al., 1994). Some benefit may occur with intravenous immu-
noglobulin (IVIG), plasmapheresis, and corticosteroids, but hemi-
spherectomy is generally required to achieve seizure control.
0.00
Progressive Myoclonus Epilepsies
Progressive myoclonus epilepsies (PME) are a heterogeneous group Fig. 100.13 Fluorodeoxyglucose positron emission tomography co-reg-
of genetic disorders characterized by myoclonus, GTC seizures, and istered with computed tomography, demonstrating left temporal
progressive neurological dysfunction, predominately with cerebellar hypometabolism predominant in mesial temporal region. Patient had
ataxia and often with dementia (Genton et al., 2005). Included in the left hippocampal sclerosis.
group are Unverricht-Lundborg disease, Lafora body disease, mito-
chondrial encephalopathy with ragged red fibers, and ceroid lipofus- Treatment for progressive myoclonic epilepsy remains symp-
cinosis, among others. Unverricht-Lundborg disease was also called tomatic at this time. Seizures are often resistant to medical therapy.
Baltic myoclonus, but it is recognized now as a worldwide condition. It Valproate is considered the drug of choice for most patients, but other
is due to a mutation in the cystatin B gene (Genton, 2010). The onset is broad-spectrum seizure medications have a role. In particular, there is
typically between 7 and 16 years of age, initially with action myoclonus, anecdotal evidence of perampanel being particularly effective against
then later development of tonic-clonic or clonic-tonic-clonic seizures. myoclonus and GTC seizures in some patients (Ferlazzo et al., 2017).
The myoclonus worsens progressively and greatly limits motor func-
tion. Ataxia occurs and is generally mild, but it can be very aggravated Gelastic Seizures with Hypothalamic Hamartoma
by the use of phenytoin. Phenytoin can also cause mild dementia. Gelastic seizures with hypothalamic hamartoma typically starts with
Lafora disease typically starts between 6 and 19 years of age. Initial gelastic seizures in early life, with other seizures also becoming asso-
seizures are GTC or myoclonic, but affected individuals may also have ciated later on (Berkovic et al., 2003). There may be cognitive and
focal aware visual seizures. The condition progresses with increasingly behavioral disturbances. Some individuals have precocious puberty
severe myoclonus, ataxia, and dementia. Death typically occurs 2–10 and a short stature. MRI reveals a hypothalamic hamartoma that can
years after onset of symptoms. The condition is caused by loss-of- vary in size and appearance (Fig. 100.15). Seizures originate within the
function mutations in EPM2A or NHLRC1, which encode laforin and hamartoma.
malin, resulting in accumulation of abnormal glycogen in Lafora bod-
ies (Nitschke et al., 2018). The diagnosis can also be made by detection Febrile Seizures
of Lafora bodies in skin biopsies. Febrile seizures are not traditionally diagnosed as a form of epilepsy
Myoclonic epilepsy with ragged red fibers (MERRF) has a vari- per se, even though the condition is characterized by epileptic seizures
able age at onset. In addition to myoclonus, GTC seizures, and ataxia, (Berg et al., 2010). The condition affects 2%–5% of children, mostly
there may be signs to suggest mitochondrial disease, such as deafness, between 3 months and 6 years of age. It is the most common form of
myopathy, optic atrophy, or lipomas. More than one mitochondrial seizure in children (Knudsen, 2000) and a benign disorder in the vast
mutation causes MERRF. It could be diagnosed with muscle biopsy majority of those affected. Most febrile seizures are GTC in semiology.
showing typical ragged red fibers. The condition can also be diagnosed They are typically symmetrical, last less than 15 minutes, and usually
with genetic testing from skin or muscle. only one seizure occurs in association with a particular illness. Febrile
Fig. 100.14 Rasmussen encephalitis in an 18-year-old man with left focal motor seizures since age 3 and pro-
gressive left hemiparesis. Fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) shows
right hemisphere atrophy with widening of sulci and ventricular enlargement. Atrophy is very pronounced in the
right hippocampus. There is also increased T2 signal on the right most pronounced in the right insular region.
seizures that satisfy the above criteria are called simple febrile seizures. a hippocampal malformation, most commonly hippocampal malro-
Complex febrile seizures are defined by one or more of the following tation, suggesting that this congenital malformation may have predis-
three criteria: prolonged duration of greater than 15 minutes, focal posed them to febrile status epilepticus (Shinnar et al., 2012). It is not
features (either focal ictal features or lateralized postictal weakness), yet known if these radiological findings are associated with develop-
or the occurrence of more than one seizure in 24 hours or with the ment of temporal lobe epilepsy.
same febrile illness. Most affected children will not have a recurrence Evidence exists that febrile seizures have a strong genetic influence.
of a febrile seizure in their lifetime. Approximately 30%–40% will The inheritance is most probably polygenic in the majority of children,
have at least one recurrence, but multiple recurrences are infrequent. but several reports indicate clear autosomal dominant transmission in
Predictors of recurrence are early age at onset (<1 year), the presence some families. Several mutations have been described, some in fami-
of epilepsy or febrile seizures in first-degree relatives, and attendance at lies with pure febrile seizures and others in families with both febrile
daycare, which increases the risk of febrile infectious illnesses. seizures and epilepsy.
Even though febrile seizures are a benign condition and the vast Some genetic epilepsy syndromes are known to start with febrile
majority of affected children never develop afebrile seizures, they do seizures. One of these is Dravet syndrome or severe myoclonic epilepsy
increase the risk of later epilepsy. In one important study, the risk of infancy (see earlier discussion). The febrile seizures in this condi-
of later epilepsy was 7% by age 25 years (Annegers et al., 1987). In tion tend to be prolonged and often asymmetrical. Fever appears to
another study of children seen in the emergency room for their first be a trigger for seizures, but the subsequent course of the condition is
febrile seizure, the risk of afebrile seizures was 6% at 2 years (Berg and progressive, with afebrile seizures and neurological decline eventually
Shinnar, 1996). The factors that predict later epilepsy include pre- developing. Dravet syndrome is usually due to a truncating mutation
existing neurodevelopmental abnormalities, complex features (proin the SCN1A sodium channel or GABRG2 GABAA receptor subunit
longed duration, focal features, and multiple occurrences per day), a gene. GEFS+ is an autosomal dominant syndrome with heterogeneous
family history of epilepsy, and recurrent febrile seizures. The presence clinical expression. Some individuals have the typical febrile convul-
of one complex feature increases the risk to 6%–8%, two complex fea- sion syndrome with some febrile seizures that disappear by age 6 years,
tures, 17%–22%, and all three complex features, 49% (Annegers et al., while others have febrile seizures persisting beyond age 6 or occurring
1987). Complex features tend to predict an increased risk of focal epi- in conjunction with other seizure types (see Fig. 100.8).
lepsy, while a large number of febrile seizures and a positive family Single febrile seizures are more likely to be polygenic, whereas fam-
history of epilepsy increase the risk of later generalized epilepsy. Febrile ilies with single-gene inheritance are more likely to include recurrent
seizures may be prolonged to qualify for the definition of febrile sta- febrile seizures. Digenic inheritance has been described (Baulac et al.,
tus epilepticus. Febrile status epilepticus may injure the hippocampus 2001); affected individuals had two mutations, and those unaffected
(VanLandingham et al., 1998), with unilateral increased hippocam- had either one or no mutation.
pal T2 signal on MRI in about 11.5% of affected children (Shinnar Since most febrile seizures are benign, there is usually no need to
et al., 2012). This acute MRI finding is frequently followed by devel- treat affected patients with prophylactic daily medication. Intermittent
opment of hippocampal sclerosis on follow-up imaging (Lewis et al., medication may be given at the time of fever. For example, diazepam
2014). Another 10.5% of children with febrile status epilepticus had may be given orally or rectally in patients with frequent recurrent
Fig. 100.15 Hypothalamic hamartoma (see arrows) in a subject with gelastic seizures and short stature.
Left to right, top row, T1-weighted coronal, fluid-attenuated inversion recovery (FLAIR) coronal; bottom
row, T1-weighted axial, T1-weighted sagittal section. There is also cerebral atrophy with widened sulci and
ex-vacuo ventricular enlargement.
febrile seizures. Rectal diazepam can be administered for prolonged epilepsy. However, it is difficult to consider these risk factors as causes
febrile seizures (Knudsen, 2000). of later epilepsy.
Infections are an important risk factor for epilepsy. The risk of later
Causes and Risk Factors epilepsy is higher for both meningitis and encephalitis if seizures occur
Seizures and epilepsy can result from inherited or acquired factors during the acute illness. The relative risk of later epilepsy was increased
or a combination of both. Several genetic epilepsy syndromes were 16-fold after encephalitis and 4-fold after bacterial meningitis (Annegers
described earlier. The following discussion will focus on acquired et al., 1988). The risk of later epilepsy was greatest with infection prior
causes and risk factors, which vary considerably depending on age. to age 5. Early occurrence of meningitis or encephalitis prior to age 4
In children, developmental brain malformations are an important predicted mesial temporal localization with hippocampal sclerosis, and
cause of epilepsy. These can be generalized, hemispheric, or focal. better outcome with temporal lobectomy (O’Brien et al., 2002).
They are also classified as related to abnormal cell proliferation or
differentiation, including tuberous sclerosis, focal cortical dysplasia, Head Trauma
and hemimegalencephaly; as related to abnormal neuronal migra- Head trauma is an important risk factor for epilepsy, with the great-
tion, including lissencephaly, subcortical band heterotopias, and est risk seen in association with penetrating head injury, head injury
periventricular nodular heterotopias; and as related to abnormal with depressed skull fracture, and severe head trauma with prolonged
cortical organization, including polymicrogyria and schizencephaly. loss of consciousness. In a landmark study, mild traumatic brain injury
Some of these malformations are genetically determined—for exam- (characterized by absence of fracture and a loss of consciousness or
ple, tuberous sclerosis, lissencephaly, subcortical band heterotopia, post-traumatic amnesia for <30 minutes) was associated with only a
and bilateral periventricular nodular heterotopia. Many of these mal- 1.5-fold increase in risk of epilepsy, which was not statistically significant
formations have other associated neurological disorders or physical (Annegers et al., 1998). Patients with moderate head injury, defined as loss
findings, and most are easily diagnosed on MRI. Focal malformations of consciousness or post-traumatic amnesia for 30 minutes to 24 hours
associated with epilepsy are less likely to have other neurological or a skull fracture, had a 2.9-fold increase in risk, while those with severe
manifestations than hemispheric or generalized malformations. The head injury, including brain contusion or intracranial hematoma or loss
severity of epilepsy and its response to therapy can be quite variable, of consciousness or post-traumatic amnesia for more than 24 hours, had
but it is commonly drug-resistant, prompting evaluation for surgical a 17-fold increased risk. The risk was highest in the first year after the
treatment. injury but remained increased thereafter for a duration that varied with
Risk factors for epilepsy in early life include neonatal seizures and severity of the injury. For those with moderate brain injuries, the risk
febrile seizures, both of which are conditions not considered forms of was markedly increased for up to 10 years only; for those with severe
traumatic brain injury, the risk continued to be increased. The Vietnam

Head Injury Study (VHIS), in which 92% of subjects had penetrating
head injuries, found a 53% prevalence of post-traumatic epilepsy approx-
imately 15 years after the injury. The risk was 580 times higher than that
of the general age-matched population in the first year after injury, and it
was still 25 times higher after 10 years (Salazar et al., 1985). A follow-up
study in a subgroup of the original patients found that 12.6% of individ-
uals who had post-traumatic epilepsy developed epilepsy more than 15
years after the injury (Raymont et al., 2010). Early seizures appeared to be
a strong risk factor for late seizures, but early seizures were usually related
to the severity of the head injury and intracranial lesions.
Changes in the brain reflecting the process of epileptogenesis are
likely in the latent period between the head injury and onset of chronic
epilepsy. Among several therapeutic measures tested for efficacy
in preventing epilepsy after head injury, none have proven effective
(Temkin, 2009). However, phenytoin was effective in preventing sei-
zures in the first week (Temkin et al., 1990). Levetiracetam was equally
effective in preventing early seizures (Inaba et al., 2013).
Vascular Malformations Fig. 100.16 Left Mesial Temporal Cavernous Malformation.

The two vascular malformations most commonly associated with epi-
lepsy are arteriovenous malformations (AVMs) and cavernous mal-
formations. Venous malformations, also called venous anomalies, may middle cranial fossa, most often medially. They are easily overlooked
be accidental findings not directly related to epilepsy unless associ- on MRI imaging, and have to be specifically looked for in patients with
ated with a cavernous malformation. Arteriovenous malformations are presumed nonlesional temporal lobe epilepsy. Their diagnosis may be
high-pressure vascular malformations with arteriovenous shunting. supported by identification of a defect in the floor of the anterior mid-
They are a tangle of feeding arteries and draining veins without inter- dle cranial fossa on three dimensional CT images. When confirmed
vening capillary bed. They may come to attention during evaluation as etiology of drug-resistant temporal lobe epilepsy, an excellent post-
for seizures or after they bleed; they may also be incidental when imag- surgical outcome can be predicted. There is evidence that a limited
ing is performed for unrelated reasons. Because of the high pressure, inferior temporal pole resection sparing the hippocxampus may be
they are susceptible to bleed at a rate of 1%–3% per year, which is the sufficient for excellent outcome (Tse et al 2020).
main reason they require therapy. Surgical treatment is effective, with
Brain Tumors
one series reporting 94% of patients seizure free, most on no ASMs
(Piepgras et al., 1993). Patients with small AVMs were more likely to Brain tumors are a common cause of epilepsy, particularly drug-
present with hemorrhage, whereas those with large AVMs were more resistant epilepsy. Most drug-resistant epilepsy occurs with low-grade
likely to present with seizures. The best seizure outcome was seen with tumors, especially those in the temporal lobe (Rajneesh and Binder,
resection of small AVMs. Endovascular treatment with embolization 2009). Low-grade tumors associated with epilepsy are gangliogliomas,
and radiosurgery can also improve seizure control, though to a lesser dysembryoplastic neuroepithelial tumors (DNETs), and low-grade
extent. Stereotactic radiosurgery rendered more than 50% of patients gliomas. Excellent seizure control most often occurs after removal of
seizure free and was more likely to be successful when the preoper- gangliogliomas and DNETs. As expected, incomplete resection is asso-
ative seizure frequency was low and the AVM was small (Schauble ciated with less likelihood of seizure control.
et al., 2004). Seizures contribute to the morbidity of malignant brain tumors in
Cavernous malformations consist of blood-filled epitheli- approximately a quarter of patients. Grade 3 anaplastic astrocytomas
um-lined caverns with no discrete arteries or veins (Kraemer and are more likely to present with seizures at onset than glioblastoma
Awad, 1994). On MRI they have a characteristic “popcorn” appear- multiforme (Moots et al., 1995).
ance with mixed signal within the lesion and a rim of decreased
Parasitic Infections
signal, reflecting hemosiderin (Fig. 100.16). They may be multiple
in approximately a third of cases. Cavernous malformations are Neurocysticercosis is thought to be the leading cause of acquired epi-
low-pressure lesions with a much smaller risk of bleeding than lepsy in adulthood in the developing world, but it is an uncommon
AVMs. They are strongly associated with epilepsy. If seizures are cause of epilepsy in developed countries. Seizures are thought to occur
controlled with medical therapy, there is no clear indication for in 70%–90% of patients (Pal et al., 2000). Seizures in most patients
surgical resection. However, when epilepsy is drug resistant, resec- can be controlled with ASMs. When epilepsy is drug resistant, patients
tion of the cavernous malformation is associated with excellent with living cysticerci in the brain can benefit from albendazole, an anti-
results, provided the hemosiderin-stained brain tissue surrounding parasitic treatment, in combination with dexamethasone (Garcia et al.,
it is removed (Awad and Jabbour, 2006). Intraoperative monitor- 2004).
ing with electrocorticography can also improve surgical outcome Other parasitic infections are also common causes of seizures and
(Van Gompel et al., 2009). Excellent results were also reported with epilepsy in the developing world, particularly cerebral malaria with
stereotactic laser ablation, which may be an alternative to open sur- Plasmodium falciparum.
gery (Willie et al., 2019).
Stroke
Anterior temporal encephaloceles are emerging as an underrecog-
nized etiology of temporal lobe epilepsy with important therapeutic Stroke increases the risk of seizures and epilepsy at any age, but it
implications. They are usually in the floor or anterior aspect of the is the most common cause of seizures in the elderly (Menon and
Shorvon, 2009). As in post-traumatic seizures, early seizures that arm and face, often before the appearance of the other manifestations
occur within 2 weeks of the stroke most often do not progress to of memory loss, MRI changes, and hyponatremia (Irani et al., 2011).
chronic epilepsy, but they do increase the risk of chronic epilepsy. These seizures respond very well to immunotherapy, but poorly to
As with head trauma, the risk of chronic epilepsy is highest in the ASMs (Irani et al., 2013; Thompson et al., 2018). Other neuronal
first year after stroke, with a 17-fold increase in the risk compared cell membrane targets include α-amino-3-hydroxy-5-methyl-4-isox-
to population in the community. Approximately 30% of individuals azole-propionic acid (AMPA) and GABAA and GABAB receptors
who have early post-stroke seizures develop later epilepsy. This is a (Bataller et al., 2010; Hoftberger et al., 2013; Petit-Pedrol et al., 2014).
16-fold increase in risk compared to individuals who did not have An immune basis of epilepsy should be suspected in individuals
early seizures. Seizures and even status epilepticus can be a presenting who have other autoimmune disease, abrupt or recent onset of sei-
symptom of acute stroke. zures (particularly if resistant to ASMs and progressive in frequency
As expected, strokes involving the cortex are more likely to produce and severity), associated manifestations such as behavioral changes
epilepsy than deep white-matter strokes. The incidence of seizures is and psychosis, faciobrachial dystonic seizures, severe memory
also higher in patients with intracerebral hemorrhage. disturbances, and abnormal signal on MRI in the hippocampi. A
scoring system has been suggested to identify patients with serum
Inflammatory and Autoimmune Disorders antibodies suggesting an autoimmune etiology (Dubey et al., 2017).
Immune disorders increase the risk of epilepsy and seizures (Ong et al, The identification of immune origin is important for treatment of
2014). In systemic lupus erythematosus, the risk of seizures is 12%– seizures. ASMs alone are often ineffective while immunotherapy is
20% and is more likely with anticardiolipin and anti-Smith antibodies particularly effective, especially in patients with antibodies directed
(Najjar et al., 2008). The risk of epilepsy is also increased in primary against cell membrane targets (de Bruijn et al., 2019; Malter et al.,
CNS inflammatory conditions such as multiple sclerosis. Between 2% 2010).
and 6% of patients with multiple sclerosis have seizures. Those who An immune origin is suspected in several well-described epileptic
do tend to have more extensive cortical involvement with inflamma- syndromes. These include West syndrome, Lennox-Gastaut syndrome,
tory disease. Seizures are more likely to occur in the context of acute LKS, and Rasmussen syndrome. All are discussed earlier in the chapter.
relapse, but some patients develop chronic epilepsy. Seizures are a
more common acute manifestation of acute disseminated encephalo- Other Risk Factors
myelitis, noted in approximately 50% of patients. However, chronic Other risk factors have been specifically investigated in older adults.
epilepsy is much less likely, with only about 5% affected. Several risk factors for stroke are independently associated with
Hashimoto encephalopathy is a steroid-responsive encephalopathy increased risk of epilepsy, without evidence of any stroke. For exam-
usually presenting with behavioral-cognitive abnormalities. Seizures ple, hypertension is associated with a 1.57-fold increase in the risk (Ng
occur in 60% of individuals. Patients have elevated antithyroid anti- et al., 1993). Left ventricular hypertrophy without diuretic treatment
bodies, but it is not clear that these antibodies are responsible for the was associated with an 11-fold increased risk (Hesdorffer et al., 1996).
clinical manifestations (Castillo et al., 2006). Diuretics were protective, as left ventricular hypertrophy treated with
Autoimmune limbic encephalitis is an increasingly recog- diuretics carried no increase in risk (Hesdorffer et al., 1996).
nized cause of seizures and epilepsy. Suggested diagnostic crite- Dementia, particularly Alzheimer disease, has been associated with
ria include (1) subacute onset of short-term memory loss, altered epilepsy, with up to a 10-fold increase in risk compared to a reference
mental status, or psychiatric symptoms, (2) at least one of new population (Hauser et al., 1986). Patients who developed seizures had
focal CNS findings, seizures not explained by prior epilepsy, cere- a younger age at onset of dementia, with seizures tending to be a late
brospinal fluid (CSF) pleocytosis, or MRI features suggestive of feature first seen an average of 6.8 years after onset (Mendez et al.,
encephalitis, and (3) reasonable exclusion of alternative causes 1994). Using very conservative criteria, the incidence of seizures was
(Graus et al., 2016). It can be paraneo-plastic or nonparaneoplas- found to be 1.5%, but still with an eightfold increase in risk compared
tic. The most commonly associated neoplasms are small-cell lung to an age-matched population (Scarmeas et al., 2009).
cancer, testicular cancer, thymoma, breast cancer, or teratoma. Major depression seemed to increase the risk of epilepsy sixfold in
Perhaps the most meaningful classification of autoimmune limbic patients 55 years or older. This was the case without any prior neuro-
encephalitis is by the antibody target; associated antibodies may logical insult (Hesdorffer et al., 2000). Attempted suicide also increased
be directed against intracellular cytoplasmic/nuclear antigens or the risk of epilepsy (Hesdorffer et al., 2006).
against antigens on the plasma membrane. The latter have a better Alcohol abuse is known to be associated with acute withdrawal
prognosis with appropriate therapy, with a greater possibility of seizures within 48 hours of stopping alcohol. However, chronic alco-
reversing the clinical manifestations. The most common antibod- hol intake was also associated with increased risk of chronic epilepsy,
ies directed against intracellular targets are anti-Hu, anti-Ma, anti- related to the amount of alcohol use. The increased risk was almost
amphiphysin, and anti-CV2/CRMP5 (Gaspard, 2016). Anti-glutamic 20-fold for the heaviest drinkers (Ng et al., 1988).
acid decarboxylase (Anti-GAD) antibodies may fall into this category, Heroin increased the risk of unprovoked seizures threefold, while
but it is not clear if the antibodies are pathogenic or an epiphenom- marijuana seemed to confer protection (Ng et al., 1990). Cocaine may
enon (Spatola and Dalmau, 2017). The most common antibodies reduce seizure threshold in individuals with epilepsy, but it is not clear
against plasma membrane antigens include anti–N-methyl-d-as- that it is an important risk factor for chronic epilepsy (Koppel et al., 1996).
partate (NMDA) receptor antibodies (Dalmau et al., 2008; Titulaer
et al., 2013) and anti-LGI1 antibodies previously thought to repre- Causes of Acute Symptomatic Seizures
sent anti-potassium channel antibodies (LGI1 is a component of the Acute symptomatic seizures occur in close temporal relationship
potassium channel complex) (Lai et al., 2010). Anti-NMDA receptor with an acute CNS insult—metabolic, toxic, structural, infectious,
antibody encephalitis most often presents with psychiatric symp- or inflammatory (Beghi et al., 2010). Many of the causes of epilepsy
toms, but most patients will have seizures in the course of the disease. already discussed can also cause acute symptomatic seizures. Metabolic
Anti-LGI1 encephalitis often presents with faciobrachial dystonic and toxic causes of acute symptomatic seizures do not usually cause
seizures, with distinctive brief unilateral dystonic posturing of the chronic epilepsy.
Metabolic disturbances known to cause seizures include hypogly- incidence was after age 75. The increased incidence in older age was
cemia, hyperglycemia, hyponatremia, hypocalcemia, hypomagnese- not seen in developing countries. Incidence is slightly higher in males
mia, and uremia (Beghi et al., 2010). Withdrawal from chronic alcohol and higher in groups with lower socioeconomic status. The finding
abuse may be associated with GTC seizures as well as other manifesta- was not accounted for by known risk factors such as head injury and
tions of withdrawal, typically within 48 hours of the last alcohol intake. stroke.
Acute withdrawal from benzodiazepines and barbiturates can also be Prevalence of epilepsy is defined as number of individuals with epi-
associated with withdrawal seizures, more commonly when short- lepsy divided by total population at a point in time. This is most often
acting agents are involved. active prevalence, referring to active epilepsy at the time of the study,
Several illicit drugs produce acute symptomatic seizures, particu- as opposed to lifetime prevalence, which includes anyone who devel-
larly cocaine and other stimulants taken in excess. oped epilepsy prior to the study. The age-adjusted prevalence tends
Several medications can trigger acute symptomatic seizures at high to be lower in developed countries. In door-to-door surveys, the age-
doses or in susceptible individuals. These same medications, as well as adjusted prevalence ranged from 2.7 per 1000 in Italy to 7.1 per 1000
metabolic derangements, can also trigger seizures in people with epi- in Mississippi. Prevalence is higher in males and also higher in groups
lepsy, at lower thresholds than for people without epilepsy. with low socioeconomic status.
Cumulative incidence is the estimate of the proportion of individ-
uals who will have developed epilepsy by a certain age. In Rochester,
SEIZURE PRECIPITANTS Minnesota, at age 80 the cumulative risk of epilepsy was 4%, and the
Some patients with epilepsy report seizure precipitants that will not cumulative risk for all unprovoked seizures was more than 5% (Hauser
trigger seizures in unaffected individuals. More than 50% of subjects et al., 1993). The cumulative incidence of all epilepsy was 1.2% through
with epilepsy reported at least one precipitant (Frucht et al., 2000; age 24 (Hauser et al., 1993).
Nakken et al., 2005). Emotional stress and sleep deprivation were the
most commonly reported precipitants. Other precipitants were fatigue, Epidemiology of the First Unprovoked Seizure
fever or illness, flickering light, and menstruation. In some epileptic Studies of recurrence after the first unprovoked seizure have predom-
syndromes and epilepsies (e.g., BECTS, frontal lobe epilepsy), seizures inantly focused on patients who present with a GTC seizure, with or
occur preferentially in sleep. without focal onset. Milder seizures are much less likely to present
Several medications can reduce the seizure threshold, including tri- to medical attention after their first occurrence. A meta-analysis of
cyclic antidepressants, bupropion, various antipsychotics, CNS stimu- observational studies estimated a 2-year recurrence risk of approxi-
lants, fluoroquinolone antibiotics, older antihistaminics, meperidine, mately 40% (Berg and Shinnar, 1991). Two large randomized trials
and tramadol. Fever can reduce the threshold for seizures in patients gave slightly different estimates for recurrence in patients random-
with known epilepsy. Hyperventilation is well known to precipitate ized to treatment (Berg, 2008). One predicted a recurrence risk of
generalized absence seizures. It can also precipitate other seizure types 51% at 2 years after the initial seizure (First Seizure Trial Group,
to a much lesser extent (Arain et al., 2009; Guaranha et al., 2005). 1993), and the other estimated the risk at 39% at 2 years, 51% at 5
One likely common reason for precipitation of seizures is missing years, and 52% at 8 years (Marson et al., 2005). The risk of recurrence
antiepileptic medication doses. Breakthrough seizures can occur with is highest in the first 2 years. Treatment reduced the risk by 60% in
missing any of the ASMs. However, carbamazepine and oxcarbazepine one study (First Seizure Trial Group, 1993) and 30% in the second
are associated with more severe seizures upon abrupt withdrawal (Azar study (Marson et al., 2005).
et al., 2008b; Marciani et al., 1985). The two factors that most influenced recurrence rate were an
A prominent precipitation of seizures in association with the abnormal EEG and an abnormal neurological status. Individuals with
menstrual cycle has been termed catamenial epilepsy. This is reported a normal EEG and normal neurological status had a risk of recurrence
in approximately 55% of women (Herzog, 2008). The most common of 25% at 2 years and 30% at 4 years (Kim et al., 2006).
pattern of clustering of seizures is perimenstrual, typically in the 3 The risk of recurrence increases remarkably after a second seizure.
days before and 3 days after onset of the period. Less common pat- In one prospective study in adults the 2- and 5-year risks of recurrence
terns are periovulatory (occurring around ovulation) and luteal, in after the first seizure were 27% and 33%, and after the second seizure
association with inadequate luteal phase cycles. The mechanism of were 61% and 73% (Hauser et al., 1998).
catamenial epilepsy is thought to be related to the opposite effects
of estradiol and progesterone on seizure threshold. Estradiol is a MORBIDITY AND MORTALITY
proconvulsant, whereas progesterone has an anticonvulsant effect.
Progesterone therapy has been suggested as a treatment when cat-
Morbidity and Comorbidity
amenial epilepsy is not responsive to standard ASMs (Herzog et al., Compared to the general population, individuals with epilepsy are at
2012). risk for increased morbidity and mortality. A large European cohort
study of predominantly young patients diagnosed within the previous
5 years showed a significantly greater cumulative probability of illness
EPIDEMIOLOGY OF EPILEPSY AND SEIZURES than controls (49% by 12 months and 86% by 24 months in patients vs.
Descriptive Epidemiology 39% and 75% in controls) (Beghi and Cornaggia, 2002). The chance of
The incidence of epilepsy is defined as number of new cases in a unit illness tended to increase with number of seizures, and there was also a
of time divided by the total population at risk. The overall incidence significant correlation between the number of illnesses and seizure fre-
in North America, adjusted for age, varied from 16 to 51 per 100,000 quency. However, most of the illnesses reported were trivial. Patients
persons per year (Banerjee et al., 2009). The incidence is similar in with epilepsy differed from controls predominantly in ear, nose, and
European studies, but figures were at times higher in developing throat complaints. Accidents were also considerably more common in
countries, up to 111 per 100,000 in a study in rural Chile. Incidence patients than controls (17% and 27% by 12 and 24 months compared
is high in the first decade of life, lowest in adult years until the fifth to 12% and 17% for controls). The number of wounds increased with
decade of life, then higher thereafter. In US studies, the highest the number of ASMs, which may reflect impairment of attention as
a result of seizure medications. Nervous system disorders that were proven effective in migraine prophylaxis and are approved for this
more common in patients than in controls included headache and ver- indication by the US Food and Drug Administration (FDA).
tigo/dizziness (van den Broek and Beghi, 2004). Sleep disorders are also a known comorbidity of epilepsy. Epilepsy
Several studies support an increased incidence of psychiatric disor- patients frequently have excessive daytime sleepiness, which is mul-
ders in epilepsy. A cross-sectional study that included 5834 individuals tifactorial (Manni and Tartara, 2000). Several studies have suggested
with epilepsy suggested that persons with epilepsy have double the risk that the prevalence of obstructive sleep apnea may be relatively high
of psychiatric disorders and an increased risk for neurodegenerative in individuals with epilepsy as compared with controls (Kaleyias et al.,
conditions, particularly dementias and Parkinson disease, cardio- 2008; Manni and Terzaghi, 2010; Manni et al., 2003). Sleep apnea is
vascular disorders, cerebrovascular disorders, upper-gastrointestinal even more prevalent in individuals with drug-resistant epilepsy (Malow
hemorrhages, fractures, pneumonia, chronic lung diseases, diabetes, et al., 2000b) and may play a role in drug resistance. Sleep apnea may
and brain tumors (Gaitatzis et al., 2004). A US survey also found an worsen seizure control by fragmenting nocturnal sleep and mimick-
almost threefold greater frequency of serious mental illness and an ing sleep deprivation. In one study in older epilepsy patients, obstruc-
increase in physical comorbid conditions including cancer, arthritis, tive sleep apnea was more common in those with new-onset or newly
heart disease, stroke, asthma, severe headaches, lower back pain, and worsened epilepsy than in individuals with stable or well-controlled
neck pain (Strine et al., 2005). It is likely that individuals with lon- epilepsy (Chihorek et al., 2007). In those patients with coexistent epi-
ger duration of epilepsy and drug-resistant epilepsy contribute to the lepsy and sleep apnea, there is evidence that treatment of the sleep
higher morbidity in the cross-sectional surveys. apnea may have a beneficial effect on seizure control (Malow et al.,
A survey designed to measure a wide spectrum of neuropsychiat- 2008). Other sleep disorders associated with epilepsy include insom-
ric and pain comorbidities found several neuropsychiatric disorders nia. In particular, sleep-maintenance insomnia was reported more fre-
to be more than twice as prevalent in patients with self-reported epi- quently than in controls (Khatami et al., 2006). Polysomnography in
lepsy as in those without epilepsy (Ottman et al., 2011). These disor- patients with epilepsy demonstrates reduced percentage of sleep time
ders included bipolar disorder, attention-deficit/hyperactivity disorder spent in rapid eye movement (REM) sleep, increased waking after sleep
(ADHD), and movement disorders/tremor. The last two had not onset, prolonged REM latency, and increased number of stage shifts
been reported in previous national surveys. A survey of frequency and (Touchon et al., 1991). The findings are more common with temporal
severity of depressive symptoms in community-based patients with lobe epilepsy. The decrease in REM is more pronounced if seizures
epilepsy or asthma found evidence of depression in 36.5% of epilepsy occurred during the early part of the night (Bazil et al., 2000).
subjects compared to 27.8% of asthma subjects and 11.8% of healthy
controls. Patients with epilepsy are more likely to be depressed than Mortality in Epilepsy
patients with asthma, suggesting that depression is not solely related to Epilepsy carries a two to three times higher mortality rate than that of
a chronic illness (Ettinger et al., 2004). The presence of depression was the general population (Tomson, 2000). The standardized mortality
associated with worse quality-of-life scores. As a result, clinicians eval- ratio in an early study was 2.3 through 29 years of follow-up (Hauser
uating patients with epilepsy are advised to discuss mood and quality et al., 1980). The most significant increase in standardized mortality
of life as part of the evaluation (Ettinger et al., 2004). ratio was noted early after diagnosis (Neligan et al., 2011). The stan-
Psychiatric symptoms need to be detected early and treated effec- dardized mortality ratio does depend on the seizure type. For example,
tively, avoiding the erroneous supposition that depression is a normal GTC seizures were associated with increased mortality, while absence
reaction to the epilepsy (Garcia-Morales et al., 2008). The presence seizures were not (Hauser et al., 1980). Patients who became seizure
of depression should influence the selection of ASMs, avoiding drugs free after epilepsy surgery had the same mortality rates as the general
that are known to be associated with depression and favoring med- population (Sperling et al., 1999). The highest mortality is found in
ications such as lamotrigine with a known positive mood effect. In epilepsy patients with intellectual disability or cerebral palsy (Forsgren
addition, there should be a low threshold for prescribing specific anti- et al., 2005). Premature mortality in epilepsy may be seizure-related,
depressant or mood-stabilizing medications, as well as consulting a may be due to the underlying cause of epilepsy, or may be a result of
psychiatrist. Compared to controls, the risk of suicidal behavior and conditions only indirectly related to epilepsy, such as cerebrovascular
suicide is increased in persons with epilepsy. The relationship between disease, pneumonia, and neoplastic disorders (Forsgren et al., 2005).
depression/suicidality and epilepsy is bidirectional, with a higher risk There is also increased mortality due to suicide (Bell et al., 2009).
of developing epilepsy in those with a past history of suicidality, and a Seizure-related deaths include death from status epilepticus, accidents
higher risk of suicidality in individuals with epilepsy (Hesdorffer et al., and drowning, and sudden unexpected death in epilepsy (SUDEP)
2006). In subjects who developed epilepsy, the incidence of depression, (Forsgren et al., 2005).
anxiety, and suicide attempts was increased even 3 years before epi- SUDEP is defined as “sudden, unexpected, witnessed or unwit-
lepsy diagnosis, suggesting that some mechanisms underlying reduced nessed, nontraumatic and nondrowning death, occurring in benign
seizure threshold may also increase the risk for psychiatric disorders circumstances, in an individual with epilepsy, with or without evi-
and suicide (Hesdorffer et al., 2012a). Psychiatric comorbidity at time dence for a seizure and excluding documented status epilepticus”
of epilepsy diagnosis is an unfavorable prognostic indicator for seizure (Nashef et al., 2012). Sudden unexpected death has a 27-fold higher
freedom with pharmacological therapy (Hitiris et al., 2007; Petrovski rate than in controls and is the most common cause of epilepsy-
et al., 2010). Lifetime psychiatric history was also a predictor of worse related death (Holst et al., 2013). When SUDEP is witnessed, it is most
outcome after anterior temporal lobectomy for drug-resistant tempo- often associated with a GTC seizure near the time of death (Tomson
ral lobe epilepsy (Kanner et al., 2009). et al., 2005), and the vast majority of unwitnessed SUDEP is associ-
Other comorbidities associated with epilepsy include migraine. The ated with tongue biting or incontinence, suggesting recent GTC sei-
rate ratio for migraine was 2.4 for individuals with epilepsy in compar- zures (Langan, 2000). The most important risk factor for SUDEP is
ison with controls (Ottman and Lipton, 1994). In addition, specific a high frequency of bilateral tonic-clonic seizures (Hesdorffer et al.,
epileptic syndromes have a greater association with migraine (Kossoff 2012b). SUDEP is most commonly sleep-related and unwitnessed,
and Andermann, 2010). The comorbidity of migraine may influence and patients are found in a prone position (Liebenthal et al., 2015),
the choice of ASM. Some ASMs such as topiramate and valproate have with similarity to infant death syndrome. There is strong evidence
that central apnea plays an important role in SUDEP. Ictal apnea brief period of repetitive action potentials. The action potentials are
and hypoxia are common (Bateman et al., 2008; Nashef et al., 1996). transmitted from VPM to S1bfd to form EEG spikes as well as to nRT,
Pronounced oxygen desaturation occurred even in focal seizures that which provides feedback inhibition to VPM. Third, VPM and nRT
did not progress to bilateral convulsions, most commonly with sei- neurons are highly interconnected—both within and between the tha-
zures of temporal lobe onset. The duration of the seizure and elec- lamic nuclei. The interconnectedness produces the synchrony of neu-
trographic evidence of contralateral spread influenced the degree of rons during the oscillation
desaturation. An EEG analysis suggested that prolonged generalized In nonepileptic individuals, VPM burst-mode firing and CTC
EEG suppression was more commonly seen with seizures recorded in oscillations produce sleep-related low-frequency delta activity and
individuals who later died of SUDEP. Beyond 80 seconds of postictal high-frequency sleep spindles. Absence seizure research has focused
generalized EEG suppression, the odds of SUDEP were quadrupled. on identifying physiological conditions that cause this naturally oscil-
It is thought that the generalized EEG suppression reflects profound lating circuit to produce pathological spike-wavedischarges (SWDs).
postictal cerebral dysfunction that may be a mechanism for central High-resolution electrophysiological recordings in CAE animals
apnea (Lhatoo et al., 2010). revealed that SWD spikes originate in S1bfd and spread to the thalamus
It is now increasingly recognized that patients deemed at high risk within 10–100 ms (Meeren et al., 2002; Polack et al., 2007). Selective
for SUDEP need to be informed about this potential complication. modulation of S1bfd, nRT, and VB by lesioning, pharmacological, and
Education about SUDEP is not necessary in patients with well-con- optogenetic methods revealed that all three circuit elements play crit-
trolled seizures, but it is important for noncompliant individuals who ical roles in SWD and elucidated some of the physiological conditions
could reduce the risk of SUDEP with improved compliance, and for that promote seizures. First, unilateral inhibition of somatosensory
patients with drug-resistant epilepsy who are excellent candidates for cortex GABAA receptors produces SWDs (Steriade and Contreras,
epilepsy surgery, which reduces the risk of SUDEP when successful (So 1998) whereas blockade of action potentials in S1bfd, but not other
et al., 2009). cortical regions, abolish bilateral SWDs (Polack et al., 2009; Sitnikova
and van Luijtelaar, 2004). These results highlight a principal role of
somatosensory cortex in absence seizures. Similarly, in nRT, bilateral
PATHOPHYSIOLOGY AND MECHANISMS increased tonic or phasic GABAA inhibition (Hosford et al., 1997; Liu
et al., 1991) and unilateral lesioning (Meeren et al., 2009) reduces/
Seizures are transient neurological events resulting from excessive and eliminates SWDs whereas bilateral GABAA antagonism increases them
hypersynchronous brain activity that present in a multitude of forms (Aker et al., 2002). Finally, tonic VB hyperpolarization increases SWDs
such as brief, abrupt behavior arrest and staring (typical absence), (Cope et al., 2009; Hosford et al., 1997; Liu et al., 1991; Sorokin et al.,
impaired awareness and automatisms (FIAS) and tonic-clonic sei- 2017), whereas facilitation of synaptic VB GABAA signaling does not
zures. Seizures exhibit such diverse behavioral manifestations because change them (Hosford et al., 1997). Conversely, reduction of VB tonic
each seizure type activates different brain circuits. Therefore, disinhibition decreases SWDs (Cope et al., 2009; Sorokin et al., 2017).
cussions of epilepsy pathophysiology must be done in context of the It should be noted that while enhanced tonic inhibition can produce
circuits that produce each seizure. The two most-extensively studied SWDs, it is not necessary for their formation (Zhou et al., 2015).
seizure circuits are the ones that produce typical absence seizures and Although typical absence seizures can arise in patients with
hippocampal focal seizures. Therefore, in this section, we will describe acquired brain lesions (Wakamoto, 2008), they occur most often with
the circuits that engaged in each of these seizure types as well as known IGE syndromes that, by definition, are not associated with gross ana-
pathophysiological mechanisms that produce the excessive and hyper- tomical changes. Most IGE cases arise from complex inheritance, but
synchronous activity within the circuits during a seizure. some IGE syndromes are monogenic (familial or sporadic [de novo])
(Macdonald et al., 2010), and the mutations often occur in synaptic
Typical Absence Seizures protein genes such as neurotransmitter receptor and voltage-gated
Generalized seizures such as typical absence seizures engage wide- ion channel genes. These monogenic epilepsy mutations have spe-
spread regions in both cerebral hemispheres extremely rapidly and cific molecular consequences for the mutant proteins they encode.
thus give the appearance on clinical EEG of activating the entire cor- This has been studied in detail for mutations in genes for subunits
tex instantaneously. However, functional MRI (fMRI) (Carney et al., of the inhibitory GABAA receptors, which have been associated with
2012; Gotman et al., 2005), magnetoencephalography (MEG) (Miao multiple genetic epilepsies syndromes, including CAE, JME, GEFS+,
et al., 2014; Stefan et al., 2009; Tenney et al., 2014; Westmijse et al., Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and
2009), and high-density EEG (Holmes et al., 2004) studies revealed Doose syndrome (Macdonald et al., 2010). We will discuss the human
that generalized seizures engage distinct brain networks that often GABAA receptor subunit gene (GABR) mutations that produce CAE
involve the thalamus and frontal and parietal cortices. in GABRA1, GABRB3, and GABRG2 to illustrate some of the effects of
In rodent models, typical absence seizures also activate discrete, GABR mutations that produce CAE and SCN1A mutations to produce
interconnected cortical and thalamic regions including the somato- Dravet syndrome, since the results reported for GABRs and SNC1A
sensory barrel cortex (S1bfd) and the thalamic reticular (nRT) and ven- could be generalizable to CAE and Dravet syndrome mutations in
troposterior medial (VPM) nuclei (for in-depth reviews, see Fogerson other synaptic protein genes.
and Huguenard, 2016; Luttjohann and van Luijtelaar, 2015). Three The GABAA receptor is a ligand-gated, chloride-selective ion
key anatomical/physiological features of this cortico-thalamo-corti- channel responsible for most synaptic inhibition in the CNS and is a
cal (CTC) circuitry promote oscillations. First, excitatory neurons in heteropentamer whose expression and current kinetic properties are
VPM project to the inhibitory GABAergic neurons in nRT, which then determined by the subunit combination of the receptor. While there
provide feedback inhibition to VPM. Second, VPM neurons fire in are numerous genes that encode subunits and subunit subtypes of the
two modes—tonic and bursting. In the bursting mode, a VPM neu- GABAA receptor (α1–6, β1–3, γ1–2, δ, ε, θ, and π), the majority of the
ron pacemaker-like current (Ih) activates upon hyperpolarization and GABAA receptors in the CNS are composed of 2 α, 2 β, and a single γ or
the resultant depolarization activates a T-type calcium channel (T-type δ subunit. To date, numerous GABR mutations have been associated
current) that transiently further depolarizes the neurons allowing a with autosomal dominant monogenetic epilepsy syndromes, which
are primarily in GABRA1, GABRB1, GABRB2, GABRB3, and GABRG2 2007) experienced spontaneous seizures. The hippocampi of Scn1a
subunit genes. All the the GABR epilepsy mutations reported thus far deletion mice exhibited reduced sodium currents in the interneurons,
have resulted in loss- or reduction- in function of the corresponding but not the pyramidal neurons. The R140X mutation reduced spike
GABAAR subunit. However, the currently studied mutations produce amplitudes in cortical layer II/III interneurons. These findings sug-
loss of function by a variety of different mechanisms including mes- gested that Dravet syndrome mutations reduce interneuron function,
senger (m)RNA through nonsense-mediated decay, misfolding, and resulting in disinhibition.
degradation of the nascent polypeptides, dominant negative reduc-
tions in wild-type GABAA receptor expression, impaired receptor Hippocampal Focal-Onset Seizures
oligomerization, formation of insoluble protein aggregates, and altered The current epilepsy classification system (Fisher et al., 2017) does not
electrophysiological properties. Specific potential therapies for each of group focal seizures based upon the presumed region of onset (e.g.,
these molecular consequences have been proposed. frontal, temporal, etc.), a decision made in light of current research
The human S326fs328X mutant α1 subunit causes CAE (Maljevic that revealed that focal-onset seizures, like generalized-onset seizures,
et al., 2006). The mutation impairs GABAA receptor function by engage and influence long-range brain networks. Nevertheless, unlike
causing loss-of-function due to frameshift or deletion of GABRA1 generalized epilepsies, focal epilepsies, especially those that initially
that produces degradation of the mutant mRNAs by nonsense medi- engage the mesial temporal lobe, are very responsive to targeted sur-
ated mRNA decay (NMD). Electrophysiological studies demon- gical ablation (Hoyt and Smith, 2016; Jermakowicz et al., 2017) and
strated that heterozygous loss of the α1 subunit expression reduces thus it is practical to consider the pathophysiological processes that
synaptic GABAA currents in excitatory neurons in both cortical layer produce excessive and hypersynchronous discharges in these distinct
VI and VB without changing VB tonic inhibition (Zhou et al., 2013, structures. Therefore, we will examine the processes thought to form
2015). seizures in the hippocampus, the most extensively studied structure in
The human P11S, S15F, and G32R mutant β3 subunits cause CAE mesial temporal lobe seizures.
(Tanaka et al., 2008) by decreasing GABAA receptor current. The cur- Much of the neuronal signaling through the hippocampus is medi-
rent reduction is due to impaired function of surface GABAA receptors ated through the so-called “trisynaptic circuit” consisting of (1) ento-
without altering surface expression of mutant β3 subunits (Tian and rhinal cortex perforant path projections to dentate gyrus granule cells
Macdonald, 2012). (DGCs), (2) DGC axons (mossy fibers) projections to CA3 pyramidal
The human IVS6+2T>G mutant γ2 subunit also causes CAE neurons, and (3) Schaffer collaterals from CA3 cells to CA1 pyramidal
(Kananura et al., 2002). The decrease of GABAA receptor current is neurons. In the nonepileptic animals, DGCs are relatively nonexcitable
produced by a premature stop codon in the mutant gene that pro- and thus perforant path stimulation produces few action potentials
duces NMD, thus decreasing γ2-subunit mRNA and surface GABAA (“sparse activation”), a property thought to be important for cognitive
receptors. functions such as memory encoding and pattern separation (Cayco-
Neurons express α1β3γ2 subunits, nRT neurons express α3β3 Gajic and Silver, 2019; Hainmueller and Bartos, 2018). In addition,
subunits, and VBn neurons express α1β2γ2 subunits, suggesting that DGC sparse activation limits the propagation of seizures from the
locations that express ternary α1β3γ2 receptors and binary α3β3 β3 entorhinal cortex to the cortex (Behr et al., 1996, 1998; Dreier and
subunit-containing receptors are responsible for generating CAE. In Heinemann, 1991), a property referred to as “dentate gating” (Dengler
contrast it is likely that locations that express β1 or β2, but not β3, and Coulter, 2016; Dudek and Sutula, 2007). Consistent with these
subunits do not generate CAE. early studies, optogenetic inhibition and excitation selectively applied
Thus, the GABRA1 and GABRG2 mutations that produce typical to DGC have reduced and increased, respectively, the frequency and
CAE cause degradation of mutant mRNA by NMD without altering duration of electrographic seizures as well as the progression to a con-
the function of successfully assembled and trafficked receptors. The vulsive seizure (Bui et al., 2018; Krook-Magnuson et al., 2015; Tung
resultant reduced subunit expression reduces cell-surface expression of et al., 2018). In addition, optogenetic excitation of dentate gyrus mossy
the mutated subunit. In contrast, the GABRB3 mutation that produces cells decreased seizure duration and the fraction of electrographic sei-
typical CAE alters the function of the ion channel without altering zures that evolved into a convulsion (Bui et al., 2018), a result consis-
receptor function. tent with the feedforward inhibition of mossy cells to DGC.
Altered inhibitory neurotransmission may also contribute to the Much of the research into the pathogenesis of hippocampal
pathology of Dravet syndrome, a genetic epilepsy syndrome that focal-onset seizures has focused on uncovering mechanisms by which
confers febrile seizures and generalized seizures including myoclonic dentate gating is diminished. Unlike the absence seizure network, there
seizures and atypical absence seizures. Approximately 85% of Dravet is little evidence to suggest that genomic mutations play the predom-
patients possess mutations in the SCN1A gene, which encodes the α inant role in altering neural transmission through the dentate gate.
subunit of the neuronal voltage-gated sodium channel type 1. The Therefore, this section will discuss alterations in dentate gyrus micro-
majority (78%) of Dravet syndrome SCN1A mutations are predicted circuitry, DGC excitability, and GABAergic inhibition, that modify
to be particularly disruptive to protein function; these disruptive DRG sparse activation.
mutations include amplification, frameshift, truncation, deletion, or Histological analysis of dentate gyri from both humans and epilep-
duplication mutations. Interestingly, both pyramidal and GABAergic tic animals demonstrate that DGC mossy fibers form collateral connec-
neurons derived from induced pluripotent stem cells from two Dravet tions (mossy fiber sprouting) on DGC dendrites in the dentate gyrus
patients showed increased, not decreased, sodium channel currents, inner molecular layer. These aberrant connections provide recurrent
hyperexcitability, and spontaneous bursting (Liu et al., 2013). These synaptic excitation to DGC (Scharfman et al., 2003) and thus may
findings suggested the possibility that overcompensation by a different be the mechanism by which dentate gating is reduced. However, the
sodium channel α subunit could also contribute to the pathophysiol- epileptogenic role of mossy fiber sprouting is unclear. The recurrent
ogy of Dravet syndrome. However, different results are obtained when excitatory signaling is weak (Scharfman et al., 2003) and, in one mouse
Dravet syndrome is modeled in mice. Both heterozygous Scn1a dele- model, administration of rapamycin, an inhibitor of the mammalian
tion mice (Yu et al., 2006) and mice that heterozygously contained the target of rapamycin (mTOR) signaling pathway reduced mossy fiber
Dravet-associated Scn1a R1407X nonsense mutation (Ogiwara et al., sprouting but did not change seizure frequency (Buckmaster and Lew,
2011; Heng et al., 2013), a result that suggested that although mossy imitators of seizures include shuddering attacks and stereotypies or
fiber sprouting is a very common histological finding, it may be an epi- repetitive behaviors that can be mistaken for seizures. Gastroesophageal
phenomenon that does not disrupt dentate gating or promote seizures. reflux may be associated with posturing (Sandifer syndrome); a greater
However, because rapamycin affects many cellular processes, includ- occurrence of spells following feeding may be a clue to the diagnosis.
ing the sprouting of inhibitory interneuron axons (Buckmaster and Breath-holding spells represent a form of syncope that may be asso-
Wen, 2011), it is possible that antiepileptogenic reductions in mossy ciated with tonic posturing and a few jerks (Laux and Nordli, 2005).
fiber sprouting could be counterbalanced by other pro-epileptogenic Either cyanosis or pallor can accompany these breath-holding spells,
effects. The development of techniques to selectively reduce mossy and both are precipitated by injury or frustration, but cyanotic spells
fiber sprouting is needed to clarify its role in disrupted dentate gating. are preceded by crying.
Altered DGC electrophysiological properties may also contrib- Imitators of epilepsy that are more common in old age include tran-
ute to reduced dentate gating and hippocampal seizures. Compared sient ischemic attacks (TIAs) and transient global amnesia. Transient
with controls, DGCs from epileptic rats exhibited depolarized resting ischemia generally causes negative symptoms.
potentials, increased action potential firing rates, and prolonged action With loss of function such as weakness or numbness, whereas sei-
potential waveforms (Althaus et al., 2015). In addition, ectopic DGC, zures involving sensory or motor cortex are more likely to produce
neurons born in the dentate gyrus subgranular proliferative zone that positive symptoms such as twitching or paresthesias. However, sei-
mature after the epileptogenic insult and fail to migrate properly to zures may occasionally present with only negative symptoms, and TIAs
the granule zone (Kron et al., 2010), possess increased firing rates rarely present with limb shaking. Limb shaking as a feature of TIAs has
compared with their normotopic counterparts (Althaus et al., 2015). been associated with high-grade stenosis or occlusion of the internal
Therefore, ectopic DGC also likely increase dentate gyrus excitability. carotid artery (Persoon et al., 2010). Although TIAs tend to be longer
The presence of increased slow-wave oscillations (SWO, 0.1–2.0 Hz) in duration than seizures (most seizures last <2 minutes and most TIAs
in membrane potential may increase seizures in the epileptic dentate last >2 minutes), limb-shaking TIAs are short, usually shorter than 5
gyrus. Although healthy DGCs rarely exhibit spontaneous SWO, status minutes and even shorter than 1 minute. One feature that could dis-
epilepticus produces strong, long-duration SWO that are in phase with tinguish them from seizures is precipitation by rising or exercise and
neocortical oscillations (Ouedraogo et al., 2016). Depolarizing phases association with weakness of the affected limb (Persoon et al., 2010).
of the SWO will facilitate dentate transmission at the time of increased TIAs can be misdiagnosed as seizures, but the more common scenario
neocortical neural activity and thus promote seizures. is to misdiagnose negative motor seizures or sensory seizures as TIAs.
Finally, reduced inhibitory GABAergic signaling may also dis- The presence of a sensory march should be suggestive of an epileptic
rupt dentate gating. Animal models of hippocampal epilepsy have nature.
reduced parvalbumin-, somatostatin-, and neuropeptide Y-expressing Transient global amnesia is a condition in older individuals char-
GABAergic inhibitory interneurons in the dentate (Kobayashi and acterized by memory loss without impairment of other cognitive
Buckmaster, 2003; Sun et al., 2007) and fewer fibers in the dentate function, and affected subjects are able to engage in complex activ-
inner molecular layer express the inhibitory neuromarker, cholecys- ities. Most transient global amnesia episodes last hours and are sin-
tokinin (Sun et al., 2014). Although exceptions exist (Dengler et al., gle events, although they may repeat in a minority of individuals. The
2017), DGCs in epilepsy models exhibit a lower frequency of inhibi- nature of transient global amnesia is not totally clear.
tory postsynaptic currents (IPSCs) (Kobayashi and Buckmaster, 2003; Conditions that can imitate seizures and epilepsy through much of
Sun et al., 2014; Zhang et al., 2007), a finding consistent with reduced the life span include nonepileptic psychogenic seizures, syncope, clas-
presynaptic inhibitory interneurons. In addition to reduced frequency, sical migraine, and a number of sleep and movement disorders. These
several (Dengler et al., 2017; Kobayashi and Buckmaster, 2003; Zhang will be discussed in greater detail.
et al., 2007) (but not all [Sun et al., 2014]) studies found reduced syn-
aptic DGC ISPC amplitudes. The finding that supplementation of glu- Psychogenic Nonepileptic Seizures
tamine, a GABA precursor, restores dentate gating in epileptic mice Psychogenic nonepileptic seizures (PNES), also called psychogenic non
(Dengler et al., 2017) suggests that reduced presynaptic GABA biosyn- epileptic events, pseudoseizures, or pseudoepileptic seizures, are the most
thesis is a factor that reduces DGC IPSC amplitudes. common imitators of seizures and epilepsy in referral centers. These
In conclusion, seizure pathophysiology is complex and must be are emotionally triggered attacks not associated with any paroxysmal
studied in the contexts of the neural circuits that produce each seizure. epileptic activity in the brain. Most are the result of somatoform disor-
The networks that generate typical absence and hippocampal focal sei- der, with a variety of reported traumatic antecedents, particularly sex-
zures have been most thoroughly studied. Absence seizures are asso- ual or physical abuse in women (Duncan and Oto, 2008). Antecedents
ciated with many different genetic mutations that alter the physiology or historical precipitants of PNES include head injury, which is also a
of different components of the thalamocortical networks. In contrast, common and important risk factor for epilepsy. In one study, 33% of
hippocampal focal seizures are associated with post transcriptional patients with head injury and seizures had PNES on video-EEG mon-
changes, some of which may alter physiology in the dentate gyrus. itoring (Hudak et al., 2004). PNES may also appear after surgery and
Studies of both these networks have revealed distinct areas that can be can be one explanation for apparent failure of epilepsy surgery (Ney
modulated to reduce seizures. et al., 1998; Parra et al., 1998; Reuber et al., 2002). This emphasizes the
need for video-EEG evaluation of patients who have had recurrence
of seizures after epilepsy surgery. A diagnosis of fibromyalgia or a his-
DIFFERENTIAL DIAGNOSIS tory of chronic pain were found to be predictors of PNES (Benbadis,
Seizures and epilepsy have many imitators, some of which are age 2005). The neurobiology of PNES is not known, but imaging studies
specific. In infants, the list includes apnea, either central or obstruc- have suggested altered functional connectivity of several brain regions
tive, which can be a seizure manifestation but can also be nonepilep- in patients with PNES as compared to normal controls (Perez and
tic. Jitteriness associated with a variety of metabolic disturbances can LaFrance, 2016).
imitate clonic or myoclonic seizures. Exaggerated startle can also be PNES are diagnosed in a considerable proportion of patients
mistaken for tonic seizures. After the neonatal period, early childhood referred for drug-resistant seizures. The population-based incidence
has been estimated at between 1.4 and 4.6 per 100,000 person-years of in conjunction with ASM withdrawal. Epileptic seizures may evolve to
observation. In one study, the incidence was highest between 15 and bilateral tonic-clonic activity, which provides a definitive diagnosis. In
24 years of age (Sigurdardottir and Olafsson, 1998) and in another one study comparing patients with frontal lobe FIAS and patients with
between 25 and 45 years of age (Szaflarski et al., 2000). All studies PNES, there was no significant difference in the history of psychiatric
agree that there is a higher prevalence in women (70%–80%). The disease, ictal pelvic thrusting, rocking of body, side-to-side head move-
various patterns of clinical manifestations of PNES can be classified ments, or rapid postictal recovery (Saygi et al., 1992). Of interest, turn-
in three broad categories: psychogenic motor seizures with prominent ing to a prone position occurred only in frontal lobe FIAS. Nocturnal
motor activity, psychogenic minor motor or trembling seizures with occurrence, short ictal duration, younger age at onset, stereotyped
tremor of the extremities, and attacks with motionless unresponsive- movements, and abnormal MRI or EEG favored frontal lobe FIAS.
ness or collapse (Groppel et al., 2000; Meierkord et al., 1991; Selwa Others have also suggested that while epileptic seizures are very stereo-
et al., 2000). In children, prolonged staring and unresponsiveness was typed, PNES tend to have a lot of variability. However, this notion has
the most common pattern, while motor activity was more common in been disputed (Seneviratne et al., 2010).
adolescents (Kramer et al., 1995). Pseudo-status epilepticus is a common occurrence in PNES,
The diagnosis of PNES depends on prolonged video-EEG monitor- reported in a greater proportion of patients than status epilepticus in
ing with recording of typical attacks. The use of suggestion may facil- patients with epilepsy (Dworetzky et al., 2006). As expected, it tends to
itate the precipitation and recording of attacks. Hyperventilation and be resistant to treatment with ASMs, until the development of stupor
photic stimulation are usually adequate suggestion techniques; sugges- or coma, which may lead to intubation. Its early recognition is essential
tion methods should not involve patient deception. In some individu- to prevent potentially harmful interventions.
als, suggestion may precipitate atypical attacks; to verify that recorded
events are typical of what occurs at home, it is crucial to seek the input Syncope
of family members who have witnessed attacks. PNES may coexist Syncope is an abrupt transient loss of consciousness caused by
with epilepsy. Early studies suggested that more than 50% of patients decreased cerebral perfusion. It is an important condition in the dif-
with PNES also have epilepsy, but most studies now agree on a much ferential diagnosis of epilepsy in the elderly as well as teenagers and
smaller proportion, probably not more than 10% or 15% (Benbadis young adults. Although syncope is mostly recognized by loss of posture
et al., 2001; Lesser et al., 1983; Martin et al., 2003). and limp unresponsiveness, the majority of closely observed individ-
A number of studies have tried to identify features that suggest uals will have brief transient motor manifestations early after loss of
PNES origin (Avbersek and Sisodiya, 2010). In a comparison of epilep- consciousness. The most common motor manifestation is myoclonus
tic GTC seizures and PNES with motor activity, features that predicted that is most often multifocal and arrhythmic (Lempert et al., 1994).
PNES were out-of-phase upper and lower extremity movements, Other motor manifestations may also occur, including posturing, head
absence of vocalization or vocalization at the very onset of seizures, turning, upward eye movement, oral automatisms, and righting move-
forward pelvic thrusting, absence of whole-body rigidity, and side-to- ments (Lempert et al., 1994). The motor manifestations, particularly
side head movements. No single feature was totally predictive by itself, myoclonus, are an important factor in the misdiagnosis of syncope as
and these features were particularly strong predictors when combined seizures. Although syncope with myoclonus has been referred to as
(Gates et al., 1985), but such clinical features can also be seen in frontal “convulsive syncope,” there is no associated EEG discharge, and the
lobe FIAS and other hypermotor seizures (Saygi et al., 1992). Other origin is thought to be in the brainstem. Syncope can have a variety of
features that may help discriminate PNES from epileptic seizures mechanisms, some benign and others serious. In younger individuals,
include pseudosleep at onset (Benbadis et al., 1996b); preictal behav- the most common is neurally mediated syncope. This can be triggered
ioral changes (Moore et al., 1998); discontinuous seizure activity; pro- by a variety of factors, including intense pain, emotion, and standing
longed seizure duration; eye closure during unresponsiveness (Chung for prolonged periods of time in hot or crowded places. In addition,
et al., 2006; DeToledo and Ramsay, 1996); resistance to eye opening; syncope can be precipitated in some individuals by micturition, defe-
eye fluttering; certain vocalizations such as stuttering, gagging, gasp- cation, or cough. Neurally mediated syncope tends to have a prodrome
ing, screaming, weeping, or moaning; emotional display during events; of lightheadedness, nausea, pallor, cold sweating, graying of vision, and
emotional triggers; precipitation of typical events by suggestion; and hearing becoming distant, as well as other visual or auditory halluci-
attacks occurring in the clinic waiting room or admitting office. nations (Carreño, 2008; Crompton and Berkovic, 2009; Lempert et al.,
Tongue biting and incontinence occur more commonly with epilep- 1994). Syncope may also be due to orthostatic hypotension, cardiac
tic seizures but are also frequently reported by patients with PNES arrhythmias, and structural cardiopulmonary disease (Carreño, 2008;
(Peguero et al., 1995). Injuries to the tongue during epileptic seizures Crompton and Berkovic, 2009). Syncope due to cardiac arrhythmia
tend to affect the side of the tongue. Biting the tip of the tongue or the is usually more abrupt with no preceding symptoms. In the differen-
lip was suggestive of PNES (DeToledo and Ramsay, 1996). Self-injury tiation of syncope from seizures, features that favor syncope include
was also reported by patients with PNES, but one study suggested that known heart disease, prior confirmed syncope, precipitation by pro-
burn injuries were specific for epileptic seizures (Peguero et al., 1995). longed standing or rising to an upright position, presence of dehydra-
The presence of postictal stertorous respiration is very helpful to diag- tion, the typical neurocardiogenic syncope prodrome described earlier,
nose epileptic convulsive seizures (Sen et al., 2007), whereas shallow description of pronounced pallor by witnesses, absence of tonic or
rapid respiration was more likely after PNES (Azar et al., 2008a). clonic activity, description of multifocal myoclonus lasting less than 15
The gold standard for diagnosing PNES is the recording of typi- seconds, and recollection of loss of consciousness. Features that would
cal attacks with EEG-video and demonstrating typical semiology and favor seizures include previous seizures, known cortical brain lesion,
absence of EEG changes peri-ictally with habitual attacks (Perez and presence of tongue biting, incontinence, cyanosis, postictal confusion,
LaFrance, 2016). Neurologists have to be aware that some epileptic postictal headache, and lack of recollection of loss of consciousness
seizures have no EEG correlate. For example, frontal lobe FIAS of (Crompton and Berkovic, 2009). Syncope may rarely trigger an epi-
orbitofrontal or cingulate origin commonly have no associated EEG leptic seizure (Stephenson et al., 2004). These seizures, referred to as
changes, nor do supplementary motor seizures. For definitive diagno- anoxic-epileptic seizures, are to be distinguished from the much more
sis, it is often necessary to record multiple attacks and observe changes common nonepileptic “convulsive” syncope.
Migraine use of a scale (Derry et al., 2006) or a structured interview (Bisulli

Epilepsy and migraine both present with paroxysmal manifestations et al., 2012).
as a result of cerebral cortex involvement (Kossoff and Andermann, Some manifestations of narcolepsy can imitate seizures. These
2010). Types of migraine that are most likely to be confused with sei- include sleep attacks, cataplexy, sleep paralysis, and hallucinations
zures are classical migraine with visual or somatosensory aura, basi- during the transition between waking and sleep. Attacks of cataplexy
lar migraine, and acute confusional migraine (Carreño, 2008; Kossoff are brought on by emotional stimuli and are characterized by loss of
and Andermann, 2010). Occipital lobe seizures may be followed by a muscle tone, which may result in loss of posture. Cataplexy may include
migraine-like headache that makes it hard to distinguish them from some jerky motions that could imitate seizure activity. However, an
a classical migraine with a visual aura. Helpful distinguishing fea- important distinguishing feature is total preservation of consciousness
tures include duration of the aura. The aura in migraine typically and complete memory of the events. The association with other mani-
lasts 5–60 minutes (Carreño, 2008), reflecting that cortical spread- festations of narcolepsy should help establish the diagnosis.
ing depression (the main pathophysiology of migraine) results from
Paroxysmal Movement Disorders
a slow depolarization that spreads at about 3 mm/min (Crompton
and Berkovic, 2009). In contrast, epileptic discharges propagate at Paroxysmal movement disorders that can be confused with epilepsy
a much higher speed; epileptic auras are usually less than 30 sec- include nonepileptic myoclonus, paroxysmal dyskinesia, and hyperek-
onds in duration. Another helpful distinction is that the visual aura plexia (Crompton and Berkovic, 2009). Myoclonus may be generated
in migraine is most commonly a fortification spectrum or scintil- at any level of the CNS; epileptic myoclonus is generated at the level of
lating scotoma, whereas colored circles are the most common aura the cortex and is usually associated with a scalp EEG discharge. In the
in occipital lobe seizures (Carreño, 2008; Kossoff and Andermann, case of focal cortical myoclonus, the distinction can be harder to estab-
2010). Migraine without headache, also called migraine equivalent, lish (Crompton and Berkovic, 2009). Paroxysmal dyskinesia can be
can be an even more difficult diagnostic challenge. Basilar migraine classified into two broad categories: kinesigenic and noinkinesigenic,
starts with brainstem manifestations that include dysarthria, vertigo, both usually familial (Fahn and Frucht, 2008). In paroxysmal kinesi-
changes in hearing, diplopia, and ataxia, and then involves loss of genic dyskinesia, the attacks are often brought on by a sudden move-
consciousness. ment or startle, usually after a period of inactivity. The movements are
Migraine and epilepsy have a greater overlap than would be any combination of chorea, athetosis, ballism, and a dystonic posture
expected by chance. The prevalence of each is increased in the pres- (Fahn and Frucht, 2008). They can be bilateral or alternate sides, which
ence of the other, and some epileptic syndromes (e.g., benign epi- is helpful in distinguishing them from epileptic seizures that generally
lepsy with occipital paroxysms, BECTS) have a particularly higher produce consistently unilateral posturing. Other helpful distinguish-
incidence of migraine (Kossoff and Andermann, 2010). In addition, ing features are that consciousness is always preserved, and there is no
a rare condition referred to as “migralepsy” (or migraine-triggered epi- postictal change. However, the condition responds very well to ASMs.
lepsy or migraine-triggered seizures) is characterized by seizures that The attacks in paroxysmal nonkinesigenic dyskinesia are longer (min-
occur during or shortly after the migraine aura. Certain antiseizure utes to hours as compared to seconds), less frequent, and precipitated
medications such as valproate and topiramate are used successfully in not by movement but rather by alcohol, caffeine, stress, excitement, or
migraine prophylaxis, but others such as oxcarbazepine or carbamaz- fatigue. The attacks do not usually respond to ASMs (Fahn and Frucht,
epine do not seem to be effective. However, acute abortive therapy for 2008). Hyperekplexia is an inherited disorder in which there is an exag-
the two conditions is totally different. geration of startle reflexes (Crompton and Berkovic, 2009). The exag-
gerated startle has to be distinguished from startle-evoked seizures,
which are most often of supplementary motor origin.
Sleep Disorders
Parasomnias are the most important imitators of seizures in the cate-
gory of sleep disorders (see Chapter 101). These include sleep walking
EVALUATION AND DIAGNOSIS
(somnambulism), sleep talking, night terrors, confusional arousals, The clinical history is always a cornerstone in the evaluation of seizures
and REM behavior disorder. They may imitate frontal lobe seizures and epilepsy. Other elements of the evaluation depend on the clinical
that occur preferentially or even exclusively in sleep. Somnambulism, presentation; different testing is recommended in patients presenting
sleep talking, and night terrors typically start in childhood and tend with new-onset seizures, patients with recently drug-resistant seizures,
to disappear in adolescence. They are most likely to arise out of slow- or patients pursuing epilepsy surgery. This section will therefore be
wave sleep in the first half of the night, usually after a latency of 90 subdivided based on the particular presentation.
minutes from sleep onset. Frontal lobe seizures are more likely to
arise out of stage 1 or 2 sleep (Carreño, 2008). These events are more Evaluation of Recent-Onset Seizures and Epilepsy
likely to be seizures if they occur in the first hour of sleep or in the Evaluating an individual with one or more attacks that could repre-
transition between waking and sleep. REM behavior disorder is char- sent seizures always starts with an in-depth history. Tests such as EEG
acterized by loss of muscle atonia during REM sleep, which results and brain imaging should primarily supplement the history and help
in acting out dreams. The behavior includes verbalization and vocal- classify seizures/epilepsy and identify underlying pathology. Ideally, at
ization, as well as motor activity that may be violent (e.g., kicking, the end of the evaluation, the seizure diagnosis and classification are
punching) and getting out of bed. Affected individuals will be aware confirmed, an epilepsy syndrome has been diagnosed if that is possi-
that they have been dreaming and may report the content of their ble, and any structural etiology has been identified. The best treatment
dreams. REM behavior disorder is more likely in the second half of options can then be determined, and in some cases it may be possible
the night when REM sleep is most likely to occur (Carreño, 2008). to predict prognosis.
REM behavior disorder rarely starts before age 50; it is most often
a chronic disorder associated with a synucleinopathy, particularly History
Lewy body dementia (Crompton and Berkovic, 2009). The differen- The patient with possible seizures should be asked about potential
tiation of parasomnias and frontal lobe seizures may be aided by the seizure triggers, any symptoms preceding the event, and recollection
of what happened during the event. However, in many instances the with seizures or epilepsy, the EEG is the most helpful test to confirm
patient can only provide an incomplete or distorted account because the diagnosis, help classify the epilepsy as focal or generalized, and even
of altered consciousness; it is therefore crucial to obtain an inde- help identify the specific syndrome in some instances.
pendent history from a witness. If possible, more than one witness The routine EEG is typically 20–30 minutes long. It should include
should be interviewed to assess the consistency of the description, standard activation procedures such as hyperventilation and pho-
because the recollection of events by the witness may also be dis- tic stimulation. The waking recording should include eyes-open
torted by panic. The final account of the event should list its com- and eyes-closed conditions. Ideally there should also be a recording
ponents in temporal order starting with prodrome, aura, objective of drowsiness and sleep, but that may be difficult to obtain without
manifestations, and then postictal signs and symptoms. The inter- sleep deprivation. Routine EEG is unlikely to record seizures, with the
viewer should ask about urinary incontinence, tongue biting, postic- exception of generalized absence seizures that can be easily precipi-
tal confusion, and postictal muscle soreness. Additional questions to tated by hyperventilation in the untreated patient. The main contribu-
be asked depend on the specific differential diagnosis in each case. In tion of a routine EEG is the recording of interictal epileptiform activity,
instances when multiple attacks have occurred, the family may have which includes spikes, sharp waves, spike-and-wave discharges, and
captured events on home video. Review of such video segments can polyspike-and-wave discharges.
be extremely helpful. A number of criteria help identify discharges as epileptiform. They are
The past medical history may identify important risk factors for typically of high voltage in comparison with the surrounding EEG activ-
epilepsy or for other disorders. This should include a history of ges- ity. Their duration is 70–200 ms for sharp waves and less than 70 ms for
tation, birth, developmental milestones, and illnesses in infancy and spikes; when recorded from the scalp, epileptiform discharges are usu-
childhood. Of particular importance are febrile seizures and CNS ally longer than 20 ms. Epileptiform discharges tend to have more than
infections such as meningitis or encephalitis, all of which are associ- one phase, and the predominant component is negative. That negative
ated with increased risk of epilepsy. Any head trauma should be inves- component tends to be asymmetrical; when the epileptiform discharge
tigated with questions about loss of consciousness and its duration, is recorded from the first input in a channel, it has a shorter and low-
and history of depressed skull fracture or other intracranial pathology. er-voltage ascending segment and a longer and higher-voltage descend-
Other epilepsy risk factors to investigate will depend on age at onset— ing segment (Gotman, 1980; Fig. 100.17). Epileptiform discharges tend
for example, history of stroke becomes important when epilepsy starts to have an aftergoing slow wave, and they tend to arise from an abnormal
in old age. background. The criteria mentioned above are not necessarily all satis-
Family history of afebrile seizures and other paroxysmal disorders fied. However, the more criteria satisfied, the more confident one can
as well as family history of febrile seizures should be obtained. The be about the epileptiform nature of the discharge. Many physiological
family history can be optimized by first asking the patient or informed potentials and normal variants are sharp in configuration and may be
relative about the number of first-degree and second-degree relatives misdiagnosed as epileptiform. In fact, misinterpretation of the EEG is
in every category. This may help with the recall of who is affected. It one of the most common reasons for overdiagnosis/misdiagnosis of epi-
is often best to obtain family history from a senior female relative who lepsy. Another reason is inadequate history and failure to obtain a thor-
is likely to be more informed about the family than younger and male ough description of events from witnesses (Smith et al., 1999).
members. The first interictal EEG is normal in about 50% of patients with
Review of systems should be expanded with respect to CNS abnor- epilepsy (Salinsky et al., 1987). Additional routine EEGs can improve
malities. If specific syndromes are suspected, the review of systems the yield, but there is little to be gained after four normal EEGs. With
should include symptoms related to other organs that may be affected multiple recordings, more than 90% of individuals with epilepsy will
in these syndromes. have epileptiform EEG abnormalities recorded (Salinsky et al., 1987).
Several studies have explored ways to improve the yield of the first
Physical and Neurological Examination EEG in epilepsy. One study found that a sleep-deprived EEG was
superior to a routine EEG and to an EEG with medication-induced
The most important aspects of the examination will vary depending on
sleep (Leach et al., 2006). Prolonging recording time increases the
age and specific circumstances. In children, careful examination of the
yield of EEG. One study found that a 4-hour outpatient video-EEG
skin is important for identification of neurocutaneous disorders that
study added considerably to the yield of a 20-minute EEG, particu-
are often associated with epilepsy. Dysmorphic features may suggest
larly in patients with focal epilepsy (Modur and Rigdon, 2008). Even
certain chromosomal abnormalities. The neurological examination
shorter extension of recording time from 30 minutes to ≥45 minutes
may reveal abnormalities of mental status or motor and reflex asym-
increased detection of epileptiform discharges by about 20% and
metries that could help with lateralization of the epileptogenic zone in
event capture by around 30% (Burkholder et al., 2016). Timing of
focal epilepsy. However, most individuals will have a normal neuro-
the EEG is also important. In generalized epilepsy, a morning EEG
logical examination.
is more likely to yield epileptiform abnormalities than an afternoon
EEG (Labate et al., 2007). In patients with JME, a slightly sleep-
Electroencephalography deprived EEG obtained predominantly after a nap is the most useful,
The EEG is a graphic representation of voltage change over time. Each since both seizures and epileptiform discharges are more likely after
EEG channel records the potential difference between two electrode arousal from sleep.
positions on the scalp. In referential recordings, the first input in each Epileptiform discharges are more likely to be focal in patients
channel represents the active electrode, while the second input rep- with focal seizures and more likely to be generalized in patients with
resents the reference, which should be ideally neutral but often is not. generalized-onset seizures. The EEG can record generalized absence
In bipolar recordings, each channel represents the difference in poten- seizures, which are reliably precipitated with hyperventilation in the
tial between adjacent electrodes organized in a logical montage. Digital untreated child, and can demonstrate interictal epileptiform dis-
EEG recordings that have become standard allow reformatting of EEG charges that are characteristic of certain syndromes (see Figs. 100.5,
montages and the judicious use of filters to optimally visualize interic- 100.7, 100.9–100.11). For most patients with focal seizures, the local-
tal EEG activity as well as the ictal onset. When the history is consistent ization of epileptiform discharges corresponds to the epileptogenic
Fp1-Ave
Fp2-Ave
F3-Ave
F4-Ave
C3-Ave
C4-Ave
P3-Ave
P4-Ave
O1-Ave
O2-Ave
F7-Ave
F8-Ave
T7-Ave
T8-Ave
P7-Ave
P8-Ave
Fz-Ave
Cz-Ave
Pz-Ave
50 µV
1000 ms
12:22:11 PM Average, 10 secs/screen, 5µV/mm, 70.0 Hz, 1.000 Hz, 60 Hz
Fig. 100.17 Left temporal epileptiform discharges emanating from an abnormal background. Note the asym-
metrical waveform of sharp waves.
zone, but this is not always true. Some patients with seizures arising and in that setting is preferably obtained with and without contrast. If
from one temporal lobe may have bitemporal independent epilepti- it is possible to wait for an MRI, the emergency CT scan can be skipped.
form discharges. Temporal lobe epileptiform discharges may also be In children with new-onset seizures, imaging may require con-
predominant in patients who have epilepsy of frontal, parietal, or scious sedation or general anesthesia. An imaging study is not always
occipital origin. Some patients with generalized-onset seizures may required and may be omitted in children with a confident diagnosis
have focal or multifocal epileptiform discharges in addition to gener- of a genetic epilepsy syndrome such as CAE or BECTS. If there is any
alized discharges. indication for a neuroimaging study, MRI is preferred. Published
Besides its diagnostic role, the EEG can help determine prognosis guidelines recommend elective MRI in the presence of unexplained
after a first seizure. An abnormal EEG has been consistently associ- cognitive or motor impairment or neurological exam abnormality,
ated with an increased risk of seizure recurrence in both children and focal-onset seizure, an EEG not characteristic of a benign focal epilepsy
adults, particularly if the abnormality is epileptiform. In untreated of childhood or IGE, or in children younger than 1 year of age (Hirtz
patients, the risk of seizure recurrence was increased by a factor of 1.54 et al., 2000). Emergency imaging is also recommended in any child
if the EEG was abnormal (Kim et al., 2006). exhibiting a prolonged postictal focal deficit.
The routine EEG has important limitations. It is an indirect assess-
ment because it does not usually record the ictal events for which the Other Testing
patient is seeking evaluation. Some patients may have both epileptic Most patients presenting to the emergency room with their first
and nonepileptic seizures or may have nonepileptic seizures together seizure will have blood studies performed routinely, but the value
with epileptiform EEG abnormalities that reflect a seizure tendency in of such testing is not established. While a small proportion of
the absence of actual seizures. Some patients with focal epilepsy may patients have metabolic abnormalities with the first seizure, most
have generalized EEG abnormalities that reflect an inherited general- abnormalities are not clinically significant. Metabolic blood testing
ized seizure tendency even though they do not have generalized-onset should be guided by specific clinical circumstances based on the
seizures. Because of all these reasons, prolonged EEG-video moni- history and examination. Published guidelines suggested obtaining
toring may be superior for definitive diagnosis of events in question. blood glucose, blood cell counts, and electrolyte panels, particularly
However, prolonged video-EEG monitoring is expensive and there- sodium, in specific clinical circumstances (Krumholz et al., 2007).
fore reserved for patients who have had recurrent attacks with atypical A lumbar puncture is only indicated if there is reason to suspect an
manifestations and a nondiagnostic routine or sleep-deprived EEG. infectious or inflammatory etiology (e.g., if the patient is febrile).
Video-EEG monitoring is also indicated for patients who continue Toxicology screening should similarly be restricted to specific clin-
to have seizures despite adequate treatment, raising the possibility of ical circumstances.
incorrect seizure diagnosis or classification.
Evaluation of Drug-Resistant Seizures and Epilepsy
Neuroimaging When seizures are drug resistant, it is important to reassess the diag-
Neuroimaging is always indicated in adults with new-onset seizures or nosis of epilepsy. Reevaluation of the history may identify features
epilepsy to identify structural causes of epilepsy, some of which may suggestive of a nonepileptic origin of attacks or incorrect classifica-
require treatment of their own (Krumholz et al., 2007). After the first tion of seizures that resulted in an incorrect therapeutic choice. The
unprovoked seizure, imaging in adults has an approximately 10% yield task may be facilitated by having the description of multiple events
of clinically significant findings, leading to the diagnosis of disorders such to assess precipitating factors and variability or consistency of the
as a brain tumor or other structural lesions. Computed tomography (CT) seizure manifestations. The patient should be questioned about
remains the test most likely to be obtained in the emergency room after potentially remediable factors such as alcohol or drug abuse, abuse of
the initial seizure, but CT will often miss temporal lobe pathology because caffeine, the use of concomitant medications that can reduce the sei-
of bone streak artifact. MRI is the imaging modality of choice for iden- zure threshold, sleep deprivation, or poor compliance with prescribed
tifying brain pathology in patients with new-onset seizures or epilepsy, treatment. Most often, additional investigation is needed, particularly
prolonged video-EEG recordings to capture typical events for defin- recording the EEG directly from the brain with implanted electrodes,
itive diagnosis. the ictal onset zone may be missed unless the electrodes were placed
directly over that zone.
Prolonged Electroencephalographic Recordings The irritative zone is the zone that generates interictal epilepti-
Prolonged EEG or video-EEG monitoring increases the probability form discharges. In the most straightforward situation, the irritative
of capturing events. Modalities include short-term video-EEG for 2–8 zone is localized within the epileptogenic zone. However, in some
hours, ambulatory EEG with or without video, and long-term video- cases there may be multiple irritative zones, only one of which corre-
EEG. Short-term monitoring is ideal for individuals whose attacks are sponds to the epileptogenic zone. One of the more common scenar-
very frequent or can be provoked by certain stimuli. It is often very ios is bilateral mesial and lateral temporal irritative zones in a patient
useful for young children who tend to have multiple daily attacks. Its with a unilateral mesial temporal epileptogenic zone. The relation-
advantages include that it can be an outpatient procedure, making it ship between the irritative zone and the epileptogenic zone may be
convenient and less expensive. Ambulatory EEG also has the advantage even more complex. For example, a mesial frontal epileptogenic zone
of being an outpatient procedure, and it allows for patients to be eval- may have a corresponding mesial frontal irritative zone that cannot
uated in their natural environment with its stressors and other seizure be detected by scalp EEG, and bilateral temporal irritative zones that
triggers. Although it can theoretically be performed with concomitant do not generate seizures.
video, video monitoring is not usually part of this procedure, and the The ictal symptomatogenic zone is the region that produces the sei-
exact correlation between EEG and clinical changes is not possible. The zure manifestations. If the epileptogenic zone is in primary sensory or
absence of concomitant video makes it difficult to eliminate artifact motor cortex, the initial seizure manifestations may be related to the
as the source of apparent discharges. Ambulatory EEG is neverthe- function of that cortex; in that situation, the ictal symptomatogenic
less useful to evaluate EEG changes with attacks that occur daily and zone corresponds to the ictal onset zone. However, in many instances,
involve loss of consciousness, since events with loss of consciousness the ictal onset zone is located in silent cortex, and the initial clinical
are expected to produce EEG changes if they are epileptic in nature. manifestations reflect activation of distant nonsilent areas along the
Ambulatory EEG is less useful for evaluation of subjective events or path of seizure propagation. The ictal symptomatogenic zone may be
other events without altered consciousness, which may be FAS. This more valuable for lateralization than exact localization because it is
is because FAS often have subtle or even no associated EEG change. most likely that seizures will spread within the hemisphere of origin
Home video-EEG monitoring allows review of event semiology and before spreading to the contralateral hemisphere. However, this is not
may be appropriate if medication withdrawal is not needed to precip- always the case.
itate events. The epileptogenic lesion is a structural brain abnormality that is
Inpatient video-EEG monitoring may be the most definitive long- presumed to be the cause of the epilepsy and is usually identified
term video-EEG modality, as it allows observation in conjunction with on MRI. The relationship of the epileptogenic lesion to the seizure
ASM withdrawal. This is necessary when attacks are infrequent and par- onset zone is variable. Some lesions such as cortical dysplasia or
tially controlled with medications. The recording can continue for several hypothalamic hamartoma are intrinsically epileptogenic, and sei-
days up to weeks if needed. Withdrawal of ASMs may unmask epilepti- zures may arise from within the lesion. On the other hand, seizures
form EEG abnormalities (true with some ASMs such as benzodiazepines, usually arise from brain-surrounding cavernous malformations
valproate, and levetiracetam) and may also allow greater seizure propa- and benign tumors. In the case of very large lesions, seizures may
gation that can confirm the diagnosis for some seizures of unclear nature. arise from one aspect of the surrounding brain. It is important to
Methods that can be used to help precipitate attacks include hyperven- keep in mind that certain lesions are incidental and not necessarily
tilation, photic stimulation, sleep deprivation, and other precipitants related to the epilepsy. For example, arachnoid cysts and venous
reported by the patient. Inpatient long-term video-EEG monitoring is malformations are often unrelated or indirectly related to the epi-
the best modality for localization of the epileptogenic zone in patients lepsy (through association with cortical malformation) (Arroyo
undergoing evaluation for epilepsy surgery. and Santamaria, 1997; Morioka et al., 2006; Paetau et al., 1992).
Another important factor to keep in mind is that there may be mul-
Evaluation of Patients for Epilepsy Surgery tiple lesions, only one of which is responsible for seizure genera-
Some 35% of patients with focal-onset seizures are resistant to ASM tion. In general, the identification of an epileptogenic lesion greatly
therapy (Kwan and Brodie, 2000a), making them candidates for epi- improves the confidence of congruent electrical localization of the
lepsy surgery. Unless there is a clear contraindication to such surgery, ictal onset and irritative zones. Failure to remove the epileptogenic
these patients typically undergo a presurgical evaluation, the goal of lesion partially or completely is an important cause of surgical fail-
which is to localize the epileptogenic zone. The epileptogenic zone is ure (Cendes et al., 1995; Clarke et al., 1996).
defined as the zone whose resection is necessary and sufficient to elim- The functional deficit zone, responsible for functional deficits, can
inate seizures (Lüders, 2008; Rosenow and Luders, 2001). This zone be measured in a variety of ways including neurological examination,
cannot be directly defined by any test but can be estimated by a num- neuropsychological testing, interictal EEG focal attenuation and slow
ber of other zones. activity, local glucose uptake by PET, or local cerebral blood flow by
The ictal onset zone (also called seizure onset zone or pacemaker interictal PET with [15O]H2O or interictal single-photon emission
zone) is the area of cortex that is generating seizures (Carreño and computed tomography (SPECT). While the functional deficit zone
Lüders, 2008). This zone, if accurately defined, is contained within may include the epileptogenic zone, it is often considerably larger.
the epileptogenic zone but may be smaller than the epileptogenic For example, hypometabolism may involve the whole temporal lobe
zone. Thus it is possible that seizures start in a section of the epi- and even extend beyond the temporal lobe in patients with temporal
leptogenic zone, but other parts of that zone are able to take on the lobe epilepsy and hippocampal sclerosis, in whom the epileptogenic
function of seizure generation once the ictal onset zone is removed. zone may be limited to the hippocampus and parahippocampal gyrus
Identifying and defining the ictal onset zone can be challenging, since (Henry and Roman, 2011).
the earliest detected ictal activity may have already undergone consid- The remainder of this section will discuss individual elements of the
erable spread from where the seizure actually originated. Even when presurgical evaluation.
symptomatogenic zone (Loddenkemper and Kotagal, 2005). For exam-

Neurological History
ple, early head turning in temporal lobe epilepsy tends to be ipsilat-
Identifying specific risk factors in the history can help predict the epi- eral to the seizure focus, and late head turning preceding evolution to
leptogenic lesion. For example, a history of febrile status epilepticus bilateral tonic-clonic activity tends to be contralateral (Fakhoury and
in infancy has a strong correlation with the pathology of hippocam- Abou-Khalil, 1995). Lip smacking and other oroalimentary autom-
pal sclerosis (Cendes et al., 1993). Meningitis and encephalitis occur- atisms are characteristic of temporal lobe involvement. Extremity
ring prior to age 5 are also associated with temporal lobe epilepsy dystonic posturing is a strong contralateral lateralizing sign (Kotagal
and hippocampal sclerosis, whereas the same risk factors occurring et al., 1989). While extremity automatisms are not directly lateraliz-
after age 5 appear to predict neocortical epileptogenic zones (Marks ing in general, manipulative automatisms tend to be ipsilateral to the
et al., 1992; O’Brien et al., 2002). Similarly, earlier head trauma may seizure onset zone when associated with contralateral dystonic postur-
also predict hippocampal sclerosis, though hippocampal sclerosis ing (Dupont et al., 1999). Nonmanipulative automatisms, particularly
may also be seen after head trauma at an older age (Diaz-Arrastia RINCH motions, tend to be contralateral (Kelemen et al., 2010; Kuba
et al., 2000; Marks et al., 1995). The description of the seizure aura et al., 2013; Lee et al., 2006). Unilateral eye blinking tends to be ipsi-
and other early seizure semiology helps with the localization of the lateral to the seizure focus (Benbadis et al., 1996a). Well-formed ictal
ictal symptomatogenic zone. Certain auras such as rising epigastric speech is usually indicative of nondominant temporal lobe involve-
sensation are characteristic of mesial temporal localization, while ment, whereas postictal aphasia suggests dominant temporal lobe
elementary auditory hallucinations at seizure onset favor a lateral involvement (Gabr et al., 1989). Ictal vomiting, ictal spitting, ictal
temporal localization and elementary visual hallucinations favor an drinking, and postictal urinary urgency have all been associated with
occipital localization (Henkel et al., 2002; Palmini and Gloor, 1992). right temporal lobe origin, but exceptions have been reported (Knake
The description of seizure semiology by witnesses is also helpful, et al., 2005; Loddenkemper and Kotagal, 2005). Ictal pouting suggests
particularly for lateralization. However, since the recording of clin- anterior cingulate localization (Souirti et al., 2014).
ical seizures is an important component of presurgical evaluation,
analysis of video-EEG recorded seizure semiology supersedes the Magnetic Resonance Imaging
description provided by witnesses for the purpose of localization and A high-resolution MRI is crucial for definition of the epilepto-
lateralization. genic lesion (see Figs. 100.12 and 100.16). For optimal detection of
mesial temporal sclerosis, the MRI should include oblique coro-
Neurological Examination nal images perpendicular to the axis of the hippocampus, including
The neurological examination can identify focal neurological deficits T1-weighted, T2-weighted, and fluid-attenuated inversion recovery
that help define the functional deficit zone, but the examination is (FLAIR) sequences. These images should ideally have a slice thickness
most often noncontributory. of at most 1.5 mm. Ideally the MRI should also include a sequence
with T1-weighted thin adjacent images for reformatting and surface
Electroencephalographic and Video-Electroencephalographic rendering. The use of surface coils together with 3-tesla MRI can be
Recordings very helpful in the definition of cortical dysplasia (Knake et al., 2005).
EEG/video-EEG is a cornerstone of the presurgical evaluation, contrib- In addition, methods of postprocessing, such as texture or morpho-
uting to the localization of four zones. The interictal focal attenuation metric analysis, can also be very helpful in identifying cortical dys-
and focal slow activity contribute to the definition of the functional plasia (Bernasconi et al., 2001; Wagner et al., 2011). Diffusion tensor
deficit zone; the fields of the interictal epileptiform discharges define imaging helps define white-matter tracts. Asymmetries may help in
the irritative zones; and the electrographic localization of seizure onset lateralization in temporal lobe epilepsy (Ahmadi et al., 2009). Three-
helps define the ictal onset zone. However, it is important to recognize dimensional reconstruction of white-matter tracts, also known as trac-
that what appears to be the initial localization of the ictal discharge may tography, allows visualization of altered connectivity in association with
represent seizure activity propagated from a distant location not directly cortical dysplasia (Colombo et al., 2009). Diffusion-weighted imaging
accessible to EEG electrodes. There is evidence to suggest that for ictal is occasionally useful in localization and lateralization (O’Brien et al.,
EEG activity to be visible on scalp EEG, it should involve at least 10 cm2 2007; Wehner et al., 2007).
of cortex (Tao et al., 2007). Therefore, the initial ictal onset may be visible
Positron Emission Tomography
only after considerable seizure spread. The use of additional electrodes
beyond the International 10–20 electrode placement can be useful. This PET imaging uses positron-emitting isotopes to image metabolism,
includes additional closely spaced electrodes in the 10-10 system, or perfusion, synthesis of neurotransmitters, and receptor density.
electrodes outside of the 10-10 system, such as true anterior temporal The synthesis of positron-emitting ligands requires a cyclotron on
electrodes, sphenoidal electrodes, zygomatic electrodes, or cheek elec- site. As a result, PET availability has been relatively limited to major
trodes. The International Federation of Clinical Neurophysiology has academic centers. At present, the most commonly used ligand is
18F-fluorodeoxyglucose (FDG), which allows the imaging of glu-
recommended the standard addition of six inferior temporal electrodes
to the 10–20 electrode placement to improve detection of epileptiform cose uptake/metabolism in the brain. FDG-PET is almost always an
activity (Seeck et al., 2017). While clinical scalp EEG is two-dimen- interictal study; ictal PET is usually fortuitous and difficult to plan.
sional, three-dimensional localization of interictal and ictal EEG signals FDG-PET contributes to the definition of the functional deficit zone.
is possible with electrical source imaging. This technique’s precision is Approximately 80% of patients have a discrete region of hypometab-
enhanced with higher-density EEG using at least 64 electrodes from the olism that has a good correlation with the side of the epileptic focus
10-10 system. Source imaging is used more often with MEG, discussed in temporal lobe epilepsy (Abou-Khalil et al., 1987). The region of
later in this chapter. For patients in whom the ictal onset zone cannot PET hypometabolism is usually larger than the epileptogenic zone (see
be properly defined by scalp EEG, it may be necessary to implant intra- Fig. 100.13). PET hypometabolism has a greater correlation with the
cranial electrodes, discussed later in this section. ictal onset zone than scalp EEG-defined ictal onset (Engel et al., 1982).
The analysis of seizure semiology by video-EEG provides sev- FDG-PET is particularly useful in patients without MRI abnormali-
eral localizing and lateralizing signs that help define the ictal ties. The identification of temporal hypometabolism corresponding
to well-localized electrographic ictal onset and interictal epileptiform is the inverse square of the distance from the source. MEG does not
activity on EEG may permit sufficient confidence to proceed with epi- detect pure hippocampal spikes but can detect propagated spikes, and
lepsy surgery without invasive monitoring (Carne et al., 2004). FDG- the dipole orientation is then helpful to distinguish mesial from lat-
PET can be misleading in some patients with extratemporal epilepsy, eral sources (Knowlton and Shih, 2004). MEG appears slightly more
showing temporal hypometabolic zones (Radtke et al., 1994). As with sensitive for convexity neocortical sources than EEG, detecting sources
other diagnostic techniques, FDG-PET cannot be used in isolation. involving 3–4 cm2 of cortex as opposed to 6 cm2 of cortex for the EEG.
PET using flumazenil images central benzodiazepine receptor den- The latest-generation MEG machines typically contain 300 or more
sity. Zones of decreased benzodiazepine receptor density are smaller sensors covering most of the head and allowing accurate estimation of
than, and encompassed in, areas of hypometabolism by FDG-PET. the magnetic source dipole origin.
They have a greater specificity for the ictal onset zone (Burdette By using fiducial markers, structural MRI, and core registration,
et al., 1995; Savic et al., 1993). In addition, flumazenil PET may iden- the magnetic source can be displayed on the structural MRI, which has
tify heterotopic neurons not visible on MRI (Hammers et al., 2005). been referred to as magnetic source imaging (Knowlton and Shih, 2004;
PET scanning using 11C-α-methyl-l-tryptophan (AMT) images sero- Stefan et al., 2011). Magnetic source imaging can be applied to spon-
tonin synthesis and is helpful in identifying the epileptogenic tuber in taneous magnetic activity as well as to event-related magnetic fields.
patients with tuberous sclerosis and multiple tubers (Chugani et al., MEG is used mostly for evaluation of interictal epileptiform activity
1998; Fedi et al., 2003). The epileptogenic tuber usually has increased and thus helps define the irritative zone. While EEG is best at record-
serotonin synthesis. This PET modality has also been found useful in ing epileptiform discharges with a vertical dipole (perpendicular to the
cortical dysplasia (Chugani et al., 2011; Juhasz et al., 2003). gyral surface), MEG best records horizontal dipoles parallel to the sur-
face, so MEG and EEG are complementary in this regard. Availability
Single-Photon Emission Computed Tomography of MEG remains limited to major academic centers.
SPECT uses a gamma-emitting tracer to image regional cerebral blood MEG is also very useful for localization of cortical functions prior
flow. The technique is widely available and is less expensive than PET. to epilepsy surgery, through the recording and localization of event-
Interictally, regions of reduced metabolism also tend to have reduced related fields. MEG has been used effectively for localization of sensory
blood flow, but interictal SPECT is less sensitive than interictal FDG- and language functions (Abou-Khalil, 2007; Papanicolaou et al., 2004).
PET and therefore is not widely used. The main benefit of SPECT is There is evidence to also suggest that it may be able to lateralize mem-
ictal imaging. When the ligand is injected intravenously (IV) at the very ory functions (Ver Hoef et al., 2008).
onset of seizures, greater uptake is noted in the ictal onset zone (Fig.
100.18). However, if the injection is late, the focal hyperperfusion may Functional Magnetic Resonance Imaging
represent seizure propagation. The value of ictal SPECT is enhanced by Local cerebral activation produces a local increase in glucose metab-
subtraction and co-registration with MRI (SISCOM) (O’Brien et al., olism, cerebral blood flow, and cerebral metabolic rate for oxygen.
1998, 2000; Van Paesschen et al., 2007). SISCOM is particularly valu- The cerebral blood flow increase tends to surpass the increase in cere-
able in extratemporal epilepsy and in patients who have had persistent bral metabolic rate for oxygen so that cerebral activation results in an
seizures after epilepsy surgery (Wetjen et al., 2006; see Fig. 100.18). increase in the capillary and venous oxygenation level and a relative
reduction in deoxyhemoglobin. Deoxyhemoglobin is paramagnetic,
Magnetic Resonance Spectroscopy so an increase in oxygenation produces an increase in magnetic sig-
Magnetic resonance spectroscopy (MRS) provides quantitative histo- nal. Blood oxygenation level-dependent (BOLD) contrast is the basis
chemical information, applied mostly to the hydrogen atom and, to a of fMRI; fMRI has been used predominantly for localization of corti-
lesser extent, phosphorus. The most commonly measured substances cal functions that have to be spared in epilepsy surgery. It can effec-
are N-acetyl aspartate (NAA), which is localized in neurons and tively localize motor and sensory cortex as well as language cortex
decreased with neuronal injury, and creatine and choline, which are (Chakraborty and McEvoy, 2008; Janecek et al., 2013). There is also
increased with gliosis and increased membrane turnover. The NAA- increasing evidence that it can localize memory functions (Binder
to-creatine ratio is highly sensitive in detecting mesial temporal struc- et al., 2010).
tural and functional abnormalities. The ratio is decreased in abnormal The use of fMRI for epilepsy localization is more experimental at
regions. When data are acquired in parallel from a large number of this point. It usually requires concomitant EEG recording during fMRI
voxels, the voxels that are statistically abnormal can be color coded, acquisition (Gotman et al., 2006; Zijlmans et al., 2007). Interictal epi-
generating a map of abnormal areas. In patients with MTLE, there are leptiform discharges are associated with a hemodynamic change that
decrements in the NAA/creatine ratio that extend along the majority usually has a latency of several seconds. The hemodynamic change
of the hippocampal formation and are more pronounced anteriorly can reflect activation, deactivation, or both. Defining the regions of
(Hetherington et al., 2004). The contralateral hippocampus is involved the brain with hemodynamic changes in response to interictal epilep-
to a lesser degree, so asymmetries are useful in lateralization of MTLE. tiform discharges helps define the irritative zone. The most significant
The NAA/creatine ratio appears to have a large functional component. hemodynamic response was recently found to correspond to the sei-
The ratio improves contralaterally with successful epilepsy surgery zure onset zone in most patients (Khoo et al., 2017). However, only
(Kuzniecky et al., 2001). MRS can also be used to measure other com- patients with frequent epileptiform discharges can be studied with
pounds such as lactate and GABA (Petroff et al., 2001). EEG-fMRI.
Magnetoencephalography Neuropsychological Testing

Electric currents which produce voltages on the scalp that serve as the Neuropsychological testing helps in the definition of the functional
basis for EEG also produce magnetic fields that can be measured with deficit zone. The battery of tests evaluates cortical functions of left and
MEG. Just like EEG, MEG can track magnetic brain activity in real right temporal, frontal, parietal, and occipital lobes. Some tests also
time. It has an advantage over EEG in that magnetic signals are not help identify mesial versus lateral temporal dysfunction. Localizing
distorted by differences in conductivity between the brain, skull, and information helps to support other tests in the presurgical evalua-
scalp. However, MEG has similar signal drop-off with distance, which tion. Neuropsychological testing can also help predict postoperative
Fig. 100.18 Ictal single-photon emission computed tomography (SPECT) (top left and middle), magnetic
resonance imaging (MRI) (bottom), and subtracted ictal SPECT co-registered to MRI (SISCOM) (top right) in
patient with drug-resistant seizures persisting after right temporal lobectomy. The two coronal ictal SPECT
images demonstrate right orbitofrontal hyperperfusion (arrows) corresponding to a region of subtle increased
T2 signal, thickened cortex, and blurred gray/white junction on MRI (arrows). MRI images from left to right
are coronal fluid-attenuated inversion recovery (FLAIR), coronal T1, and axial T2 images. Surgical pathology
was cortical dysplasia with balloon cells. SISCOM demonstrates hyperperfusion corresponding to the orbi-
tofrontal pathology.
deficits, particularly when the planned resection will remove function- • B itemporal ictal onsets or bitemporal frequent epileptiform activ-
ing cortex. ity.
• An epileptogenic zone that overlaps with functional cortex.
Wada Test • Extratemporal or neocortical nonlesional epilepsy.
The Wada test involves intracarotid injection of anesthetic, usually • Ill-defined epileptogenic zone or incongruent data. It is generally
amobarbital, to examine language and memory functions in the essential to have a hypothesis for the location of the epileptogenic
contralateral hemisphere. The Wada test was initially designed to zone in one or two regions prior to invasive recording.
lateralize language function, but its use was later expanded to exam- Different types of electrodes can be used for different indications for
ine memory lateralization and assess the risk of memory loss after invasive EEG. Subdural grid electrodes are useful for better localization
temporal lobe surgery. It is also useful for defining the functional of a well-lateralized epileptogenic zone and for mapping of functional
deficit zone in the mesial temporal region. For example, if a patient cortex with electrical stimulation in order to preserve it at the time of
fails memory testing after injection of the left hemisphere but passes surgery. Depth electrodes are useful for lateralization of ictal onset in
memory testing after injection of the right hemisphere, this suggests a patient with apparent bilateral mesial temporal foci, or for recording
that the right mesial temporal structures are functionally inadequate from relatively inaccessible regions, such as the insula, depth of sulci, or
to support memory. Because the Wada test is invasive, there have heterotopias. Subdural or epidural strip electrodes are useful for bilat-
been many efforts to replace it (Abou-Khalil, 2007); fMRI and MEG eral coverage or for sampling large areas without craniotomy. Foramen
can reliably identify the hemisphere dominant for language functions ovale electrodes, inserted through the foramen ovale to record from
and can obviate the need for Wada test when memory testing is not mesial temporal cortex, are useful for lateralization of the epileptogenic
necessary. zone in patients with apparent bilateral mesial temporal foci. Epidural
peg electrodes are inserted into an opening in the skull, outside the
Invasive Electroencephalographic Recordings dura. Their use eliminates muscle artifact. They can be used to sample
Surgery may proceed without invasive testing if presurgical results electrical activity from large superficial cortical regions.
are congruous, if there is a structural or clear functional lesion corre- Subdural electrodes allow mapping of cortical functions with elec-
sponding to consistent electrical localization, and if there is no definite trical stimulation if there is a possibility that surgery may put these
risk to eloquent cortex. Indications for invasive EEG include: functions at risk. Stimulation of primary motor or primary sensory
• An epileptogenic zone that is well lateralized but not well localized; cortex typically produces positive responses, whereas stimulation of
for example, unclear whether frontal or temporal, anterior tempo- association cortex produces disruption of function if the patient is
ral or posterior temporal, or mesial or lateral temporal. engaged in a task that requires the function of that cortex. Localization
of language cortex requires the patient to be involved in language discussion of epidemiology of the first unprovoked seizure) (Krumholz
activities during electrical stimulation. Depth electrodes implanted et al., 2015). Delay in initiation of therapy until after the second unpro-
stereotactically have become the dominant method of invasive EEG voked seizure does not affect the odds of subsequent long-term remis-
recording due to greater tolerability, lower complication rate, and sion. Rarely, some mild forms of epilepsy may not require therapy.
superior flexibility (Mullin et al., 2016; Schmidt et al., 2016). For example, in BECTS, seizures may be infrequent, occur in sleep,
and remit at puberty. In some patients with JME, seizures are clearly
linked to sleep deprivation or binge alcohol consumption, and may be
MEDICAL THERAPY managed with lifestyle adjustments only, especially when myoclonic
Medical therapy is generally the first-line treatment after the diagno- seizures are the only seizure type. In the vast majority of individuals,
sis of epilepsy has been made (Fig. 100.19). Its goal should be com- however, medical therapy is necessary.
plete seizure freedom in the absence of medication side effects. Since
the choice of therapy depends on seizure and epilepsy classification, Initiating Therapy
ideally there should be enough evidence to diagnose the seizure type The many ASMs available for prescription include classical ASMs that
and the epilepsy syndrome prior to deciding on initial therapy. The were marketed before 1980 and many new ASMs that have been mar-
treating physician must have a low threshold for reevaluating the keted since 1993. Knowledge of their pharmacokinetic properties is
diagnosis when therapy fails, particularly when the diagnosis of epi- essential for safe and effective use (Table 100.2). Choice of the first ASM
lepsy is based on history alone without supportive EEG or imaging depends primarily on the classification of seizure type and epilepsy syn-
data. drome (Table 100.3) but should also take into consideration factors such
Pharmacotherapy is not always necessary after a single unprovoked as age, gender, comorbid conditions, and individual circumstances. The
seizure, particularly when the risk of recurrence appears low, based ASM choice should consider the ASM’s spectrum of efficacy, its specific
on known predictors (e.g., with a normal EEG and MRI; see earlier pharmacological properties in relation to the patient’s specific needs, its
Epilepsy diagnosis
First monotherapy
Second monotherapy or
adjunctive therapy
Refer to epilepsy center

Reassess diagnosis; video-EEG Not epilepsy
monitoring Revise therapy
Structural
Consider/evaluate for epilepsy
Nonstructural with Yes, proceed with
surgery for TLE with
generalized onset seizures presurgical evaluation,
hippocampal sclerosis or focal
then epilepsy surgery
epilepsy with well-defined and
resectable epileptogenic lesion
Revise ASM therapy

Continue trials of medical No Dietary therapy may be
therapy: additional one to Continue trials of medical considered sooner in
five ASM regimens therapy: additional one to five motivated individuals or
ASM regimens those that are tube-fed
Consider VNS, dietary In event of persistent ASM

therapy, neurostimulation, failure (whether due to lack of
Good candidate—
corpus callosotomy efficacy or poor tolerability), re-
proceed with epilepsy
evaluate for epilepsy surgery,
surgery
including invasive EEG-video
monitoring if appropriate
Not a surgical candidate

Consider VNS, dietary therapy,
neurostimulation, palliative
epilepsy surgery
Fig. 100.19 Treatment Algorithm for Epilepsy. Additional steps assume that seizures are not controlled
despite adequate trial of well-tolerated medication. AED, Antiepileptic drug; EEG, electroencephalographic;
TLE, temporal lobe epilepsy; VNS, vagus nerve stimulation.
safety profile in the patient’s age and gender group, as well as its efficacy and eslicarbazepine acetate have clinical trial evidence supporting their
in the patient’s comorbid conditions. Whenever possible, these determi- use as initial monotherapy (Kanner et al., 2018a). A large community-
nations should be based on solid evidence derived from well-designed based study found that lamotrigine was significantly better than carba-
studies. The ASMs with FDA-approved indications outside of epilepsy mazepine, gabapentin, and topiramate and had a nonsignificant advan-
include clonazepam (panic attacks); carbamazepine (trigeminal neural- tage compared to oxcarbazepine with respect to time to treatment failure
gia, bipolar disorder); valproate (migraine prophylaxis, acute treatment, (Marson et al., 2007a). However, lamotrigine requires slow titration and
and maintenance for mania/bipolar disorder); gabapentin (postherpetic would not be an appropriate first choice when a rapid onset of action is
neuralgia); lamotrigine (maintenance for bipolar disorder); topiramate needed. When rapid therapeutic effect is required, oxcarbazepine and
(migraine prophylaxis); and pregabalin (diabetic peripheral neuropathy, levetiracetam may be the drugs of choice because they can be started at
postherpetic neuralgia, fibromyalgia). However, several ASMs are used an effective dose. Topiramate also requires slow titration. Because of its
off-label for a variety of nonepilepsy indications ranging from insom- cognitive adverse effects, it is not generally the first drug of choice unless
nia to restless legs syndrome and essential tremor, based on trial data or comorbidities (e.g., migraine, obesity) favor its use.
anecdotal evidence (Azar and Abou-Khalil, 2008). For generalized-onset seizures, the initial ASM is dependent on the
For focal-onset seizures, carbamazepine or phenytoin may be used seizure type(s). For pure generalized absence seizures, ethosuximide
first, but newer drugs have clear pharmacokinetic advantages, particu- is the first drug of choice, based on a comparative trial with valproate
larly absence of enzyme induction (French et al., 2004). Oxcarbazepine and lamotrigine, in which it had the best balance of efficacy and toler-
and topiramate were the only ones with official FDA indications, until ability (Glauser et al., 2010). Valproate was equally effective and may
2016 when the FDA allowed a drug’s efficacy as adjunctive therapy in be the best choice if there are concomitant GTC seizures or generalized
adults to be extrapolated to efficacy in monotherapy (Abou-Khalil, myoclonic seizures because ethosuximide efficacy is limited to gen-
2019). Lamotrigine, gabapentin, levetiracetam, zonisamide, lacosamide, eralized absence seizures. For IGE with GTC seizures, valproate was
TABLE 100.2 Antiepileptic Drug Absorption, Elimination Half-Life, Formulations (Displayed in

Order They Were Marketed in the United States)
Oral Bioavailability Half-Life (Hours)*
High: ≥90% Short: ≤10

Antiseizure Intermediate: ≥70–<90% Intermediate: >10–<30 Intravenous Extended-Release Requires Slow
Medication Low: <70% Long: ≥30 Formulation Oral Formulation Titration
Phenobarbital High Long X
Primidone High Intermediate X
Phenytoin High Intermediate X† X
Methsuximide‡ High Long
Ethosuximide High Long
Clonazepam High Long
Carbamazepine Intermediate Intermediate X X
Valproate High Intermediate X X
Felbamate High Intermediate
Gabapentin Low§ Short
Lamotrigine High Intermediate X X
Topiramate Intermediate Intermediate X X
Tiagabine High Short X
Levetiracetam High Short X X
Oxcarbazepine‡ High Intermediate X
Zonisamide High Long
Pregabalin High Short
Lacosamide High Intermediate X
Rufinamide Intermediate Short X
Vigabatrin High Short¶
Ezogabine/retigabine Low Short X
Clobazam High Long
Perampanel High Long
Eslicarbazepine High Intermediate
Brivaracetam High Short X
Cannabidiol Low Long +
Cenobamate Intermediate Long X
*The t1/2 for antiseizure medication (ASM) given as monotherapy in a young adult.
†Parenteral formulation is also available as fosphenytoin, a phenytoin prodrug that can be administered intramuscularly.
‡Applies to active metabolites (N-desmethyl methsuximide for methsuximide, monohydroxy derivative [MHD] for oxcarbazepine).
§Gabapentin bioavailability decreases with increasing dose, ranging from ≈60% after a single 300 mg dose to ≈30% at 4800 mg/day given in three
divided doses.
¶The duration of ASM effect is much longer than expected for the short t .
1/2
TABLE 100.3 Established Efficacy of Antiseizure Medications by Seizure Type (FDA Indications
and Class I–III Evidence)
Fda-Approved Indications
Other
Monotherapy Versus Noteworthy
Adjunctive Therapy Efficacy
Indication* Seizure Type or Syndrome Indication Evidence
Antiseizure Generalized Therapy and

Medication Monotherapy Adjunctive Focal Tonic-Clonic Absence Myoclonic LGS IS Seizure Type
Phenobarbital X X X
Primidone X X X
Phenytoin X X X X
Methsuximide X X X Two class IV trials
supporting efficacy
for focal-onset
seizures
Ethosuximide X X X
Clonazepam X X X† X
Carbamaze- X X X
pine
Valproate X‡ X X X‡ X X‡ Initial monotherapy
for generalized
tonic-clonic and
myoclonic seizures
Felbamate Conversion to X X X‖ X‖
monotherapy§
Gabapentin X X Initial monotherapy
for focal seizures
Lamotrigine Conversion to X X X X‖ Initial monother-
monotherapy§ apy for absence
seizures
Topiramate X X X X X‖
Tiagabine X X
Levetiracetam X X X X Initial monotherapy
for focal seizures
Oxcarbazepine X X X
Zonisamide X X Initial monotherapy
for focal seizures
Pregabalin X X
Lacosamide X X X
Rufinamide X X‖
Vigabatrin X¶ X X X¶
Ezogabine/ X X
retigabine
Clobazam X X
Perampanel X X X X Efficacy against
myoclonic seizures
Eslicarbaze- X X X
pine
Brivaracetam X X X
Cannabidiol X X (also DS)
Cenobamate X X X
DS, Dravet syndrome; FDA, US Food and Drug Administration; IS, infantile spasms; LGS, Lennox-Gastaut syndrome.
*The FDA indications for older antiseizure medications (ASMs) (first 7 rows) are less specific with respect to monotherapy versus adjunctive indication,
and even with respect to seizure type. Official labeling may not specify monotherapy versus adjunctive therapy for older ASMs marketed prior to 1993.
†For patients who have failed ethosuximide.
‡The official FDA indication is initial monotherapy for absence or partial seizures and adjunctive therapy “in patients with multiple seizure types that
include absence seizures.” Valproate is widely considered a monotherapy drug of choice in patients with idiopathic generalized epilepsy with tonic-
clonic or myoclonic seizures.
§For partial-onset seizures only.
‖Adjunctive in LGS.
¶Monotherapy only for infantile spasm.
significantly better than both lamotrigine and topiramate for time to The neurologist will often need to reduce the dose of the initial ASM
treatment failure (Marson et al., 2007b) and may be the first drug of when adding a second ASM with a similar mechanism of action. A
choice for men, in the absence of prohibitive comorbidities. However, better understanding of the epilepsy pathophysiology in individ-
valproate is teratogenic, with dose-related increased risk of major con- ual patients may improve the selection of ASMs in the future, with a
genital malformation, permanent cognitive impairment, and increased greater role for mechanism of action.
risk of autism in the exposed fetus. A different ASM should be used There are limited examples of epilepsy genetics predicting ASM
first in women with IGE, but valproate may be used at a low dose if efficacy. Autosomal dominant nocturnal frontal lobe epilepsy is par-
other ASMs fail to control seizures (Montouris and Abou-Khalil, ticularly responsive to carbamazepine and its analog, oxcarbazepine
2009). While no ASM has official FDA initial monotherapy indica- (Picard et al., 1999; Raju et al., 2007). Dravet syndrome, which is usu-
tion for generalized myoclonic seizures, valproate is clearly effective, ally caused by a sodium channel mutation, may have seizure aggrava-
and levetiracetam, which has FDA approval as adjunctive therapy for tion with the use of agents acting on the sodium channel, particularly
generalized myoclonic seizures (Noachtar et al., 2008), may also be lamotrigine (Guerrini et al., 1998).
effective in monotherapy. Weaker evidence exists for efficacy of topi-
ramate, zonisamide, and lamotrigine (lamotrigine may even aggravate Antiseizure Medication Considerations Based on Age
myoclonic seizures in some individuals) (Biton and Bourgeois, 2005; and Gender
Crespel et al., 2005; Genton et al., 2006; Prasad et al., 2003). The newest Age and gender may have an influence on ASM selection (Azar
drugs perampanel and brivaracetam also have anecdotal evidence of and Abou-Khalil, 2008). In the pediatric age group, specific epi-
efficacy. lepsy syndromes have implications for ASM efficacy. Tolerability
For all epilepsy indications, treatment is initiated with an ASM profiles may also be different for children and adults, which may
monotherapy. In the absence of urgency, it is preferable to start at a low influence the risk/benefit ratio for specific agents. Serious rashes
dose and titrate slowly, even for ASMs that can be started at a higher from lamotrigine, behavioral adverse effects from levetiracetam,
effective dose. The initial target dose is often the minimal effective dose and oligohidrosis from topiramate and zonisamide are more likely
that has been demonstrated in clinical trials, keeping in mind that the in children, while hyponatremia from oxcarbazepine and aplastic
pivotal clinical trials may have underestimated or overestimated that anemia from felbamate are much less likely. Valproate-induced
dose in some instances. If the initial target dose is not sufficient, the liver failure is more likely in children younger than 2 years of age.
ASM dose can then be titrated gradually until efficacy is established. In women of childbearing potential, certain ASMs may reduce the
For patients with infrequent seizures, it may take a long time to deter- efficacy of oral contraception, and valproate is to be avoided for
mine when an effective dose has been reached. Therefore it is wise for two important reasons: higher risk of congenital malformations
the initial target dose to be an average rather than a minimum effective in the exposed fetus and increased risk of polycystic ovaries and
dose. Before a medication can be considered ineffective, it usually has hyperandrogenism (Lofgren et al., 2007).
to be titrated to the highest tolerated dose. If a medication fails due to In the elderly, a key consideration is interaction with other medi-
lack of efficacy, the neurologist may choose either replacement mono- cations, which favors newer nonenzyme-inducing ASMs (Arain et al.,
therapy or adjunctive therapy with another medication. The available 2009). Some ASM adverse effects are more likely in the elderly—for
evidence is that the two options do not differ significantly in either example, reversible parkinsonism and cognitive impairment from val-
efficacy or tolerability (Beghi et al., 2003; Kwan and Brodie, 2000b). If proate (Armon et al., 1996) and hyponatremia from oxcarbazepine,
the initial therapy has been completely ineffective, then replacement particularly when combined with diuretics or other agents that may
monotherapy is the best choice. If the initial therapy was partially effec- lower sodium (Dong et al., 2005). Several trials have examined the com-
tive, adjunctive therapy may be a consideration. If medication failure is parative efficacy and tolerability of ASMs in the elderly. Lamotrigine
due to lack of tolerability, then replacement monotherapy is the clearly and gabapentin were better tolerated than immediate-release carba-
preferable option. Replacement monotherapy usually requires initially mazepine in new-onset geriatric epilepsy (Brodie et al., 1999; Rowan
adding the new ASM before withdrawing the old agent. However, et al., 2005), but no difference was found between lamotrigine and
overnight switch is possible for some ASMs such as carbamazepine and extended-release carbamazepine (Saetre et al., 2007).
oxcarbazepine (Albani et al., 2004).
Adjunctive therapy should take into consideration any possible phar- Pharmacoresistance, Tolerance, and Seizure Aggrava-
macodynamic or pharmacokinetic interactions between the medications tion
in question (Table 100.4). Ideally, the added medication should not have Persistence of seizures despite ASM therapy should always prompt
adverse pharmacokinetic or pharmacodynamic interactions (Abou- reevaluation of the diagnosis; one of the most common causes of
Khalil, 2017). All ASMs are appropriate for adjunctive therapy (Kanner apparent drug resistance is misdiagnosis of nonepileptic psycho-
et al., 2018b). Some ASM combinations have a suggestion of synergy. genic seizures. Other causes of apparent pharmacoresistance include
For example, the lamotrigine and valproate combination seems to have breakthrough seizures related to noncompliance, sleep deprivation
greater efficacy than what would be predicted by the efficacy of each (particularly in IGE), alcohol or drug abuse, and co-medications that
ASM alone (Brodie and Yuen, 1997). There is also evidence favoring the reduce the seizure threshold. In addition, seizures may appear resistant
combination of lamotrigine and levetiracetam (Kinirons et al., 2006). because of incorrect ASM selection or inadequate ASM use.
At present, the ASM mechanism of action (Table 100.5) is not cru- Approximately a third of individuals with epilepsy will not become
cial for initial ASM selection (Guimaraes and Ribeiro, 2010), but there seizure free at follow-up despite adequate ASM therapy (Chen et al.,
is a suggestion that combining two ASMs with different mechanisms 2018; Kwan and Brodie, 2000a). However, the definition of the exact
may have a greater chance of efficacy than combining two ASMs with time point when epilepsy is considered drug resistant has not been
the same mechanism (Brodie and Sills, 2011; Margolis et al., 2014). agreed upon. An ILAE task force recommended the definition of
Mechanism of action may be a predictor of adverse effects from phar- drug-resistant epilepsy as “failure of adequate trials of two tolerated,
macodynamic interactions. For example, dizziness, ataxia, and diplo- appropriately chosen and used antiepileptic drug schedules (whether
pia are more likely when combining lacosamide with another agent as monotherapies or in combination) to achieve sustained seizure free-
that acts on the sodium channel (Novy et al., 2011; Sake et al., 2010). dom” (Kwan et al., 2010).
TABLE 100.4 Hepatic Metabolism, Enzyme Induction/Inhibition, Pharmacokinetic Interactions,

and Protein Binding
Hepatic Affected Affected
Hepatic Hepatic Enzyme Enzyme by Enzyme by Enzyme Protein
Metabolism Induction Autoinduction Inhibition Inducers Inhibitors Binding
High: >90% +Minimal

Intermediate: ++Intermediate
Antiseizure ≥50% to ≤90% +++Pronounced +Affected High: ≥85%
Medication Low: <50% −Absent −Not Affected Low: <85%
Phenobarbital Intermediate +++ − − + + Low
Primidone Intermediate +++ − − + + Low
Phenytoin High +++ − − + + High
Methsuximide Low + − − + − Low
Ethosuximide Intermediate − − − + − Low
Clonazepam Intermediate − − − − − High
Carbamazepine High +++ +++ − + + Low
Valproate High − − +++ + + High
Felbamate Intermediate + − ++ + + Low
Gabapentin None − − − − − None
Lamotrigine High + + − + + None
Topiramate Low +* − +* + − Low
Tiagabine High − − − + − High
Levetiracetam None − − − ± − Low
Oxcarbazepine High ++† − +† + + Low
Zonisamide Intermediate − − − + + Low
Pregabalin None − − − − − None
Lacosamide Low − − − + − Low
Rufinamide High + − + + + Low
Vigabatrin None + − − − − None
Ezogabine/reti- Intermediate − − − + − Low
gabine
Clobazam High + − + + + Low
Perampanel High + − − + − High
Eslicarbazepine High + − + + − Low
Brivaracetam High − − − + − Low
Cannabidiol High − − + + + High
Cenobamate High + − ++ + − Low
*Applies to dose ≥200 mg.
†Applies to dose ≥900 mg.
Drug resistance may be related to the underlying epilepsy pathol- seizure free if the first ASM was ineffective, while 41%–55% became
ogy. Idiopathic epilepsy is less likely to be drug resistant than symp- seizure free if the first ASM was not tolerated owing to side effects or
tomatic epilepsy (Berg et al., 2001b). In one large study, 82% of idiosyncratic reaction (Kwan and Brodie, 2000a). In a follow-up report
patients with generalized idiopathic epilepsy were seizure free for the of 1795 patients, the 1-year seizure-free rate was 50.5% on the first
past year as compared with only 35% of symptomatic focal epilepsy, drug regimen, 11.6% on the second regimen, and 4.4% on the third
25% of patients with cerebral dysgenesis, 11% of patients with tempo- regimen (Chen et al., 2018).
ral lobe epilepsy due to mesial temporal sclerosis, and 3% of patients Other studies have suggested that continued ASM trials have a
with dual pathology (Semah et al., 1998). Initial seizure frequency was greater chance of achieving remission than suggested by the study
also a predictor (Berg et al., 2001a). In one study, drug resistance was of Kwan and Brodie. In one study of continued ASM trials in drug-
seen in 51% of individuals who had more than 20 seizures before start- resistant epilepsy, 14% achieved a 6-month terminal seizure remission
ing treatment, versus 29% of those who had fewer than 20 seizures after 3 years of follow-up with medication therapy only (Callaghan
(Kwan and Brodie, 2000a). Other predictors of drug resistance were et al., 2007). In a separate study, about 16% of all drug introductions
history of acute symptomatic or neonatal status epilepticus and focal resulted in seizure freedom for more than 12 months, and 28% of
EEG slow activity. Age at onset between 5 and 9 years predicted a lower patients were rendered seizure free by a drug introduction over 5 years
risk of resistance (Berg et al., 2001a). of follow-up (Luciano and Shorvon, 2007). Negative clinical predictors
Resistance to the first ASM predicts resistance to the next ASM. In in these studies included history of status epilepticus, younger age at
the landmark study of Kwan and Brodie, 47% of patients with newly intractability, greater number of failed drug therapies, and presence
treated epilepsy became seizure free with the first ASM monotherapy, of intellectual disability. Shorter-duration epilepsy and idiopathic epi-
13% with the second ASM monotherapy, and 1% with the third ASM lepsy were favorable predictors. Failure of ASM therapy suggests the
monotherapy. Among patients who failed the first ASM, 11% became need to consider alternative therapies discussed later in this chapter.
TABLE 100.5 Key Known Antiseizure Medication Mechanisms of Action

High- α2δ-Subunit
Voltage of Voltage-
Activated Activated
Antiseizure Sodium Potassium Enhancing Glutamate Calcium T-Calcium Calcium
Medication Channels Channel GABA Receptor Channels Channels Channels SV2A Comment
Phenobarbital X X X
Primidone X X
Phenytoin X
Methsuximide ? X
Ethosuximide X
Clonazepam X
Carbamazepine X
Valproate X X X
Felbamate X X X X NMDA receptor
antagonism
Gabapentin X
Lamotrigine X X
Topiramate X X X Kainate and AMPA
receptor antag-
onism
Tiagabine X Inhibition of GABA
reuptake
Levetiracetam X
Oxcarbazepine X
Zonisamide X X
Pregabalin X
Lacosamide X Selective enhancing
of slow inactiva-
tion of voltage-
gated sodium
channels
Rufinamide X
Vigabatrin X Irreversible inhi-
bition of GABA
transaminase
Ezogabine/reti- X Enhancing of
gabine transmembrane
potassium
currents
Clobazam X
Perampanel X Noncompetitive
antagonism of
AMPA glutamate
receptors
Eslicarbazepine X
Brivaracetam X
Cannabidiol X Also modulates
intracellular
calcium
Cenobamate X X
AMPA, α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; GABA, γ-aminobutyric acid; NMDA, N-methyl-d-aspartate; SV2A, synaptic vesicle
protein 2A.
Drug resistance does not always manifest early in the course of epi- for at least 1 year at the last clinic visit. Upon reviewing the course
lepsy. It may develop after a variable latency, may be overcome with of seizure control, 37% achieved early and sustained seizure freedom,
the use of a new ASM, and may be punctuated by periods of drug 22% had sustained seizure freedom after a delay, 16% had a pattern of
responsiveness, particularly with the use of new ASMs (Schmidt and alternating seizure freedom and relapse, while 25% never attained sei-
Loscher, 2005a). In the follow-up study by Brodie and colleagues of zure freedom (Brodie et al., 2012). In one group of patients evaluated
1098 patients with newly diagnosed epilepsy, 68% were seizure free for resective epilepsy surgery, the mean latency to failure of the second
ASM was 9.1 years (range, 0–48), and 26% of patients reported at least Long-term adverse effects of ASMs are often overlooked but could
1 year of seizure freedom after the second unprovoked seizure (Berg be more concerning because they are difficult to reverse or at times
et al., 2003). are irreversible. Common examples include weight gain seen with
Pharmacoresistance may have more than one mechanism. One valproate and pregabalin, and weight loss noted with topiramate
proposed mechanism is that ASMs do not reach the epileptogenic and zonisamide. Barbiturate chronic use may be associated with fro-
zone in sufficient concentration because of multidrug transporters zen shoulder and Dupuytren contractures. One of the more recently
that transport ASMs out of neurons. A number of findings support appreciated chronic adverse effects of ASMs is reduction in bone min-
this hypothesis indirectly, but there is no direct evidence of cau- eral density. This is most likely to occur with chronic use of enzyme-
sality (Schmidt and Loscher, 2009). Another key hypothesis is that inducing ASMs but has also been associated with valproate and other
the ASM target (e.g., channels, receptors) is no longer sensitive nonenzyme-inducing agents (Ensrud et al., 2004, 2008; Farhat et al.,
to the ASM. Disease severity may play a role and may have com- 2002). It is unclear whether any ASM is not detrimental to bone den-
mon neurobiological factors with pharmacoresistance (Schmidt sity, and bone mineral density reduction may have different mecha-
and Loscher, 2009). Another explanation for the loss of an ASM nisms with different drugs. It is therefore advisable to monitor bone
response is tolerance, which is established with benzodiazepines density with chronic ASM therapy, and to supplement vitamin D and
but likely occurs with other ASMs as well (Loscher and Schmidt, calcium. The enzyme-inducing ASMs carbamazepine and phenytoin
2006). have been associated with serological markers of vascular risk, ame-
Seizure aggravation may occur with a number of medications liorated upon switching to lamotrigine or levetiracetam (Mintzer
(Chaves and Sander, 2005). This is most common in generalized epi- et al., 2009). Another long-term adverse effect of ASMs is potential
lepsy, where ASMs such as carbamazepine, oxcarbazepine, phenytoin, for teratogenicity (Kluger and Meador, 2008) as well as reduced IQ in
tiagabine, gabapentin, or vigabatrin may increase the number of sei- exposed infants. This adverse effect is most pronounced with valproate
zures or provoke the appearance of new seizure types (myoclonic or (Meador et al., 2009). Valproate in utero exposure also increases risk of
absence seizures) at a therapeutic level. In addition, any ASM may autism (Christensen et al., 2013).
cause a paradoxical increase in seizures in some patients. This phenom- Idiosyncratic adverse effects are not dose dependent but rather
enon has been documented with levetiracetam (Nakken et al., 2003). depend on individual patient genetic predisposition. They most
A number of ASMs have been reported to increase seizure frequency commonly affect organs such as the liver, skin, and blood. Examples
or severity as a manifestation of toxicity, with ASM serum levels above include hepatotoxicity, which may occur with valproate and felbamate;
“therapeutic” range. This is well documented for phenytoin but may Stevens-Johnson syndrome, which may occur with several ASMs
also occur with other agents. Finally, seizure exacerbation may occur including phenytoin, carbamazepine, and lamotrigine; and aplastic
in the setting of ASM-induced encephalopathy or with sedation. For anemia, which may occur with felbamate and (more rarely) carbamaz-
example, seizures may be exacerbated with valproate-induced enceph- epine. There are some predictors for these serious adverse effects. For
alopathy, and sedative ASMs may exacerbate tonic seizures in patients example, valproate hepatotoxicity is more likely in children younger
with Lennox-Gastaut syndrome. than 2 years, particularly those with mitochondrial disease (Bjornsson,
2008). Stevens-Johnson syndrome and toxic epidermal necrolysis with
Medication Adverse Effects carbamazepine are more likely in individuals of Asian descent who
It is essential to know the most common and the most serious carry the HLA-B1502 allele. Prior immune disorder and prior cytope-
adverse effects of ASMs before using them. Such potential adverse nia are risk factors for felbamate-associated aplastic anemia (Pellock
effects should be discussed with the patient before prescribing any et al., 2006). In some instances, genetic testing may identify individuals
medication. The most common adverse effects are dose dependent at greater risk of idiosyncratic reactions, but there is a need for prog-
and will predictably occur if titration continues (Toledano and Gil- ress in the field of epilepsy pharmacogenomics (Kasperaviciute and
Nagel, 2008). Their appearance indicates that the dose should be Sisodiya, 2009).
reduced. These adverse effects are most likely to occur at the time of
greatest serum concentration following medication intake, in which Therapeutic Drug Monitoring
case they could be alleviated without dose reduction by splitting the Monitoring ASM levels should be used predominantly as an adjunct
dose, taking the medication with food, or using an extended-release to clinical decision making rather than the determinant of ASM dose.
preparation. Some dose-dependent adverse effects can be predicted An ASM is typically titrated to the lowest dose known to be effective,
by the mechanism of action. For example, the most common dose- but titration may stop earlier if it is clear that seizure freedom has
dependent adverse effects with medications acting on the sodium already been achieved at a lower dose. Once a clinically effective dose
channel (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) are has been reached, a serum drug level is then obtained for future ref-
dizziness, ataxia, and diplopia. Sedation is common and sometimes erence. Routine drug levels are not necessary, and the level does not
unavoidable with benzodiazepines and barbiturates acting on the have to be repeated after that unless a breakthrough seizure occurs.
GABA receptor. In general, dose-dependent adverse effects are revers- The new level can be compared to the baseline reference level to deter-
ible with dose reduction or medication discontinuation. Cognitive mine whether a drop in the level played a role in the seizure. A serum
and behavioral adverse effects of ASMs could be considered in the level can also be helpful to determine how much room there is to
category of dose-dependent adverse effects, although some individuals increase the dose if seizures have not yet come under control. ASM
may be predisposed by virtue of genetic or other factors. Barbiturates serum levels are valuable to help explain lack of ASM efficacy at what
and benzodiazepines are best known to affect cognition, but any ASM appears to be a relatively high dose or appearance of adverse effects
can cause impairment of concentration and memory. Among the at a relatively low dose. One explanation for lack of efficacy is non-
new ASMs, topiramate and zonisamide are the most likely to impair compliance. If seizures have not come under control and the ASM
cognition, while lamotrigine is the least likely. Depression may occur serum level is 0, it is likely that the patient is not actually taking the
with any ASM, and psychosis is an uncommon adverse effect of many medication. Another reason for a low serum level may be fast metab-
ASMs but seems more likely associated with topiramate, vigabatrin, olism, either due to genetic factors or due to enzyme induction by
and levetiracetam. a concomitant medication. Similarly, serum levels can be useful to
explain toxicity at a relatively low dose. Adverse effects may be due to The decision to withdraw medications must balance the potential
an elevated serum level as a result of slow metabolism (either due to consequences of seizure relapse and the potential benefits of eliminat-
genetic factors or to hepatic or renal dysfunction) or pharmacokinetic ing medication side effects and costs on an individual basis (Shih and
interaction. Ochoa, 2009). The risk of seizure recurrence after ASM discontinua-
A therapeutic range is quoted for some ASMs, particularly tion is lower in children than in adults, and the potential psychoso-
classical ASMs such as phenytoin, carbamazepine, and valproate. cial consequences of recurrent seizures are fewer in children. Hence
Although a useful guide, a value outside the range should never be ASM withdrawal is considered sooner in children, usually after 1 or
the only basis for dosage change. This therapeutic range may be 2 years of seizure freedom. In a meta-analysis of ASM discontinua-
helpful for patients with infrequent seizures, for whom ascertain- tion, the overall risk of relapse after ASM discontinuation was 25%
ment of effective seizure control may take a very long time. For at 1 year and 29% at 2 years. Relapse was more likely in patients with
these patients, aiming for a level in the middle of the range may remote symptomatic seizures than in patients with idiopathic seizures,
be advisable. The classical ASM for which serum levels may be the and with adolescent-onset versus childhood-onset epilepsy; an abnor-
most helpful is phenytoin. Phenytoin has nonlinear kinetics, and mal EEG was associated with a relative risk of 1.45. One study found a
its serum level can fluctuate widely with small changes in dose or greater predictive value for serial EEGs obtained after initiating ASM
bioavailability. When the dose is being titrated in a patient with withdrawal (Galimberti et al., 1993). Other factors associated with a
difficult-to-control seizures, it may be difficult to predict when greater risk of recurrence in other studies are focal seizures and longer
to stop increasing the dose, and the level may have to be checked than 5 years to attain seizure freedom. Early ASM response predicted
intermittently during this process. The usually quoted therapeutic successful ASM withdrawal in children (Shih and Ochoa, 2009). A pro-
range is 10–20 μg/mL. If the level is found to be at 20 μg/mL, addi- spective multicenter randomized study of continued ASM treatment
tional titration may result in toxicity. Nevertheless, it is ill advised versus slow withdrawal over 6 months reported that 41% of those in
to reduce the dose for a level above 20 if the patient has good seizure the withdrawal group relapsed at 2 years, compared to 22% of patients
control and no adverse effects. A therapeutic range is less estab- on continued treatment (Medical Research Council Antiepileptic Drug
lished for many of the new-generation ASMs. Lamotrigine levels Withdrawal Study Group, 1991).
have been better evaluated than other new ASMs. Toxic adverse Additional factors predicting recurrence in adults have included
effects are likely to occur with a level greater than 20 μg/mL, and longer duration of active disease, shorter number of years of seizure
few patients are expected to derive therapeutic benefit beyond this remission, abnormal psychiatric examination, presence of hippocam-
point (Hirsch et al., 2004). pal atrophy, abnormal neurological findings, IQ below 70, increased
For two medications that are highly protein bound, protein-free number of seizures, focal-onset seizures, and multiple seizure types
levels may have added value. Phenytoin and valproate are approxi- (Shih and Ochoa, 2009). Seizure relapse in adults will restrict driving
mately 90% protein bound, and the protein-free portion is responsible privileges and may endanger employment, particularly in certain occu-
for efficacy and toxicity (Levy and Schmidt, 1985). The total level is pations. There is also a concern that seizure control may be difficult to
usually a good predictor of the free level. However, in instances where regain (Schmidt and Loscher, 2005b). Hence, discontinuation of ASMs
the proportion of protein binding may be altered, the total serum level in seizure-free adults is usually delayed for at least 4 years and occa-
is a poor predictor of the protein-free level. These situations include sionally postponed indefinitely.
low-protein states such as malnutrition, hepatic failure, and renal fail- The optimal rate of ASM withdrawal after remission has not been
ure, the combined use of phenytoin and valproate, which compete for established scientifically. Abrupt discontinuation of ASMs is not
protein binding, and pregnancy. The elderly may also have a greater appropriate in this setting. Severe seizures have been reported during
protein-free portion. Valproate has saturation kinetics for protein withdrawal of some ASMs, including benzodiazepines, carbamaze-
binding such that there is a greater proportion of free valproate at pine, and oxcarbazepine. It is generally agreed that ASMs in general
higher levels. Protein-free serum levels have greater value in guiding and medications associated with tolerance (e.g., benzodiazepines) in
therapy in the special situations noted. particular should be withdrawn gradually.
Discontinuation of Antiseizure Medication Therapy SURGICAL THERAPY

Owing to the potential adverse effects of ASMs, particularly long-term
adverse effects, discontinuation of ASM therapy should be considered Timing
when it is no longer necessary. Although there are several predictors If seizures fail to come under control with medications, surgical ther-
of sustained remission on no medications, there is never a guarantee apy is considered. An ILAE task force suggested that failure of two
that seizures will not recur after ASM discontinuation. The decision tolerated, appropriately chosen, and used ASM schedules constitutes
to withdraw ASMs is easiest to make when the epileptic syndrome is medical failure (Kwan et al., 2010). This was in part based on the
known to remit. One example of such a syndrome is BECTS, which is finding that when two ASM monotherapies have failed, the chances
known to remit at puberty. On the other hand, JME, the most com- that additional medical therapy will provide complete seizure control
mon idiopathic generalized epilepsy syndrome, is known to have a very diminish considerably (Kwan and Brodie, 2000a). It is reasonable at
high risk of seizure recurrence; pharmacological therapy is expected to that point to refer the patient to an epilepsy center, particularly if the
be lifelong in the majority of patients. underlying epilepsy is surgically remediable and surgical results are
Most patients will not be diagnosed with a specific syndrome whose expected to be excellent. Examples include temporal lobe epilepsy with
course is well known. In a study of 294 children with nonsyndromic hippocampal sclerosis and focal epilepsy with underlying focal epilep-
epilepsy followed for more than 10 years, complete remission, defined togenic lesion. However, if expected surgical results are less favorable,
as 5 years seizure free and medication free, was achieved by 58% of it is reasonable to continue medical therapy using different monother-
children (Berg et al., 2011). Good seizure outcome at 2 years and no apies and various combinations (see Fig. 100.19). In a study by Selwa
known underlying cause of epilepsy were predictors of remission, et al., (2003), continued changes in ASM regimen rendered about 20%
while older age at onset was independently associated with a poorer of patients who were not candidates for epilepsy surgery seizure free at
chance of complete remission. 4-year follow-up. It is important to keep in mind that surgical outcome
and chances of seizure freedom after postoperative ASM withdrawal use a transcortical approach through the middle temporal gyrus, or
are better with earlier surgery, so epilepsy surgery should not be an inferior temporal approach. No clear difference in surgical out-
delayed for too long (Simasathien et al., 2013). come was noted in a study comparing transcortical and trans-sylvian
Evaluation for epilepsy surgery should probably not be pursued for approaches, but phonemic fluency was significantly improved after
patients who are noncompliant with medications—and therefore have transcortical but not after trans-sylvian SAH (Lutz et al., 2004). The
not actually failed medical therapy. Nor should surgery be pursued for “Spencer” approach involves resection of the anterior 3 cm of the tem-
patients with only brief, subjective FAS (i.e., isolated auras) since these poral pole to expose mesial temporal structures for resection (Spencer
seizures often persist after epilepsy surgery. et al., 1984). A favorable surgical outcome with respect to seizure con-
trol requires inclusion of the parahippocampal gyrus in the surgical
Presurgical Evaluation resection (Siegel et al., 1990). Recently, laser ablation under real-time
An extensive presurgical evaluation is necessary before consider- MR thermographic guidance has been proposed as an alternative to
ing epilepsy surgery and has already been discussed in detail (see open resection in patients with hippocampal sclerosis (Gross et al.,
Evaluation and Diagnosis). Its purposes are to (1) localize the epilep- 2018). Its main advantages are decreased surgical morbidity and better
togenic zone (whose resection is necessary and sufficient to eliminate cognitive outcome (Drane et al., 2015). This approach can also be used
seizures), (2) identify incongruent evidence that may indicate the need for other small deep epileptogenic lesions. Radiofrequency thermo-
for additional tests including invasive EEG, and (3) determine whether ablation has been used less frequently to lesion deep epileptogenic foci.
planned surgical resection poses risk to cerebral functions. Essential It can be applied via depth electrodes already implanted for localiza-
elements of the presurgical evaluation include interictal and ictal EEG, tion purposes, but with the disadvantage of less temperature control
video analysis of recorded seizures, and structural imaging with MRI (Voges et al., 2018).
to identify an epileptogenic lesion. Interictal PET scanning with FDG Lesionectomy is a suitable surgical approach when there is a well-
and neuropsychological testing are also commonly part of the pre- defined structural lesion such as benign tumor or cavernous malforma-
surgical evaluation. In cases where interictal EEG abnormalities are tion. In the latter case, the resection must include hemosiderin-stained
consistently focal and congruent with a focal unilateral structural epi- tissue surrounding the malformation. There is some evidence to sup-
leptogenic lesion, some have advocated skipping ictal EEG recordings, port the use of intraoperative electrocorticography to guide the extent
particularly where resources are limited. Complex scenarios where of resection (Van Gompel et al., 2009).
there is incongruence in the presurgical data require additional testing Nonlesional neocortical epilepsy usually requires a tailored resec-
that should include functional imaging with PET, ictal SPECT, MEG, tion after the ictal onset zone and cortical functions have been defined
or even invasive EEG with implanted intracranial electrodes. The deci- through intracranial recordings, most often using subdural grids.
sion to proceed with surgery should balance the predicted benefits of Hemispherectomy is the preferred surgical approach when the epi-
epilepsy surgery against the predicted risks of functional deficits that leptogenic zone is well lateralized but widespread in one hemisphere,
might result from surgery. and the hemisphere functions are impaired or expected to become
impaired (Limbrick et al., 2009). Examples of conditions for which
Surgical Approaches hemispherectomy is often the recommended procedure include
Epilepsy surgery can be classified as either curative or palliative. Rasmussen syndrome, Sturge-Weber syndrome, and hemimegalen-
The aim of curative surgery is to eliminate seizures completely and cephaly. The current functional hemispherectomy technique removes
potentially produce permanent remission without the need for temporal and centroparietal regions, leaving the frontal and occipital
ASMs. Palliative surgery is considered only if “curative” surgery is poles with their blood supply but disconnected from the remainder
not viable. of the brain. Hemispherectomy provides complete seizure control in
The most common epilepsy localization is mesial temporal, specifi- approximately three-quarters of patients and improved seizure control
cally amygdalohippocampal. The most common surgical approach has in the majority of the remainder (Limbrick et al., 2009). The disap-
been a temporal lobectomy in which lateral temporal cortex is resected pearance of seizures will often improve the function of the remain-
first, followed by resection of the amygdala and hippocampus. The ing hemisphere such that cognitive function and behavior are often
resection size is typically different for dominant and nondominant improved at follow-up.
resection. The lateral resection usually measures around 6 cm from If the epileptogenic zone includes eloquent cortex, resection may
the temporal pole on the right but is less extensive on the left to reduce not be possible without unacceptable deficits, and the technique of
the chance of language deficits. The typical left dominant temporal MST is then considered (Morrell et al., 1989). MST involves discon-
lobectomy measures about 4 cm from the temporal pole (Wiebe et al., nection of horizontal intracortical fibers while preserving the integrity
2001). Dominant temporal lobectomies often spare the superior tem- of vertical connections. The procedure is based on evidence that the
poral gyrus in an effort to reduce risk of language disturbance, but a ictal discharge often spreads along horizontal fibers, while cortical
randomized prospective trial did not suggest that this was associated functions tend to follow a vertical columnar organization. MST on elo-
with benefit (Hermann et al., 1999). Some centers tailor the resection quent cortex is most often performed in conjunction with resection of
based on preoperative language functional mapping with electrical adjacent nonessential cortex. More recently, hippocampal transection
stimulation or fMRI. The hippocampal resection usually measures was proposed as a memory-sparing procedure for patients with MTLE
about 3 cm. One study suggested that a more complete hippocampal without hippocampal sclerosis, who are at risk of memory decline
resection was associated with greater chance of postoperative seizure from hippocampal resection (Uda et al., 2013).
freedom (Wyler et al., 1995), but the findings were not confirmed in a Corpus callosotomy (CC) is a palliative surgical procedure involv-
second study (Schramm et al., 2011). ing partial or complete disconnection of the corpus callosum. The
For individuals with clear hippocampal sclerosis, selective amyg- procedure is most often used for drop attacks and is thought to dis-
dalohippocampectomy (SAH) is an alternative approach with less rupt rapid bilateral seizure spread responsible for sudden loss of con-
risk to language functions and equal outcome for seizure control sciousness or loss of posture without warning. CC can change seizure
(Tanriverdi et al., 2008). The original approach advocated by Yasargil characteristics such that seizures may become focal or patients may
was trans-sylvian (Siegel et al., 1990), but the same operation could have a warning, giving them time to protect themselves before further
seizure progression. In seizure types where bihemispheric synchrony is longer duration of epilepsy (Al-Kaylani et al., 2007; Kim et al., 2005;
required for seizure expression, CC may potentially eliminate clinical Lee et al., 2008). Other factors associated with recurrence were ASM
seizure manifestations. Drop attacks are the seizure type most helped reduction before 10 months (Lee et al., 2008) and normal preoperative
by CC, with benefit in about three-quarters of patients and freedom MRI (Schiller et al., 2000).
from drop attacks in more than a third (Tanriverdi et al., 2009). GTC Late relapse is not a rare event. Relapse after a 2-year remission
seizures are also helped. A two-thirds anterior callosotomy is gener- occurred in 25% of mesial temporal and 19% of neocortical epilepsy
ally performed first, with the possibility of extending the callosotomy patients in the seven-center study. Only delay to remission predicted
later if there is insufficient improvement. CC is not effective for focal relapse, and only in mesial temporal epilepsy patients (Spencer et al.,
seizures, including FIAS of temporal lobe epilepsy. It is reserved for 2005). In a study of anterior temporal lobectomy for temporal lobe
patients with severe epilepsy, falls, and injuries. The most appropri- epilepsy in 325 patients followed for a mean of 9.6 years, 55.3% of
ate candidates have symptomatic generalized epilepsy, but CC may be patients were seizure free at 2 years, 47.7% at 5 years, and 41% at
considered for patients with highly refractory GTC seizures in the set- 10 years (McIntosh et al., 2004). Patients who were seizure free at
ting of IGE (Cukiert et al., 2009; Jenssen et al., 2006b). 2 years postoperatively had a 74% probability of seizure freedom at
10 years after surgery. Long-term postoperative outcome was exam-
Surgical Results and Predictors of Surgical Freedom ined specifically in 171 patients with MRI-defined hippocampal
Epilepsy surgery can be a very effective treatment for patients who are sclerosis (Janszky et al., 2005a). Seizure freedom was noted in 80%
found to be good candidates after a presurgical evaluation. The best at 6 months, 71% at 2 years, 66% at 3 years, and 58% at 5 years.
surgical outcome has been reported in temporal lobe epilepsy sur- Predictors of outcome varied at different time points: preoperative
gery. The efficacy of temporal lobe epilepsy surgery was confirmed in FBTCS and ictal dystonia were negative predictors at 2 years; longer
a randomized controlled trial in which 80 patients with temporal lobe epilepsy duration and ictal dystonia at 3 years; and only longer epi-
epilepsy were randomly assigned to immediate temporal lobectomy or lepsy duration at 5 years.
additional ASM therapy for 1 year. At 1 year, the difference between About a third of patients who are not seizure free immediately after
the two groups was highly significant: 58% of patients in the surgical surgery eventually achieve long-term seizure freedom (Janszky et al.,
group and 8% in the medical group were free of seizures impairing 2005b). Normal MRI findings and FBTCS preoperatively were unfa-
awareness; 38% in the surgical group and 3% in the medical group vorable predictors; rare postoperative seizures and ipsilateral tempo-
were free of all seizures, including auras (Wiebe et al., 2001). ral interictal epileptiform discharges were associated with seizure-free
Many other studies have confirmed efficacy of surgery, with gener- outcome. Newly administered levetiracetam also showed a significant
ally better results for MTLE than neocortical epilepsy. In a seven-cen- positive effect on the postoperative outcome, independent of other
ter prospective observational study of resective epilepsy surgery in prognostic factors (Janszky et al., 2005b).
patients aged 12 years and older, 339 operated patients (297 mesial Patients who have failed epilepsy surgery can be considered for
temporal, 42 neocortical) were followed over 2 years (Spencer et al., reoperation, usually after at least 1–2 years. Reoperation is more likely
2005). Of these, 66% (223) experienced 2-year remission, not signifi- to be successful if the initial surgery missed the epileptogenic zone or
cantly different between mesial temporal and neocortical resections epileptogenic lesion, or if the initial resection was incomplete. Between
(68% and 50%, respectively). Seizure remission was defined as 2 years one- and two-thirds of reoperations result in seizure freedom or
completely seizure free after hospital discharge, with or without auras. near-seizure freedom (Germano et al., 1994; Gonzalez-Martinez et al.,
Only absence of GTC seizures and presence of hippocampal atrophy 2007; Holmes et al., 1999; Ramantani et al., 2013; Salanova et al., 2005;
were significantly and independently associated with remission, and Siegel et al., 2004). If the first presurgical evaluation was extensive
only in the mesial temporal resection group. and the surgery was appropriate based on the findings, reoperation is
Epilepsy surgery significantly improved quality-of-life score mea- unlikely to be successful.
sures within 6 months after surgery; subsequent changes over time Epilepsy surgery has potential adverse effects that may be expected
were sensitive to seizure-free and aura-free status (Spencer et al., in some instances, as well as unexpected complications. A contralateral
2007). Other factors reported in some studies as predictors of post- upper-quadrant visual-field loss is to be expected after temporal lobec-
operative seizure freedom after temporal lobe surgery include discrete tomy, but this is usually not of functional consequence to the patient
abnormalities (lesions and hippocampal sclerosis), unilateral ictal and (Hughes et al., 1999). Cognitive changes may occur. Dominant tempo-
interictal epileptiform discharges, and antecedent febrile convulsions ral lobe epilepsy surgery carries risks of verbal memory loss in 44% and
(not consistently reported). The etiology of head trauma, normal MRI, reduced naming in 34% of patients (Sherman et al., 2011). Memory
and absence of hypometabolism on PET were unfavorable predictors may continue to decline for up to 2 years after surgery (Alpherts et al.,
in some studies. Postoperative seizures and epileptiform activity on 2006). There is a suggestion of increased risk for memory decline in
postoperative EEG were also unfavorable predictors. In neocortical patients with larger hippocampal volumes (Baxendale et al., 2008).
epilepsy, well-circumscribed lesions (e.g., tumor, cavernoma), com- On the other hand, memory deficits associated with the function of
plete lesion resection, and focal beta or gamma activity at ictal onset the contralateral temporal lobe may improve postoperatively in some
were favorable predictors, while absence of a lesion and generalized patients with unilateral hippocampal sclerosis (Baxendale et al., 2008).
spike-and-wave EEG pattern were unfavorable predictors.
ASMs usually have to be continued for at least a period of time
OTHER THERAPIES
after successful epilepsy surgery, but the number and dose of ASMs
may be reduced prior to that time. Most commonly, medications are Other therapies are often considered only after medical therapy
tapered after 1–2 years of complete seizure freedom. However, there is fails and when surgical therapy is not possible or has also failed
a risk of recurrence in approximately one-fifth to one-third of patients (Cascino, 2008). However, alternative nonpharmacological ther-
(Kim et al., 2005; Lee et al., 2008; Park et al., 2010b; Rathore et al., apy should also be considered when patients may be candidates
2011; Schiller et al., 2000; Schmidt et al., 2004). The risk seems lower for surgery, but expectations for complete seizure freedom are low.
in pediatric patients (Lachhwani et al., 2008). Factors associated with These alternatives include dietary therapy, stimulation therapies,
greater likelihood of recurrence included older age at surgery and and radiosurgery.
Dietary Therapy therapy for children with GLUT deficiency and pyruvate dehydroge-
Dietary therapy is a very old treatment of epilepsy, first proposed in nase deficiency. Other syndromes where the ketogenic diet has been
1921 to mimic the effects of fasting by producing ketosis, acidosis, and reported to be especially beneficial include myoclonic-astatic epilepsy,
dehydration (Sinha and Kossoff, 2005). Interest in a ketogenic diet tuberous sclerosis, Rett syndrome, Dravet syndrome, and infantile
decreased with the introduction of many new ASMs in the 1990s but spasms (Kossoff et al., 2009). Absolute contraindications include mito-
increased again with the realization that the newer ASMs had only a chondrial disorders, pyruvate carboxylase deficiency, and β-oxidation
modest impact on drug-resistant epilepsy. The ketogenic diet is a very defects.
low-carbohydrate, high-fat, and low-to-adequate protein diet that Patient compliance with the ketogenic diet has proven difficult,
includes some restriction of total calories (≈75% of age recommen- so other diets have been explored in the treatment of epilepsy. The
dations). The amount of protein is based on age requirement: carbo- modified Atkins diet was created to be more palatable and less restric-
hydrates are only 5–10 g/day, and the remaining calories come from tive than the ketogenic diet. It only restricts carbohydrates (10 g/day
fat. The ratio of fat to protein plus carbohydrate ranges from 2:1 to for children and 15 g/day for adults), not protein, fat, or calories. It
4:1. The diet is typically initiated with a fast. Although the fasting is is modified from the standard Atkins diet in that the induction phase
not necessary for therapeutic efficacy, it does provide a faster onset limiting carbohydrates is indefinite, and that fat is not only allowed but
of action that may help improve compliance. Initiation with fasting also encouraged. Weight loss is not the goal of this diet, but weight loss
requires hospital admission, which may also be helpful for monitoring has been associated with improvement.
unexpected adverse effects of the diet and reviewing medications for The efficacy of the Atkins diet has been studied prospectively in
possible carbohydrate components (Sinha and Kossoff, 2005). Efficacy children and adults. In one pediatric study, 65% of children had a
of the ketogenic diet in children was confirmed in a randomized con- greater than 50% reduction in seizures (Kossoff et al., 2006), and in
trolled but unblinded trial: 38% of children who received the diet had an adult study, 47% had greater than 50% reduction at 3 months and
a greater than 50% reduction versus only 6% of controls, and 7% had 33% at 6 months, but 33% discontinued the diet before 3 months. The
a greater than 90% reduction versus none of the controls (Neal et al., modified Atkins diet also seems to work fairly rapidly; median time
2008). A blinded crossover study in children with Lennox-Gastaut syn- to seizure reduction was 2 weeks. In the adult prospective study, a
drome did not reach significance, but this may have been due to meth- higher level of ketosis was associated with improvement early on and
odological problems (Freeman et al., 2009). In a prospective study of weight loss later on (Kossoff et al., 2008c). Another study suggested
the ketogenic diet in 150 children with drug-resistant epilepsy, 3% consistently strong ketosis was important for maintaining the efficacy
were seizure free at 3 months and 7% at 12 months; 27% had a greater of diet therapy (Kang et al., 2007). The Atkins diet has advantages over
than 90% decrease in seizure frequency at 1 year (Freeman et al., 1998). the ketogenic diet in that it is easier to initiate in an outpatient setting
A multicenter study similarly showed that 10% of children with highly and requires only limited dietician input. It is more tolerable and has
refractory epilepsy were seizure free at 1 year, and 40% had a 50% or fewer adverse effects than the ketogenic diet. The presence of obesity
greater decrease in seizure frequency (Vining et al., 1998). in other family members may encourage them to try the diet as well,
The ketogenic diet is a little less effective in adolescents and adults thus improving the chances of success for the patient. The modified
than in children and is also limited by a higher rate of noncompliance Atkins diet has also been proposed as an inexpensive treatment option
in adolescents. The onset of action is very fast. In one study the median in developing countries (Kossoff et al., 2008a).
time to first improvement was 5 days, with a range of 1–65 days. The The suggestion that a lower glucose level played a role in dietary
onset of improvement was faster in children who were fasted (5 vs. efficacy prompted a trial of a low glycemic index diet (Muzykewicz
14 days), but there was no difference between 1 and 2 days of fast- et al., 2009). This diet selectively restricts high glycemic index foods
ing. Fasting had no effect on long-term efficacy. Some 75% of children that produce a substantial postprandial increase in blood glucose and
improved within 14 days. Improvement was unlikely if no benefit had insulin. The diet allows only low glycemic index carbohydrates, with
been seen by 2 months, although exceptions did exist (Kossoff et al., an overall carbohydrate intake of 40–60 g/day. There was a greater than
2008b). 90% improvement in seizure control in about 25% at 3 months, with
The mechanism of the ketogenic diet is not well understood. Its another 25% experiencing 50%–90% improvement. There was a cor-
benefit may be related to acidosis, ketosis, calorie restriction and relation between efficacy and blood glucose at 1 month and 12 months
decrease in blood glucose, dehydration, or increase in certain lipids of treatment.
(Sinha and Kossoff, 2005). Predictors of success included concomitant Overall, the advantages of dietary therapy are that it is effective, has
use of the ketogenic diet and vagus nerve stimulation (Kossoff et al., a rapid onset of action, and has different adverse effects than seen with
2007; Morrison et al., 2009). Children receiving phenobarbital in com- ASMs. Disadvantages include that dietary therapy may be socially iso-
bination with a ketogenic diet were less likely to benefit. Adverse effects lating, and compliance is difficult to maintain. The less-restrictive diets
of the ketogenic diet include constipation and worsening of reflux, are easier to follow, but they also give more opportunity for cheating
both of which can be managed with minor adjustments and stool soft- (Muzykewicz et al., 2009).
eners. Acidosis may occur, mostly at initiation and in association with
Vagus Nerve Stimulation
acute illness; it can be managed with hydration. Unexplained fatigue
could be helped by supplementation with carnitine. The potential Vagus nerve stimulation (VNS) was first approved in 1997 as the only
adverse effect of decreased growth is most likely to occur in the young- device for the adjunctive treatment of refractory focal-onset seizures
est children. Renal calculi have been reported in 5%–6% of individuals in adults and adolescents aged 12 years or older. More recently, VNS
and may be averted with improved hydration. Hyperlipidemia is of was also FDA approved as adjunctive long-term treatment for chronic
unknown long-term significance. or recurrent depression that has not responded to antidepressants.
Indications for the ketogenic diet include refractory seizures, Animal data suggested that VNS has acute abortive effects, terminat-
regardless of classification. Individuals unable to tolerate ASM therapy ing seizures that have already started (McLachlan, 1993), and acute
are particularly good candidates for the diet. The ketogenic diet is easi- prophylactic effects, reducing seizure frequency and severity during
est to manage in tube-fed patients or infants receiving formula. A keto- intermittent stimulation (Takaya et al., 1996). Efficacy in patients
genic diet is particularly beneficial and could be considered first-line with drug-resistant epilepsy was confirmed in two pivotal randomized
blinded controlled studies that demonstrated 24.5%–28% short-term The main advantages of VNS are that it does not have the ASM
reduction in seizure frequency (Handforth et al., 1998; The Vagus adverse effects of sleepiness, tiredness, dizziness, or cognitive dys-
Nerve Stimulation Study Group, 1995). The long-term continuation function. It may improve mood and promote alertness, and it gives
studies suggested increasing benefit over time, with median seizure patients and families a sense of control with the use of on-demand
reduction of 34% 3 months after the end of the second double-blind stimulation to abort seizures. In addition, compliance does not
trial, and 45% by the end of 1 year. In one cohort followed for 12 years, require patient effort. However, it does require surgical implanta-
mean reduction in seizure frequency was 26% after 1 year and 52% tion, and the battery has to be changed every 3–10 years depend-
after 12 years of treatment (Uthman et al., 2004). However, seizure ing on the stimulation parameters. It is difficult to predict who will
freedom is reported in less than 10% of patients (Ben-Menachem, benefit from this therapy, but the best candidates are patients who
2002). Hence, individuals who are excellent candidates for epilepsy are not good candidates for epilepsy surgery, have frequent seizures,
surgery should be advised of the much greater chance of seizure free- and have a consistent aura or a slow seizure progression, so that on-
dom with surgical therapy. demand stimulation could be used to abort seizures. VNS has also
Even though there are no randomized trials of VNS in patients with become frequently used in symptomatic generalized epilepsy before
drug-resistant generalized epilepsy, several studies have supported proceeding with CC (Nei et al., 2006; Rosenfeld and Roberts, 2009;
VNS efficacy in both idiopathic and symptomatic generalized epi- You et al., 2008).
lepsy (Ben-Menachem, 2002; Elliott et al., 2011; Kostov et al., 2009;
Ng and Devinsky, 2004); the same is true for VNS efficacy in children. Other Stimulation Therapies
Thus VNS efficacy does not seem to be specific for a particular form Trigeminal nerve stimulation, which had an antiepileptic effect in a
of epilepsy or particular age. The mechanism of action of VNS for rodent model of epilepsy, can be delivered noninvasively in humans
epilepsy is not totally clear. Approximately 80% of the vagus nerve is and is being investigated as an alternative stimulation modality. In a
composed of afferent myelinated fibers projecting to the nucleus of small open-label pilot study, bilateral stimulation of the ophthalmic
the tractus solitarius, which itself has widespread projections (Ben- branch produced a mean reduction in seizure frequency of 59% at 12
Menachem, 2002). In humans with implanted VNS, imaging of blood months (DeGiorgio et al., 2009). A larger blinded randomized con-
flow with PET showed that VNS increased blood flow in some regions trolled trial in 50 subjects with focal-onset seizures showed a reduc-
and decreased blood flow in others. Increased blood flow in the thal- tion in seizure frequency as measured by the response ratio, but there
amus correlated with long-term seizure control (Henry et al., 1999). was no significant difference between groups in the 50% responder
In another study using SPECT, acute reduction in amygdala perfusion rates (30.2% for the treatment group and 21.1% for the active control
and chronic reduction in hippocampal perfusion correlated with clin- group) (DeGiorgio et al., 2013). Of note is that the active treatment
ical efficacy (Van Laere et al., 2002). group showed a significant improvement in responder rate over the
The VNS device consists of a generator, usually implanted over treatment period, from 17.8% at 6 weeks to 40.5% at 18 weeks.
the chest under the left clavicle, and electrodes that are placed around Repetitive transcranial magnetic stimulation (rTMS), a noninvasive
the left vagus nerve and tunneled under the skin to connect with the cortical stimulation method, was also investigated as a treatment for
generator. VNS implantation is usually an outpatient surgical proce- drug-resistant epilepsy, with variable results:L rTMS modulates cortical
dure with rare complications, the most important of which is infec- excitability, with high-frequency rTMS enhancing and low-frequency
tion. Asystole (with full recovery) has been reported during routine rTMS decreasing cortical excitability in most individuals (Gangitano
intraoperative lead testing, approximately once for every 1000 implan- et al., 2002). Most studies used daily rTMS sessions for about 1 week,
tations. VNS is usually programmed to stimulate for 30 seconds, alter- then evaluated efficacy 2–4 weeks later. A meta-analysis deduced that
nating with 5 minutes of rest, but the duration of stimulation time low-frequency rTMS is moderately beneficial, with more improvement
on and stimulation time off can be changed. Some patients seem to in subjects who have cortical dysplasia or neocortical epilepsy, proba-
derive greater benefit from “rapid-cycle” stimulation, with 7 seconds bly because of greater and more precise access of rTMS therapy to the
of stimulation alternating with 12 seconds of rest. The first parameter more superficial seizure foci (Hsu et al., 2011).
to be titrated is current intensity, which is increased by 0.25 mA steps Various brain targets have been explored for stimulation, includ-
as needed to achieve benefit. Other output current parameters that can ing cortical and subcortical targets. Scheduled open-loop stimulation
be programmed are frequency and pulse width. The optimal stimu- to various cortical and subcortical structures, including the thalamus,
lation parameters have not been well defined and may vary between subthalamic nucleus, cerebellum, and hippocampus, demonstrated
individuals. In addition to the recurring output current cycles, a single variable success (Jobst et al., 2010a). Bilateral stimulation of the ante-
on-demand stimulation train can be programmed separately to abort rior nucleus of the thalamus was proven effective in a multicenter
seizures with the use of a magnet. On-demand stimulation is particu- double-blind randomized trial (Fisher et al., 2010). Median seizure
larly helpful to abort or attenuate seizures in individuals who have an reduction was 14.5% in the control group and 40.4% in the stimu-
aura (Morris, 2003). However, the clinical efficacy of on-demand stim- lated group during the blinded phase, and there was a 56% median
ulation is difficult to confirm with rigorous investigation. Newer VNS reduction in seizure frequency by 2 years. However, participants in the
models also offer responsive stimulation upon detection of sudden stimulated group were more likely to report depression or memory
increase in heart rate. This is based on the observation that ictal tachy- problems as adverse events. Bilateral deep brain stimulation of the
cardia is an early sign observed in the majority of patients (Eggleston anterior nucleus of the thalamus for epilepsy was first approved in
et al., 2014; Hirsch et al., 2015). Europe in 2010, then by the US FDA in 2018 (Salanova, 2018). The
The most common VNS adverse effect is hoarseness, which occurs FDA approval is for adjunctive therapy in individuals 18 years of age
during stimulation cycles. This is to be expected in most patients, but it or older diagnosed with focal epilepsy “refractory to three or more
does improve over time. The same is true of other stimulation-related anti-epileptic medications.”
adverse effects of coughing, throat pain, dyspnea, and paresthesias Responsive closed-loop stimulation delivers a stimulus to the pre-
(Ben-Menachem, 2002). VNS may also exacerbate obstructive sleep sumed seizure onset zone in response to seizure detection (Jobst et al.,
apnea, so it is important to diagnose and treat sleep apnea before initi- 2010a). The concept is based on evidence that brief stimulation can
ating VNS therapy (Malow et al., 2000a; Marzec et al., 2003). terminate seizure activity if delivered early after seizure onset. The
generator is implanted in the skull and connected to either depth or QUALITY-OF-CARE STANDARDS IN THE
subdural strip electrodes to deliver stimulation directly to one or two
seizure onset zones. The responsive stimulator device was found to
MANAGEMENT OF EPILEPSY
be effective in a pivotal randomized double-blind, sham stimulation The American Academy of Neurology developed standardized quality
controlled trial in patients with drug-resistant focal-onset seizures. The measures for epilepsy care (Fountain et al., 2011) that have since been
reduction in seizure frequency over the blinded evaluation period was updated based on new evidence and performance gaps (Fountain et al.,
37.9% in the treatment group compared to 17.3% in the sham stim- 2015; Patel et al., 2018). The latest quality measurement set includes
ulation group (Morrell, 2011). In the open-label extension, median the following:
percent reduction in seizures was 44% at 1 year and 53% at 2 years, • Counseling for women of childbearing potential, at least once a
suggesting progressive improvement with time (Heck et al., 2014). The year
device was approved by the FDA as an adjunctive therapy in individ- • Comprehensive epilepsy care center referral for discussion for
uals 18 years or older with focal-onset seizures who have undergone patients with intractable epilepsy
diagnostic testing that localized no more than two epileptogenic foci, • Quality-of-life assessment, at least once
are refractory to two or more antiseizure AEMs, and currently have • Quality-of-life outcome, at a visit at least 4 weeks after initial assess-
frequent and disabling seizures. Responsive stimulation is a suitable ment
treatment option for patients with bilateral independent seizure foci or • Depression and anxiety screening at every office visit
with an epileptogenic zone in eloquent cortex not suitable for surgical The measures were primarily developed for quality improvement
resection. projects. Providers were encouraged to identify measures most mean-
In general, the advantages of stimulation include that it is reversible ingful for their patients and to implement these measures to drive
and adjustable, unlike resective surgery. However, the optimal stimu- improvement in practice (Patel et al., 2018).
lation parameters are not generally well defined, and, to date, stimu-
lation therapies have been predominantly palliative. The decision to
pursue stimulation therapy has to balance risks and benefits in com-
SEIZURE CLUSTERS AND STATUS EPILEPTICUS
parison with other available therapies. Seizure clusters, also called acute repetitive seizures and serial seizures, are
closely grouped seizures representing an increase in seizure frequency
Radiosurgery compared to baseline, usually occurring over the span of minutes to a
Radiosurgery uses a stereotactic frame to immobilize the head while couple days. Seizure clusters may include any type of seizure and may
radiation beams are precisely directed from different angles to a target. vary in severity, but by definition there is complete recovery in between
The method delivers radiation to the target with a steep gradient so that seizures. Seizure clusters are more common in patients with drug-
regions within a few millimeters of the target receive a substantially resistant epilepsy, particularly those with remote symptomatic epilepsy
reduced radiation dose (Romanelli and Anschel, 2006). Radiosurgery and extratemporal epilepsy. Patients with seizure clusters are more likely
was initially used for treatment of brain tumors and AVMs not readily to have a history of status epilepticus. Seizure clusters themselves may or
accessible to standard surgery, with beneficial effect on seizure control. may not progress to prolonged seizures or even status epilepticus. Such
It has also been used successfully for hypothalamic hamartoma. More progression may be predictable for individual patients, based on their
recently, radiosurgery was explored for MTLE. A prospective study in seizure history. This may determine the most appropriate treatment for
three European centers reported 65% of patients seizure free at 2 years seizure clusters. Mild clusters can be treated with oral doses of benzo-
after radiosurgery. Five patients had transient side effects, including diazepines. However more severe clusters, particularly those known to
depression, headache, nausea, vomiting, and imbalance. No perma- progress to severe prolonged seizures or status epilepticus, may require
nent neurological deficit was reported, except nine visual-field defi- other routes of administration. Rectal diazepam was the only FDA-
cits. However, seizure freedom was delayed for most patients, the main approved treatment for out-of-hospital administration by nonmedical
improvement occurring between 12 and 18 months; some patients caregivers (Cereghino et al., 1998), until intranasal midazolam spray was
only became seizure free after 2 years post treatment. approved in 2019 (Detyniecki et al., 2019). Buccal midazolam is in wide
A US multicenter prospective study randomized patients to high- or clinical use in Europe and various countries (Nakken and Lossius, 2011),
low-dose radiosurgery. At 36 months of follow-up, 76.9% of patients but has not been approved in the United States. Intranasal diazepam was
randomized to the high dose and 58.8% randomized to the low dose approved by the US FDA in 2020. The efficacy of intramuscular diaze-
were free of seizures for the prior 12 months (Barbaro et al., 2009). pam delivered by autoinjector was demonstrated in a blinded controlled
Seizure remission correlated with appearance of vasogenic edema trial (Abou-Khalil et al., 2013), but this did not lead to FDA approval or
demonstrated on serial imaging after approximately 9–12 months marketing. Other approaches that were evaluated include buccal diaze-
(Chang et al., 2010). The degree of radiation-induced local vascular pam and staccato midazolam.
insult and neuronal loss was dose dependent and predicted long-term Status epilepticus was previously broadly defined as seizure activ-
seizure remission (Chang et al., 2010). Neuropsychological testing ity that continues for 30 minutes, or recurrent seizures without
showed no definite change in cognitive measures from baseline at 2 recovery between attacks. The 30-minute duration has been the
years after radiosurgery (Quigg et al., 2011). A single-blinded multi- subject of debate, since it may delay aggressive therapy, particularly
center controlled trial randomized 58 adult subjects with drug-resis- when prolonged duration can be predicted in the absence of therapy.
tant unilateral MTLE to either stereotactic radiosurgery or standard Experimental evidence suggests that irreversible neuronal injury may
temporal lobectomy (Barbaro et al., 2018). Seizure remission was start after 20–30 minutes of generalized convulsive status epilepticus
achieved in 52% of the radiosurgery and 78% of the temporal lobec- (GCSE) (Fujikawa, 1996; Meldrum and Brierley, 1973), so every effort
tomy patients. has to be made to stop seizure activity prior to that. A large body of
Radiosurgery may have a place in the treatment of drug-resistant evidence suggests that the bilateral tonic-clonic phase if focal or gener-
mesial temporal epilepsy for patients who are opposed to or at greater alized onset seizures does not last longer than 2 minutes (Jenssen et al.,
risk for complications with standard epilepsy surgery. However, the 2006a; Theodore et al., 1994) except when it evolves into status epilep-
long-term risk/benefit ratio of radiosurgery needs better definition. ticus. As a result, it has been suggested that vigorous therapy for status
epilepticus be initiated after 5 minutes of bilateral tonic-clonic activity generalized attenuation, and then periodic discharges on a relatively
(Lowenstein et al., 1999). There is also evidence that FIAS that last lon- flat background (Treiman et al., 1990). This sequence was proven in an
ger than 10 minutes will likely evolve into status epilepticus (Jenssen animal model of status epilepticus, and also suspected in human status
et al., 2006a). Based on the above, the ILAE defined status epilepticus epilepticus based on EEGs of patients studied at different stages of the
as a condition “resulting from the failure of the mechanisms respon- condition. A similar sequence may also occur in focal status epilepti-
sible for seizure termination or from the initiation of mechanisms cus, with asymmetrical or focal EEG features. The last pattern in the
which lead to abnormally prolonged seizures (after time point t1), sequence, periodic discharges on a relatively flat background, is some-
and can have long-term consequences (after time point t2)” (Trinka what problematic because periodic discharges are not specific.
et al., 2015). The time point t1 for status epilepticus was 5 minutes for The incidence of status epilepticus is likely underestimated by pub-
bilateral tonic-clonic seizures, 10 minutes for focal seizures, and 10–15 lished studies. The highest overall incidence, 41 cases per 100,000 per
minutes for absence seizures. year, was found in the prospective population-based study of status
Any seizure type may evolve into status epilepticus. Status epilep- epilepticus in Richmond, Virginia (DeLorenzo et al., 1996). The inci-
ticus may be classified based on the seizure type it evolves from. The dence of status epilepticus is elevated early in life, decreases after that,
most dangerous type of status epilepticus, GCSE, may evolve from a then increases in the elderly, with up to 98.9 annual cases per 100,000
primary GTC seizure or more often from a FBTCS. One form of sta- persons in that age group (Vignatelli et al., 2003).
tus epilepticus with a low likelihood of irreversible neuronal injury is The etiology of status epilepticus is very dependent on age. The
generalized absence status epilepticus, which evolves from generalized most common cause in children is febrile status epilepticus, account-
absence seizures. ing for more than half of cases (Rosenow et al., 2007). In adults, status
The most recent ILAE classification of status epilepticus (see Box epilepticus is much more often due to acute cerebrovascular accidents,
100.3) includes the two major categories of status epilepticus with prom- hypoxia, metabolic causes, and low ASM levels (Rosenow et al., 2007).
inent motor symptoms and status epilepticus without prominent motor It is important to recognize that the majority of patients in status epi-
symptoms, which is synonymous with nonconvulsive status epilepticus. lepticus do not have a history of epilepsy.
Status epilepticus with prominent motor symptoms includes convulsive Status epilepticus is a neurological emergency that requires prompt
status epilepticus, which has been made synonymous with tonic-clonic sta- intervention. The goal of therapy is to stop seizure activity in the brain
tus epilepticus, myoclonic status epilepticus (with coma or without coma), before neuronal injury has started. In addition, delay in initiating ther-
focal motor status epilepticus, tonic status epilepticus, and hyperkinetic status apy is associated with resistance to treatment (Treiman et al., 1998),
epilepticus. Convulsive status epilepticus can be generalized, focal evolv- probably due to alteration in the functional properties of GABAA
ing to bilateral tonic-clonic, or unknown whether focal or generalized in receptors (Goodkin et al., 2008; Jones et al., 2002; Macdonald and
onset. Nonconvulsive status epilepticus can be with coma or without coma. Kapur, 1999). Since convulsive status epilepticus is the most serious
Nonconvulsive status epilepticus without coma can be generalized as in form, its treatment will be discussed first. Treatment of status epilepti-
absence status epilepticus, or focal, with or without impairment of con- cus may have to start before arrival in the emergency room. Individuals
sciousness. Focal nonconvulsive status epilepticus without impairment of known to have recurrent status epilepticus may respond to rectal diaz-
consciousness is often referred to as aura continua. epam administered by a parent or care partner. There is also evidence
Nonconvulsive status epilepticus without coma is generally consid- to support the use of buccal midazolam, nasal midazolam, and nasal
ered a less serious medical emergency than convulsive status epilepti- lorazepam (Arya et al., 2011). Even when prehospital treatment was
cus. However, nonconvulsive status epilepticus with coma, including not effective and status epilepticus had persisted upon arrival in the
what was previously referred to as subtle convulsive status epilepti- emergency room, there was evidence that prehospital treatment with
cus is extremely serious, difficult to treat, and has a poor prognosis. rectal diazepam was associated with a shorter duration of status after
Nonconvulsive status epilepticus with coma may evolve from convul- arrival to the emergency department (Chin et al., 2008). For individ-
sive status epilepticus in which treatment has been delayed or has been uals not prepared for home treatment of status epilepticus, the use of
ineffective. It may also be seen without prior overt convulsive status 2 mg of IV lorazepam by paramedics was associated with termination
epilepticus when there has been a serious brain insult such as severe of status before arrival to the emergency room in 59.1% of individu-
traumatic brain injury, hypoxic injury, or massive strokes. In gener- als, compared to 21.1% treated with placebo (Alldredge et al., 2001).
alized absence status epilepticus, the patient usually appears awake Intramuscular autoinjector administration of midazolam by paramed-
but may be either unresponsive to verbal stimuli or may have slowed ics was found at least as safe and effective as IV lorazepam for prehospi-
or inappropriate responses. In focal nonconvulsive status epilepticus tal seizure cessation (Silbergleit et al., 2012). Intramuscular midazolam
with impaired consciousness, there is a wide spectrum of impairment could be administered faster than IV lorazepam. At arrival in the
of consciousness, responsiveness, or behavior. There may be consider- emergency department, 73.4% of 448 subjects in the intramuscular
able cyclical fluctuations in the clinical manifestations. midazo-lam group were free of seizure activity, as compared with 63%
The definitive diagnosis of nonconvulsive status epilepticus of 445 subjects in the IV-lorazepam group.
requires confirmation with EEG. Even convulsive status epilepticus Upon arrival in the emergency room, treatment of convulsive sta-
has to be differentiated from psychogenic status epilepticus or pseudo- tus epilepticus begins with basic life support measures, specifically
status epilepticus, which may require video-EEG for definitive diagno- attention to airway, breathing, and circulation (Treiman, 2007). Blood
sis. However, the EEG patterns of status epilepticus, particularly non- samples should be drawn for hematological and serum chemistry val-
convulsive status epilepticus, are not totally specific (Kaplan, 2007). ues, as well as ASM levels for patients who are already taking these
When the EEG pattern is not specific, the definitive diagnosis also medications. If blood glucose is low or cannot be measured rapidly,
requires observation of a definite clinical response to treatment, or at IV glucose should be administered, in conjunction with IV thiamine if
least restoration of normal EEG activity that was previously absent. In there is a concern for malnutrition. Based on the landmark Veterans
convulsive status epilepticus, a sequence of EEG patterns was reported, Affairs Status Epilepticus Cooperative Study, lorazepam 0.1 mg/
starting with discrete recurrent seizures separated by interictal slow kg was the most effective agent, terminating overt convulsive status
activity, merging seizures with waxing and waning ictal discharge, epilepticus within 20 minutes in 64.9% of patients (Treiman et al.,
continuous ictal discharge, continuous ictal discharge punctuated by 1998). It was much less effective in subtle convulsive status epilepticus
(nonconvulsive status epilepticus with coma), terminating it within 20 general anesthesia. If seizure activity recurs upon withdrawal of general
minutes in only 17.9% of patients with a verified diagnosis. Lorazepam anesthesia, a number of agents have been used successfully. ASMs with
was superior to phenytoin alone, which controlled overt convulsive IV formulation are used more often (Agarwal et al., 2007; Aiguabella
status within 20 minutes in only 43.6% of patients with verified diag- et al., 2011; Albers et al., 2011; Alvarez et al., 2011; Chen et al., 2011;
nosis. If the first treatment failed to control status epilepticus, the Goodwin et al., 2011; Kellinghaus et al., 2011; Koubeissi et al., 2011;
chances of control with the second treatment were minimal and mor- Misra et al., 2006; Moddel et al., 2009), but high-dose topiramate and
tality was twice as high (Treiman et al., 1998). felbamate have also been advocated as treatment options (Wasterlain
A standard treatment protocol is necessary for the hospital treat- and Chen, 2008). During the treatment of refractory status epilepti-
ment of convulsive status epilepticus. The American Epilepsy Society cus with ASMs, the cause of status has to be investigated and treated
issued an evidence-based guideline in 2016 (Glauser et al., 2016). It appropriately (Shorvon, 2011). Immunotherapy may be indicated if an
recommended initiating treatment in adults with either intramus- autoimmune therapy is suspected.
cular midazolam, IV lorazepam, IV diazepam, or IV phenobarbital The treatment of other forms of status epilepticus may be less
for a bilateral convulsive seizure that has lasted at least 5 minutes. aggressive, depending on the type of status encountered. In noncon-
Lorazepam is usually the first agent used for terminating status. If lora- vulsive status epilepticus with impaired consciousness, or focal motor
zepam is successful in stopping seizure activity, the decision to add status epilepticus, aggressive treatment should avoid depressing level
another agent depends on the underlying etiology. Lorazepam’s dura- of consciousness. It is still recommended to start with one of the ben-
tion of action is approximately 12–24 hours. If the etiology is reversible zodiazepines listed above, followed by second-line agent IV agents,
(e.g., status epilepticus due to metabolic or toxic factors), lorazepam including fosphenytoin, valproate, levetiracetam, and lacosamide.
may be the only treatment necessary. Intravenous diazepam is not rec- The use of general anesthesia should be avoided if at all possible,
ommended as the only treatment because of its rapid redistribution in because of associated increased risk of infection and death (Sutter
adipose tissue, markedly shortening its duration of action following IV et al., 2014).
administration. Another longer-acting ASM is needed if the underly- Generalized absence status epilepticus may respond to IV loraze-
ing etiology is not rapidly reversible. pam but may require additional IV valproate for control. Generalized
If convulsive status epilepticus is not controlled after lorazepam 0.1 myoclonic status epilepticus can be treated with IV lorazepam, val-
mg/kg, a second-line therapy should be initiated within 20 minutes of proate, or IV levetiracetam. Levetiracetam is the only ASM approved
seizure onset. Choices include IV infusion of 20 mg/kg of fosphenytoin by the FDA for treatment of myoclonic seizures based on class I clinical
(no faster than 150 mg/min) or 40 mg/kg of valproic acid, or 60 mg/ trial evidence.
kg of levetiracetam (Kapur et al 2019). Lacosamide is a more recently Outcome of status epilepticus depends on the underlying cause,
introduced option, supported with retrospective studies. If convulsive patient age, duration and severity of status epilepticus, and rapidity of
status epilepticus is still not responsive after 40 minutes, endotracheal therapy initiation. In the Richmond status epilepticus study, mortal-
intubation is necessary at this point, followed by general anesthesia ity was 3% for children and 26% for adults (DeLorenzo et al., 1996).
using midazo-lam, propofol, or pentobarbital. The purpose of general Status epilepticus of less than 1-hour duration had a 2.7% mortality
anesthesia is to control electrical status epilepticus in the brain. EEG rate after 1 month, compared to 32% for status epilepticus persisting
monitoring is necessary at this point because electrical status epilep- longer than 1 hour (Towne et al., 1994). Patient age and depth of coma
ticus may continue after motor activity stops. If the EEG continues to at presentation were the strongest predictors of outcome (Neligan and
show ictal activity, the anesthesia has to be deepened to a burst-sup- Shorvon, 2011). However, depth of coma is related to duration of sta-
pression pattern and even to complete suppression in some cases. tus (including delay in initiating therapy) and underlying illness.
Patients who require general anesthesia to control status epilepticus
will generally require long-term maintenance with ASMs. Serum levels The complete reference list is available online at https://expertconsult.
of ASMs must be in a high therapeutic zone prior to discontinuation of inkling.com/.
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composition, physiology, and endocytosis in a mouse model of a human
101
Sleep and Its Disorders
Alon Y. Avidan
OUTLINE
Definition of Sleep, 1665 Central Disorders of Hypersomnolence, 1690
Sleep Architecture, Sleep Hypnogram, and Sleep Stages, 1665 Sleep Apnea Syndrome, 1700
Sleep Microstructure, 1667 Restless Legs Syndrome, 1708
Ontogeny of Sleep Patterns with Age, 1667 Neurological Disorders and Sleep Disturbance, 1714
Sleep Habits, 1668 Sleep-Related Movement Disorders, 1721
Sleep Requirements and Quantity of Sleep, 1668 Parasomnias, 1722
Sleep and Dreams, 1669 Isolated Symptoms, Apparently Normal Variants, and Unresolved
Neurobiology and Pharmacology of Sleep and Wakefulness, 1669 Issues, 1729
Mechanism of Muscle Antonia During Rapid Eye Movement Sleep, 1670 Laboratory Assessment of Sleep Disorders, 1729
Circadian Rhythm and Chronobiology of Sleep, 1670 Polysomnographic Study, 1729
Circadian, Homeostatic, and Other Sleep Factors, 1671 Sleep in Other Medical Disorders, 1729.e1
Functions of Sleep, 1672 Video Polysomnographic Study, 1731
Physiological Changes In Sleep, 1675.e1 Multiple Sleep Latency Test, 1731
Somatic Central Nervous System, 1675.e1 Actigraphy, 1732
Autonomic Nervous System, 1675.e1 Special Electroencephalographic Studies in Nocturnal Seizure, 1732
Respiratory Changes, 1675.e1 Neuroimaging Studies, 1732
Cardiovascular Changes, 1675.e2 Pulmonary Function Tests, 1735
Gastrointestinal Changes, 1675.e2 Other Laboratory Tests, 1735
Endocrine Function Changes, 1675.e2 Principles of Management of Sleep Disorders, 1735
Changes in Sexual Function, 1675.e2 Treatment of Narcolepsy and Cataplexy, 1735
Thermoregulation Changes, 1675.e2 Electrodiagnosis of Respiratory Muscles, 1735.e1
Sleep Deprivation and Sleepiness, 1676 Treatment of Obstructive Sleep Apnea Syndrome, 1736
Total Sleep Deprivation, 1676 Treatment of Cheyne-Stokes Breathing
Partial and Selective Sleep Deprivation, 1676 and Central Sleep Apnea, 1737
Consequences of Excessive Daytime Sleepiness, 1676 Treatment of Insomnia, 1737
Causes of Excessive Daytime Sleepiness, 1677 Treatment of Restless Legs Syndrome-Periodic
Classification of Sleep Disorders, 1679 Limb Movements in Sleep, 1742
International Classification of Sleep Disorders, 1679 Treatment of Circadian Rhythm Sleep Disorder, 1743
Approach to a Patient with Sleep Complaints, 1680 Treatment of Parasomnias, 1743
Subjective Measures of Sleepiness, 1683 Treatment of Sleep Dysfunction Associated with Neurological
Clinical Phenomenology, 1685 Disorders, 1744
Insomnia, 1685 Conclusion, 1744

Since antiquity, scientists, philosophers, writers, and religious scholars Three basic physiological processes of life consist of wakefulness,
from all cultures and continents have repeatedly raised two fundamen- nonrapid eye movement (NREM) sleep, and rapid eye movement (REM)
tal questions—(1) what is sleep? and (2) why do we sleep?—without sleep, with independent functions and controls. The invention of the
satisfactory answers. electroencephalogram (EEG) in 1929, fundamental physiological stud-
Some 2000 years ago, Lucretius postulated that sleep is an absence ies to understand consciousness, sleep, and wakefulness in the 1930s
of wakefulness. Macnish, in 1830, proposed a variation of Lucretius’s and 1940s, and the discovery of REM sleep by Aserinsky and Kleitman
concept, defining sleep as “suspension of sensorial power in which in 1953 ushered in the golden age of sleep medicine. In the second half
the voluntary functions are absent but the involuntary functions, of the last century, substantial advances were made in our scientific
such as circulation, respiration, and other functions controlled by understanding of sleep and its disorders, and sleep medicine was estab-
the autonomic nervous system, remain intact.” Sleep, however, is lished as an important clinical discipline. Scientific progress in sleep
not simply an absence of wakefulness, nor is it simply suspension of medicine has accelerated markedly in recent years, particularly in our
sensorial power; it results from a combination of passive withdrawal appreciation of the glymphatic system and the adverse consequences
of afferent stimuli to the brain and activation of certain neurons in of poor or insufficient sleep. Neurologists are in a unique position to
selective brain areas. screen for sleep disorders for three key reasons: (1) sleep disturbances
1664
CHAPTER 101 Sleep and Its Disorders 1665
occasionally precede the diagnosis of key neurological conditions and significant cognitive performance decrements, an impairment
(insomnia in the case of Alzheimer dementia and REM sleep behavior defined as sleep inertia (Hilditch and McHill, 2019).
disorder in the case of Parkinson disease [PD]); (2) sleep disorders,
when untreated/unrecognized often increase the severity of the pri- Sleep Architecture, Sleep Hypnogram, and Sleep Stages
mary neurological disease (i.e. untreated sleep apnea in the setting of Sleep is divided into two independent states: NREM and REM sleep
epilepsy) and worsens quality of life for both patients and bedpartners/ based on physiological correlates. NREM sleep is further divided into
caregivers; (3) sleep disorders when identified and managed represent three stages, primarily on the basis of EEG criteria. NREM and REM
a unique window of opportunity in lessening the disease burden and sleep alternate, with each cycle lasting for approximately 90–100 min-
may in the future help delay and even reverse the progression of a neu- utes. Four to six such cycles are noted during a normal sleep period.
rodegenerative condition. Neurologists must be aware of the impor- The first two cycles are dominated by slow-wave sleep (stage N3), but
tance of disorders and ask their patient at least one question about in later cycles, these stages are noted only briefly and sometimes not at
their satisfaction with, or quality of, their sleep. all. Conversely, the duration of the REM sleep cycle increases from the
This chapter is intended to provide a brief overview and defini- first to the last cycle, and toward the end of the night, the longest REM
tion of sleep covering the following attributes of sleep: architecture, cycle may last as long as 1 hour. Thus, the first third of a normal sleep
requirements, function, ontogeny, dreams, the neurobiology of sleep episode is dominated by slow-wave sleep, and REM sleep dominates
and wakefulness, and review chronobiology and sleep-wake circa- the last third as illustrated in Fig. 101.1, A–C.
dian rhythm. Discussion will focus on physiological changes in nor- The hypnogram is a pictorial representation of the sleep stages of
mal sleep and will transition to a focus on sleep deprivation, excessive sleep from sleep onset to offset and is helpful following sleep study
sleepiness, and causes/consequences of excessive daytime sleepiness. staging and interpretation in serving as a fingerprint of a patient’s sleep
This chapter will review the classification of sleep disorders, outline a patterns at baseline and prior to and following treatment.
pragmatic approach to a patient with sleep complaints, review clinical In their 1968 criteria, Rechtschaffen and Kales (RK) divided NREM
spectrum of sleep disturbances, underlying pathophysiogy, best prac- sleep into stages 1, 2, 3, and 4. In 2007, this staging was modified slightly
tices for assessment,and management. For more in-depth information by an American Academy of Sleep Medicine (AASM) Task Force, and
about sleep disorders, the reader is referred to the growing number of NREM sleep is now divided into three stages: N1, N2, and N3 (slow-
sleep medicine textbooks (Avidan, 2018; Chervin, 2014; Chokroverty wave sleep). In the modified staging criteria adopted by the AASM (Iber
and Billiard, 2015; Kirsch, 2013; Kryger, 2013; Kryger, Avidan, Berry, et al., 2007), the traditional RK stage 1 NREM sleep was labeled N1, RK
2013; Kryger, Roth, and Dement, 2021). stage 2 was labeled N2, and RK stages 3 and 4 were combined into one
This review of sleep medicine is written during these unprec- stage, N3. Sleep scoring and staging is a procedure whereby the sleep
edented times due to the COVID-19 pandemic and the associated recording is broken up into 30-second segments, “epochs,” of a polysom-
sleep disorders related to anxiety, depression, and poor sleep quality nographic (PSG) tracing with a paper or monitor speed of 10 mm/sec.
related to physical and social isolation, quarantine, anxiety, stress, or Stage Wake (Fig. 101.2): Stage W is scored when more than 50% of
financial losses. As new data are emerging, neurologists are encour- the epoch consists of alpha EEG frequency. Chin EMG is relatively high
aged to appreciate the patterns and emergence of sleep disturbances, tone reflecting the high-amplitude muscle contractions and movement
insomnia, sleep disordered breathing, nightmares, fatigue, exhaus- artifacts. From stage W, patients typically proceed to stage N1, but
tion, and complex nocturnal behaviors. Current data highlights that infrequently they may enter REM sleep or stage N2 sleep directly, if the
fatigue, central hypersomnolence, and REM sleep behavior disorder pressure to do so is high (reflecting a state of severe pathological sleep
might be conferred by severe acute respiratory syndrome coronavirus deprivation such as in observed in narcolepsy).
2 (SARS-CoV- 2) infection per se, while rising rates of insomnia NREM Sleep: Accounts for the highest proportion (75%–80%) of
(“coro/covidnosomnia”) might be related mainly to confinement, sleep time in adults and is made up of stages N1, N2 (light sleep), and
anxiety, and psychosocial factors (Partinen, 2020). N3 (deep or slow-wave sleep).
Stage N1 Sleep (Fig. 101.3): Makes up approximately 3%–to-8% of
total sleep time. It is demarcated by a significant shift of alpha rhythms
DEFINITION OF SLEEP (8–13 Hz), a characteristic of wakefulness, which diminishes to less than
Sleep is defined on the basis of both behavioral and physiological cri- 50% of the epoch. N1 sleep is demarcated by the emergence of a mixture
teria (Table 101.1). The behavioral criteria include lack of mobility of slower theta rhythms (4–7 Hz) and beta waves (>13 Hz). The EMG
or slight mobility, closed eyes, a characteristic species-specific sleep- activity drops slightly, and slow rolling eye movements may be recorded.
ing posture, reduced response to external stimulation, quiescence, Vertex sharp waves are noted toward the end of stage N1 sleep.
increased reaction time, elevated arousal threshold, impaired cogni- Stage N2 sleep (Fig. 101.4): Begins after approximately 10–12 min-
tive function, and a reversible unconscious state. Physiological crite- utes of stage N1 sleep. The characteristic EEG findings of stage N2
ria (see Sleep Architecture and Sleep Stages, later) are based on EEG, sleep include sleep spindles (12–18 Hz, most often 14 Hz) and biphasic
electro-oculography (EOG), and electromyography (EMG) findings as K complexes intermixed with vertex sharp waves. The EEG recording
well as other physiological changes in ventilation and circulation. contains theta activity and fewer than 20% slow waves (0.5–2 Hz).
The moment of sleep onset is characterized by gradual shift of EEG Stage N2 sleep lasts for approximately 30–60 minutes.
wave rhythms, cognition, and mental processing. The onset of sleep Stage N3 sleep (Fig. 101.5): N3 or slow wave sleep comprises 15%-
occurs even prior to entrance to stage N1 NREM sleep and is defined to–25% of total sleep. The patient is less responsive to environmental
as subjective heaviness and ptosis of the eyelids; clouding of the senso- stimuli. It is defined by the presence of a minimum of 20 percent delta
rium; and a decrement in logical or rational perception of visual and waves ranging from 0.5–to-2 Hz and having a peak-to-peak ampli-
auditory stimuli and reduced capacity to respond with appropriate tude >75 μV. It is an important sleep stage as it is the most restorative
logic. The term predormitum was originally coined by Critchley (1955) form of sleep, but also where one is most likely to observe disorders
to describe this moment of sleep onset. The moment of sleep offset, of arousal (none-REM parasomnias) such as somnambulism and
or awakening, is also a gradual process similar to the moment of sleep sleep terrors (Previous criteria defined stage N3 with 20–50 percent
onset, but is pathologically prolonged in the setting of sleep distur- delta waves and a stage N4 with greater than 50 percent delta waves.
bances such as sleep apnea or sleep deprivation, leading to grogginess However, at present time N2 and N4 are combined as stage N3.
TABLE 101.1 Behavioral and Physiological Criteria of Wakefulness and Sleep.

Asleep: Nonrapid Eye Asleep: Rapid Eye
Attribute Awake Movement Sleep Movement Sleep
Posture Erect, sitting, or recumbent Recumbent Recumbent
Activity Present Moderately reduced, immobile; postural Absent. When present may signify
shifts REM sleep behavior disorder.
Response to stimulation Normal Mildly to moderately reduced Moderately reduced to no response
Level of alertness Alert Unconscious but reversible Unconscious but reversible
Eyelids Open Closed Closed
Eye movements Waking eye movements Slow rolling eye movements Rapid eye movements
EEG Alpha waves; desynchronized Synchronized Theta or sawtooth; mixed
frequency, desynchronized
PSG
PSG
EEG
EOG
1 sec
EMG
Neurochemistry Modulating Activity
Acetylcholine
cerebrum
(Ach)
Norepinephrine
(NE)
c.c. Serotonin
(5-HT)
.
c.c
thalamus cere-
bellum
olfactory Histamine
bulb
medulla
pituitary pons Hypocretin /
gland
Orexin
Dopamine
(Da)
*
EMG (muscle tone) Normal (Augmented) Mildly to moderately reduced Severely reduced or absent (Atonic)
EOG Waking eye movements Slow rolling eye movements Rapid eye movements
Comparison between EEG presentation, physiology, and neurotransmitter dominance in wakefulness, NREM sleep, and REM sleep. Neuromodula-
tor activity is primarily cholinergic during wake and REM sleep (green arrows); wake is supported by activity of monoamines, histamine, and hypo-
cretin/orexin (green arrows). In sleep, monoaminergic systems, including norepinephrine and serotonin and attenuated activity (pink arrows), and
are silent in REM sleep (red arrows). Whereas dopamine levels do not change dramatically across the sleep-wake cycle (asterisks), phasic events.
EEG, Electroencephalogram; EMG, electromyogram; EOG, electro-oculogram. PSG Polysomnography.
From PSG and Neurochemistry Source: Nir, Y., Tononi, G., 2010. Dreaming and the brain: from phenomenology to neurophysiology. Trends Cogn.
Sci. 14(2), 88–100. https://doi.org/10.1016/j.tics.2009.12.001. Copyright © 2010 Published by Elsevier Inc.
R or REM Sleep (Fig.101.6): The first REM sleep (R sleep) episode is Under normal circumstances, one observes an orderly progression
noted 60–90 minutes after the onset of sleep. REM sleep accounts for from wakefulness to sleep onset to NREM sleep proceeding to REM
20%–25% of sleep time. Based on EEG, EMG, and EOG characteris- sleep. A relaxed wakefulness is characterized by a behavioral state of
tics, REM sleep can be subdivided into two stages: tonic-REM and pha- quiescence and a physiological state of alpha and beta frequencies on
sic-REM. However, this subdivision is not recognized in the recently the EEG recording, waking eye movements, and increased muscle
modified staging. The EEG tracings during REM sleep are character- tone. Deviation from this progression may be seen in conditions of
ized by fast rhythms and theta activity, some of which may have a saw- sleep state instability such as in narcolepsy, characterized by short sleep
tooth appearance. A desynchronized EEG, atonia of the major muscle onset of REM sleep, or sleep fragmentation related to conditions such
groups, and depression of monosynaptic and polysynaptic reflexes are as sleep-disordered breathing (SDB). Certain medications (such as
characteristics of the tonic stage. Phasic REM sleep is characterized by antidepressants) may reduce and sometimes eliminate normal appear-
REMs in all directions, as well as phasic swings in blood pressure and ance of slow-wave or REM sleep.
heart rate, irregular respiration, spontaneous middle-ear muscle activ- Table 101.2 summarizes EEG sleep stage frequencies and Table
ity, and tongue movements. A few periods of apnea or hypopnea may 101.3 highlights the proportion of each sleep stage during NREM and
arise during REM sleep. REM sleep states.
WAKE
REM
100%
N1
75%
Total time
WAKE
NREM
N2 50% REM
Sleep spindle K-complex N1
25% N2
N3
N3 0% (SWS)
(SWS)
8 am 2 pm 8 pm 2 am 8 am
A B Hours
200 µV
1 sec
N3, deep sleep in REM in the 2nd
WAKE the 1st ½ of the night ½ of the night
REM
N1
NREM
N2
N3
(SWS)
8 PM 9 PM 10 PM 11 PM 12 PM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM 7 AM 8 AM
C Hours
Fig. 101.1 Sleep Hypnogram. A, Depiction of electroencephalogram (EEG) wake-sleep patterns in humans
for each vigilance state: wakefulness (WAKE, in yellow), REM sleep (REM, in red), non REM sleep (NREM,
in blue). In humans NREM sleep is indicated with the 3 substages (N1, N2, and N3, in different blue shades);
N3 represents the sleep characterized by slow waves (slow-wave sleep, SWS). B, Percentages of time
spent in each vigilance state over 24 hours in humans. C, Sleep hypnogram provides for a dynamic biometric
assessment of an individual’s sleep over 12 hours. Hypnogram is illustrated horizontally by convention, with
time plotted on the x-axis, against the stage of sleep on the y axis (and other physiological measures such as
oxygen levels, position, apneas, and limb movements).
Fig. 101.7 illustrates the percent sleep stage distribution during Ontogeny of Sleep Patterns with Age
the night. Sleep staging and scoring address normal adult sleep and The evolution of EEG and wake-sleep states from the fetus, preterm
the macrostructure (eBox 101.1) and microstructure (eBox 101.2) of infant, term infant, preschooler, adolescent, to adult follows in an
sleep. In patients with sleep disorders such as sleep apnea, parasom- orderly manner depending on the maturation of the central nervous
nias, or nocturnal seizures disrupting sleep, such assessments may be system (CNS). Neurological, environmental, and genetic factors, as
difficult. well as comorbid medical or neurological disorders, will have signifi-
cant effects on such ontogenetic changes. Sleep requirements change
Sleep Microstructure dramatically from infancy to old age. Newborns have a polyphasic
Sleep microstructure consists of momentary dynamic phenomena sleep pattern with 16 hours of sleep per day. The sleep requirement
defined as arousals (see eBox 101.2). decreases to approximately 10 hours per day by age 3–5 years. In pre-
An arousal is a shift in EEG frequency, and an arousal index is school children, sleep assumes a biphasic pattern. Adults exhibit a
defined as the number of arousals per hour of sleep; up to 10 can be monophasic sleep pattern, with an average duration of 7.5–8 hours
considered a normal arousal index, while a higher index signifies sleep per night.
fragmentation. The newborn infant spends approximately 50% of the time in REM
Cyclic alternating pattern (CAP) consist of repetitive cortical EEG sleep, but by age 6 years this time is decreased to the normal adult
pattern that is noted mainly during NREM sleep, lasts for 2–60 seconds, pattern of 25% (Fig. 101.9). On falling asleep, a newborn baby goes
and implies predisposition toward sleep instability. A phase of CAP immediately into REM sleep, or active sleep, which is accompanied by
is marked by increased EEG potentials, with contributions from both restless movements of the arms, legs, and facial muscles. In premature
synchronous high-amplitude slow and desynchronized fast rhythms in babies, it is often difficult to differentiate REM sleep from wakefulness.
the EEG recording. A CAP cycle consists of an unstable phase (phase By age 3 months, the NREM-REM cyclical pattern of adult sleep is
A) and a relatively stable phase (phase B) (eFig. 101.8). During phase established. However, the duration of the NREM-REM cycle is shorter
A, heart rate, respiration, blood pressure, and muscle tone increase. in infants, lasting for approximately 45–50 minutes and increasing to
The rates of CAP cycles and arousals increase in both older individuals 60–70 minutes by age 5–10 years, and to the normal adult cyclical pat-
and a variety of sleep disorders such as parasomnias. A period without tern of 90–100 minutes by age 10 years. Sleep spindles begin to appear
CAP is thought to indicate a state of sustained stability and may be at about 3 months of age; K complexes are seen by about 6 months
used to understand normal and abnormal sleep. (Fig. 101.10).
CHAPTER 101 Sleep and Its Disorders 1667.e1
eBOX 101.1 Sleep Macrostructure

Sleep states and stages
Sleep cycles
Sleep latency
Sleep efficiency (ratio of total sleep time to total time in bed, expressed as a
percentage)
Wake after sleep onset (WASO)
eBOX 101.2 Sleep Microstructure

Arousals
Cyclic alternating pattern
Sleep spindles
K complexes
eFig. 101.8 Cyclic Alternating Pattern in Human Sleep. Polysomnographic recording showing consecu-
tive stretches of noncyclic alternating pattern (nonCAP) (top), cyclic alternating pattern (CAP) (middle), and
nonCAP (bottom). The CAP sequence, confined between the two black arrows, shows three phase As and
two phase Bs, which illustrate the minimal requirements for the definition of a CAP sequence (at least three
phase As in succession). Electroencephalographic (EEG) derivation (top 5 channels in top panel): FP2-F4,
F4-C4, C4-P4, P4-02, and C4-A1. Similar EEG derivation is used for the middle and lower panels. (From Ter-
zano, M.G., Parrino, L., Smeriari, A., et al., 2002. Atlas, rules and recording techniques for the scoring of cyclic
alternating pattern (CAP) in human sleep. Sleep Med. 3, 185.)
Fig. 101.2 Polysomnographic Recording Depicting Wakefulness in an Adult. The electroencephalograms (EEG) portion of the diagram demon-
strates posterior dominant 10-Hz alpha rhythm intermixed with a small amount of low-amplitude beta rhythms (international nomenclature). Waking
eye movements are seen in the electrooculogram (EOG) in the left (LOC) and right (ROC) electrodes. Stage W is defined by the presence of alpha
rhythm noted in the occipital leads (★) increased chin EMG tone (CHIN electrode) rapid eye movements of wakefulness (LOC, ROC). Stage W is
scored when more than 50% of the epoch is composed on alpha EEG frequency over the occipital region. Submental EMG depicts relatively high
tone and will reflect the high-amplitude muscle contractions and occasionally, movement artifacts. The EOG channels will show eye blinks. As the
patient becomes drowsy, with the eyes closed, the EEG will show predominant alpha activity, while the EMG activity will become less prominent.
The EOG channels may show slow rolling eye movements. Electrooculogram (EOG): Left, LOC-A2; right, ROC-A1; LOC and ROC left and respec-
tively right outer cantus electrooculography (EOG) electrodes. Electroencephalogram (EEG): M1, Left mastoid electrode location (Reference Elec-
trode); M2, Right mastoid electrode location (Reference Electrode); C3 and O1, left central and left occipital respectively; C4 and O2, right central
and occipital respectively; F4, Right frontal electrode location. Electromyogram (EMG): CHIN electromyogram (EMG), (Chin 1–chin 2); Limb EMG (L
= left leg, R = right leg), LAT1–LAT2 (AT: Anterior Tibias Muscle); L & R ARM, L & R LEG: Left, Right, Arm and Legs EMG; Electrocardiogram (EKG).
Respiratory Channels: SNORE, Snore sensor sound; ORAL/N/O AIR-flow, Nasal–oral airflow; THOR/CHEST and ABD, chest and abdominal walls
motion effort; EtCO2, End tidal carbon dioxide; PTAF, Pressure transducer airflow; SaO2%, oxygen saturation by pulse oximetry (finger probe).
Sleep in Older Adults is impaired. Fig. 101.12 schematically shows the evolution of sleep
A characteristic feature of sleep in old age is marked attenuation state distribution in newborns, infants, children, adults, and older
of the amplitude of slow waves; therefore, during scoring of slow adults as a function of time.
sleep, which depends not only on the rate but also on the amplitude
of slow waves, the percentage of slow waves decreases, time awake Sleep Habits
increases, and light sleep (stage N1) increases (Fig. 101.11). The Additional text available at http://expertconsult.inkling.com.
other characteristic feature during old age is repeated awakenings
throughout the night, including early-morning awakenings. Older Sleep Requirements and Quantity of Sleep
people spend more time awake in bed than younger people and Sleep need is determined by heredity rather than by different person-
undergo deterioration in the quality of sleep: Sleep is lighter and ality traits or other psychological factors. Social or biological factors
more fragmented with increasing age, with reductions of slow-wave may also play a role.
sleep. Total sleep time and sleep efficiency decrease. The percentage Sleep requirement is defined as the optimal amount of sleep
of slow-wave sleep is reduced and is accompanied by an increase required to remain alert and fully awake and to function adequately
in the percentage of non-REM N1 and N2 sleep. An increase in throughout the day. Sleep requirement for an average adult is approx-
sleep latency and time spent awake after sleep onset also occurs. imately 7.5–8 hours regardless of environment or cultural differ-
While sleep need is similar to younger people, the ability to sleep ences. The 2015 Join Consensus Statement from the AASM and Sleep
Depending on the sleep habit, two groups of “circadian phenotypes” of people. The body temperature reaches the evening peak an hour
are recognized: evening types and morning types. Evening types earlier in morning types than in evening types. Morning and evening
(“owls”) have difficulty getting up early and feel tired in the morn- types are most likely determined by genetic factors. Katzenberg and
ing; however, they feel fresh and energetic toward the end of the day. colleagues (1998), using the 19-item Horne-Östberg Questionnaire to
These people perform best in the evening; they go to sleep late and determine “morningness/eveningness” in human circadian rhythms,
wake up late. In contrast, the morning types (“larks”) wake up early, discovered a CLOCK gene polymorphism associated with human
rested and refreshed, and work efficiently in the morning. The body diurnal preference.
temperature rhythm shows two different curves in these two types
Fig. 101.3 Polysomnographic Recording Shows Stage 1 Nonrapid Eye Movement (NREM) Sleep (N1)
in an Adult. The epoch demonstrates a decrease of alpha activity to less than 50% and low-amplitude beta
and theta activities. Alpha rhythm is best visualized in the posterior regions of the head (O2-M1), appearing
when closing the eyes and relaxing (at the beginning of the epoch), and disappearing when opening the eyes
(at the end of the epoch). Stage N1 sleep is scored if the alpha rhythm is attenuated or replaced by low-am-
plitude, mixed-frequency activity (4–7 Hz) for more than half of the epoch. The EMG shows less activity than
in wake, but the transition is gradual. During stage N1 sleep, breathing becomes shallow, heart rate becomes
regular, blood pressure falls, and the patient exhibits little or no body movement. The monitored patient is still
easily awakened and might even deny having slept.
Research Society (SRS) recommended that adults should sleep 7 or makes them a “more effective person,” yet 41% admit to rarely taking
more hours per night on a regular basis to promote optimal health. into account how much sleep they need in planning for the next day
The recommendations went on to highlight that sleeping less than 7 and ranked sleep second to last when asked which of five items were
hours per night regularly is associated with greater predisposition to most important to them personally (Knutson et al., 2017).
adverse health outcomes, including weight gain, insulin resistance,
cardiovascular disease, stroke, impaired immune function, increased Sleep and Dreams
pain, impaired performance, increased errors, psychiatric conditions Additional text available at http://expertconsult.inkling.com.
such as depression, and greater risk of accidents (Watson et al., 2015). Additional text available at http://expertconsult.inkling.com.
Fig. 101.13 illustrates the Join Consensus Statement from the AASM
and SRS sleep duration recommendations from infancy to older age. Neurobiology and Pharmacology of Sleep and
Wakefulness
Chronic Sleep Deprivation The neuroanatomical substrates for wakefulness and sleep (REM and
Modern society appears to be chronically sleep deprived. Data demon- NREM) are located primarily within the diencephalon and brainstem
strate detrimental loss of vigilance with progressive sleep loss, confirm- (McCarley, 2007, 2009; Steriade and McCarley, 2005; Gent, Bassetti, and
ing the possibility that sleep deprivation’s consequences are serious. Adamantidis, 2018; Knutson et al., 2017; Luppi and Fort, 2019; Saeed
Fig. 101.14 shows psychomotor vigilance task (PVT) performance et al., 2019). Fig. 101.16 summarizes the determination of sleep-wake
lapses under varying doses of daily sleep, confirming the data of serious states according to the specific site and the corresponding neurotrans-
lapses when sleep is curtailed beyond 8 hours. A poll by the National mitter responsible for either wakefulness or sleep. Neuronal networks
Sleep Foundation (NSF) in 2000, 2001, and 2002 indicated that the for achieving wake/sleep are both interconnected and redundant.
average sleep duration for Americans had fallen to 6.9–7.0 hours. Brain pathways regulating wakefulness use the cholinergic, norad-
Across the board, over the last half of the 20th century, sleep duration renergic (AKA NE=norepinephrine), dopaminergic, and histaminergic
has diminished by 1.5–2 hours leading to an epidemic of sleep depri- neurons Fig. 101.17, A. The cholinergic neurons fire at the highest rate
vation, where most people are in bed for only 5–6 hours per night on a during wakefulness and REM sleep but decrease their rates of firing at
regular basis. A more recent Sleep in America poll from the NSF found the onset of NREM sleep. Wakefulness-promoting aminergic neurons
that a majority of the public (65%) reported that getting enough sleep include noradrenergic neurons in the locus coeruleus, serotonergic
Sigmund Freud called dreams the “royal road to the unconscious,” from a cascade of disfacilitation within the brainstem. The passive
representing repressed feelings that are psychologically suppressed theory originated in the two classic preparations in cats by Bremer
in the unconscious mind. Modern sleep scientists, however, inter- (1935), noted earlier in the chapter: cerveau isolé and encéphale
pret dreams in anatomical and physiological terms. Dream research isolé. Bremer found that in cerveau isolé (e.g., midcollicular tran-
has taken a new direction since the existence of REM sleep was first section), all specific sensory stimuli were withdrawn, and the ani-
observed by Aserinsky and Kleitman in 1953. It is believed that approx- mals were somnolent, whereas in encéphale isolé (transection at C1
imately 80% of dreams occur during REM sleep and 20% during vertebral level disconnecting the entire brain from the spinal cord),
NREM sleep. these specific stimuli maintained activation of the brain and animals
REM sleep is characterized by highly emotionally charged, com- were awake (eFig. 101.15, A and B). Moruzzi and Magoun (1949)
plex, and bizarre dreams, whereas NREM dreams are more realistic postulated that withdrawal of generalized activation from ARAS is
and rational. People are generally oriented when awakening from REM responsible for somnolence in cerveau isolé preparations, whereas
sleep but are somewhat disoriented and confused when awakening activation of the midbrain reticular neurons causing direct excitation
from NREM sleep. Also, it is easier to recall REM dreams than NREM of the thalamocortical projections results in EEG desynchronizations
dreams and easier to recall dreams if the subject is awakened immedi- and behavioral arousal (see eFig 101.15, C). These observations sup-
ately after the onset of REM dreams. During REM sleep, nerve cells, port the later suggestion of Steriade and colleagues (2005) that at the
synapses, and the fibers connecting these cells become activated first onset of NREM sleep, there is a deafferentation of the brain due to
in the brainstem, then the signals are transmitted to the cerebral hemi- blockage of afferent information, first at the thalamic level, causing
sphere, which synthesizes the signals, creating colorful (most of our the waking “open” brain to be converted to a “closed” brain owing
dreams take place in natural color) or black and white images during to thalamocortical inhibition. This passive reticular theory, however,
dreams. was challenged by the experiments of Batini and colleagues in 1959,
The neurobiological significance of dreams remains unknown. producing the midpontine pretrigeminal section, which was only a
Some suggestions include activation of the neural networks in the few millimeters below the section that produced cerveau isolé. In this
brain, restructuring and reinterpretation of data stored in memory, midpontine preparation, there were persistent EEG and behavioral
and removal of unnecessary and useless information from the brain of signs of alertness, suggesting that structures located in the brainstem
a dreamer. Dream-enacting behavior (DEB) associated with abnormal between cerveau isolé and midpontine pretrigeminal preparations
movements during sleep, in the absence of muscle atonia, constitutes are responsible for wakefulness. Thus, an active inhibitory role of the
an important REM parasomnia known as REM sleep behavior disorder lower brainstem hypnogenic neurons in the region of the NTS on
(RBD). the upper brainstem ARAS was clearly demonstrated by this prepa-
ration. Both active and passive theories partly explain the generation
Neuroanatomical Substrates of Wakefulness: History and Current of NREM sleep, but the contemporary theory favors the activation
Concepts of ventrolateral preoptic (VLPO) neurons and inhibition of poste-
In the 1930s, Bremer discovered evidence of an ascending arousal sys- rior hypothalamic neurons containing histamine and hypocretin.
tem necessary for cortical arousal when he demonstrated that transec- Reduced activity of the hypocretin projections to the locus coeruleus
tion of the brainstem at the midcollicular level (i.e., cerveau isolé), but noradrenergic, midline raphe serotonergic, mesopontine dopami-
not the spinomedullary junction (i.e., encéphale isolé), produced coma nergic, and tuberomammillary hypothalamic histaminergic cells may
in anesthetized cats. Bremer hypothesized that the resulting reduction also decrease the level of arousal, causing sleepiness.
in “cerebral tone” following the cerveau isolé was due to interruption
of ascending sensory inputs—that is, a passive “deafferentation theory” Neuroanatomical Substrates for Rapid Eye Movement Sleep
of sleep (Bremer, 1935). Wakefulness is controlled by the ascending The existence of REM sleep-generating neurons in the pontine cat has
reticular activating system (ARAS) containing glutamatergic, choliner- been established by transection experiments (see eFig. 101.15) through
gic, aminergic, and hypocretinergic neurons (Steriade and McCarley, different regions of the midbrain, pons, and medulla (McCarley,
2005). Projections from the ARAS terminating in the thalamus and 2009). A transection at the junction of the pons and midbrain pro-
thalamocortical projections to widespread areas of the cerebral cortex duced all the physiological findings compatible with REM sleep in the
produce cerebral cortical activation during wakefulness. Extrathalamic section caudal to that transection, whereas in the forebrain region ros-
projections from the brainstem reticular neurons terminate in the tral to the section, the recording showed no signs of REM sleep. After
posterior hypothalamus and the basal forebrain regions; the latter transection between pons and medulla, structures rostral to the section
project to the cerebral cortex (basocortical projections) to maintain showed signs of REM sleep, but structures caudal to the section had no
wakefulness signs of REM sleep. After transection at the junction of the spinal cord
Reciprocal interaction between sleep-promoting neurons in the and medulla, REM sleep signs were noted in the rostral brain areas.
region of the NTS and wake-promoting neurons within the ARAS of Finally, transection at the pontomesencephalic and pontomedullary
the brainstem independent of the reciprocal interaction of the neu- junctions produced an isolated pons that showed all the signs of REM
rons of the forebrain also plays a role in the generation of NREM sleep. The pons is therefore sufficient and necessary to generate all the
sleep. The latter is the old reticular passive hypothesis, or the disfa- signs of REM sleep.
cilitation hypothesis, of sleep. In this model, sleep is said to result
1669.e2 PART III Neurological Diseases and Their Treatment
A Cat is comatose
Awake
Asleep
B
Cerebral cortex
Cerebellum
Afferent
collaterals
Thalamus
Subthalamus
and hypothalamus
Midbrain Pons
Bulb
Ascending reticular activating
system in brainstem
eFig. 101.15 Wake “Arousal” Center. In 1935, Bremer uncovered evidence of an ascending arousal system
necessary for cortical arousal through the ascending reticular activating system (ARAS); projections from
the ARAS terminating in the thalamus, and thalamocortical projections to widespread areas of the cerebral
cortex, inducing cerebral cortical activation during wakefulness. Transection of the brainstem at the pon-
tomesencephalic level (cerveau isolé, A), but not the spinomedullary junction (encéphale isolé, B), produced
coma in anesthetized cats resulting reduction in “cerebral tone” following the cerveau isolé was hypothe-
sized to be due to interruption of ascending sensory inputs, that is, a passive deafferentation theory of sleep.
More than a decade after Bremer’s transection experiments, Moruzzi, a student of Bremer’s, and Magoun
demonstrated that electrical stimulation of the rostral pontine reticular formation produced a desynchronized
electroencephalogram, an electrophysiological correlate of the conscious state, in anesthetized cats. Moruzzi
and Magoun interpreted their experimental data as evidence for an active “waking center” in the mesopon-
tine reticular formation, essentially refuting the deafferentation theory of sleep. Moruzzi and Magoun called
this brainstem system the ARAS. (A, B, Modified from Bremer, F., 1937. Bulletin de l’Académie Royale de
Belgique. 4. C, From Kryger, Meir H., Avidan, Alon Y., Richard B. Berry MD. Biology of sleep. In: Kryger MH,
Avidan, AY, Berry, R. Atlas of clinical sleep medicine. Second edition. ed. Philadelphia, PA: Elsevier/Saunders;
2013.)
neurons in the dorsal raphe of the brainstem, histaminergic neurons and then to the medial medullary region (demarcated as the magnocellu-
in the tuberomammillary nucleus of the hypothalamus, dopaminergic lar reticular formation) and the reticulospinal tract projecting to the spinal
neurons in the ventral tegmental area, substantia nigra, and ventral interneuron of the spinal cord controls REM sleep-induced muscle atonia.
periaqueductal area. An experimental lesion (☆) in the peri-locus coeruleus alpha region and
After a period of uncertainty regarding the role of dopamine, it in the medial medullary region (Panel B) produced REM sleep without
has recently been confirmed that the midbrain dopaminergic system muscle atonia (RSWA). In addition to DEB associated with RSWA, it is
(A8–A10), particularly the dopaminergic neurons in the ventral peri- thought that a structural or functional alteration of the pathway maintain-
aqueductal gray (vPAG), play an active role in maintaining wakeful- ing muscle atonia during REM sleep is most likely responsible.
ness through their widespread reciprocal connections with sleep/wake Advances in neuroimaging studies, including positron emission
regulatory systems of neurons (Fuller and Lu, 2009). Norepinephrine- tomography (PET) and single-photon emission computed tomogra-
containing locus coeruleus neurons show their highest firing rates phy (SPECT) scans, have been able to visualize dramatic changes in
during wakefulness, their lowest during REM sleep, and intermedi- function in cortical and subcortical neuronal networks in different
ate rates during NREM sleep. Pharmacological studies suggest that sleep states and stages, advancing our understanding of the functional
posterior hypothalamic histaminergic neurons also help maintain neuroanatomy of sleep/wakefulness (Dang-Vu et al., 2007). PET scans
wakefulness. have shown marked activation of the amygdala and the anterior cin-
The excitatory amino acids, glutamate and aspartate, are inter- gulate region (part of the limbic system) during REM sleep, which
mingled within the ARAS and are present in many neurons project- is, of course, generated by brainstem neurons. In contrast, in NREM
ing to the cerebral cortex, forebrain, and brainstem. These excitatory sleep, neuroimaging techniques have shown declining function in the
amino acids are maximally released during wakefulness. The discovery thalamocortical circuits, including the association cortex of the fron-
of hypothalamic hypocretin neurons and their widespread CNS pro- toparietal and temporal lobes. Thus, the brainstem, hypothalamic, and
jections has directed attention to the role of the hypocretin system in forebrain sleep/wake-promoting neurons modulate functions of wide-
sleep/wake regulation. In 1998, deLecea and coauthors described two spread forebrain cortical areas, keeping in balance cortical and subcor-
neuropeptides in the lateral hypothalamus and perifornical region that tical circuits to control sleep/wake.
were termed hypocretin 1 and hypocretin 2. Independently in the same Additional text available at http://expertconsult.inkling.com.
year, Sakurai and colleagues (1998) described two neuropeptides in the Additional text available at http://expertconsult.inkling.com.
same region, which they named orexin A and orexin B (corresponding
to hypocretin 1 and hypocretin 2, respectively). Circadian Rhythm and Chronobiology of Sleep
It was shown thereafter that these hypocretin systems have wide- The 18th-century French astronomer de Mairan (1731) first directed
spread ascending and descending projections to the locus coeruleus, our attention to the existence of circadian rhythm when he noted that
dorsal raphe, ventral tegmental area, tuberomammillary nuclei of the in a heliotrope plant, the leaves closed at sunset and opened at sunrise
posterior hypothalamus, laterodorsal tegmental (LDT) and peduncu- even when the plant was kept in darkness (see Chokroverty, 2015a).
lopontine tegmental (PPT) nuclei, VLPO neurons in the hypothala- This observation clearly pointed to a 24-hour rhythm controlled by
mus, basal forebrain, limbic system (hippocampus and amygdala), an internal clock. The existence of such a circadian rhythm in human
cerebral cortex, thalamus (intralaminar and midline nuclei), and auto- beings and other animals was confirmed toward the last half of the
nomic neurons (nucleus tractus solitarius [NTS], dorsal vagal nuclei, last century. The term circadian rhythm originates from the Latin circa,
and intermediolateral neurons of the spinal cord). Hypocretin systems meaning “about,” and dies, meaning “day.” Human circadian rhythm
promote wakefulness mainly through excitation of tuberomammillary generally has a cycle length close to 24 hours (approximately 24.2
histaminergic, locus ceruleus noradrenergic, and midline raphe sero- hours) (Czeisler and Gooley, 2007). The existence of circadian rhythms
tonergic neurons as well as dopaminergic neurons. Reduced activity independent of environmental stimuli has been clearly demonstrated
of hypocretin systems may be partly responsible for inducing sleepi- by experimental isolation of humans from all environmental time cues
ness. These systems also suppress REM sleep through activation of the (the German term, Zeitgeber, or “time giver”), as in a cave or under-
aminergic neurons (REM-off), which in turn inhibit REM-on neurons ground bunker, to study free-running rhythms.
in the LDT/PPT nuclei. Brainstem arousal centers were identified The paired SCN, the paired nuclei above the hypothalamus, func-
and characterized, and support was later provided for the concept of tion as the body clock to control circadian rhythm (Fig. 101.20). The
sleep-promoting circuitry in the anterior hypothalamus/preoptic area, recent discovery of anatomical projections from SCN to the lateral
where the VLPO nucleus contains sleep-active cells that contain the hypothalamic neurons containing hypocretin (wake-promoting) and
inhibitory neurotransmitters γ-aminobutyric acid (GABA) and gala- anterior hypothalamic VLPO containing sleep-promoting neurons
nin (Gal), which promote sleep eFig. 101.7. suggested that the SCN may also affect sleep regulation and homeosta-
Fig. 101.17 summarizes the neuroanatomical substrates of wake- sis independent of circadian rhythm generation (Turek and Vitaterna,
fulness, REM and NREM sleep highlighting the neuroanatomy, 2011) (Video 101.1).
neurochemistry, and corresponding physiological activity during The existence of environment-independent autonomous rhythms
polysomnography. suggests that the human body also has an internal biological clock. The
Additional text available at http://expertconsult.inkling.com. SCN receives photic information from the retinohypothalamic tract,
which sends signals to multiple synaptic pathways in other parts of the
MECHANISM OF MUSCLE ANTONIA DURING hypothalamus, the superior cervical ganglion, and the pineal gland
where melatonin is produced and released (A). Through a polysyn-
RAPID EYE MOVEMENT SLEEP aptic projection, the SCN inhibits the activity of the superior cervical
Muscle hypotonia or atonia during REM sleep is thought to depend on ganglia (SCG), which supply the pineal gland with an excitatory, nor-
inhibitory postsynaptic potentials generated by dorsal pontine interneu- adrenaline (NA)-containing input (B). This mechanism allows light
rons sending descending axons as depicted in Fig. 101.19. The pathway to suppress the production and release of melatonin from the pineal
from the peri-locus coeruleus (Pre-Coeruleus, in the diagram) alpha gland and, subsequently, melatonin secretion is enhanced in the dark
region ventral to the locus coeruleus, to the lateral tegmental reticular tract, period (de Bodinat et al., 2010). Melatonin is a critical modulator of
In the first quarter of the last century during the great epidemic (A) Dynamic model
of encephalitis lethargica, von Economo noted that patients with REM-off
encephalitis lethargica who had excessive sleepiness had pathological
alterations in the posterior hypothalamus, whereas those with severe
insomnia had predominant lesions in the anterior hypothalamus.
These findings immediately suggested the existence of sleep/wake
centers in the hypothalamus. Sleep-promoting neurons are thought
to reside in the VLPO and the median preoptic neurons (MnPn) of REM-on
the anterior hypothalamus (Alam and Szymusiak, 2013) and in the
region of the NTS in the medulla. The hypothalamic preoptic neurons
(VLPO and MnPn) as well as melanin concentrating hormone (MCH) (B) Activation level (A)
neurons (Konadhode et al., 2015) intermingled with hypocretin neu-
rons in the lateral hypothalamus are sleep-promoting neurons. VLPO
neurons consist of two subgroups, clustered and diffuse, depending
on their distribution pattern. The tightly clustered neurons project to Wake NREM REM
the tuberomammillary nuclei and promote NREM sleep, whereas dif-
fusely distributed neurons project to the aminergic nuclei in the locus
coeruleus and the dorsal raphe region of the brainstem, participat- (C) Structural model
ing in REM sleep. The VLPO, MnPn, and MCH neurons fire actively
during NREM sleep, and their lesion induces insomnia. The GABA-
– 5HT NE
and Gal-containing VLPO and MnPn neurons project to inhibit the
arousal systems in the brain stem (locus coeruleus and dorsal raphe), – PPT mPRF
forebrain cholinergic, and posterolateral hypothalamic hypocretiner- RN (5-HT) 5HT NE LDT
+ + +
gic and histaminergic nuclei, which in turn inhibit VLPO, MnPn, and LC (NE)
MCH neurons. Ach (Ach) (glut)
The contemporary theory for the mechanism of NREM sleep sug- Ach – + Ach
gests a reciprocal interaction between two antagonistic neurons in
the VLPO area of the anterior hypothalamus and wake-promoting eFig. 101.18 McCarley-Hobson Reciprocal Interaction Model. The
neurons in the tuberomammillary nuclei of the posterior hypothala- reciprocal interaction (RI) model (A). In the original RI model: Cholinergic
REM-on neurons (Green triangle, solid line) which in turn both self-excite
mus, basal forebrain, and mesopontine tegmentum (McCarley, 2009;
and excite aminergic REM-off neurons (Red triangle, dashed line). Ami-
Steriade and McCarley, 2005).
nergic REM-off neurons both inhibit cholinergic REM-on neurons and
There are three main models to explain the mechanism of REM self-inhibit. This interaction contributes to the alternation of behavioral
sleep. The earliest and most generally well known is the McCarley- states, depicted in (B), as follows: During waking, the REM-off aminer-
Hobson reciprocal interaction model (eFig. 101.18), based on the recip- gic system is active continuously and attenuates the pontine cholinergic
rocal interaction of REM-on and REM-off neurons (McCarley, 2007). system. During NREM sleep, aminergic activity decreases, promoting
Neurons in the PPT and LDT nuclei in the pontomesencephalic region cholinergic activity to rise. The number of activated cholinergic REM-on
are cholinergic and are REM-on cells, which are responsible for REM neurons then exponentially increases due to self-excitation until suffi-
sleep, showing highest firing rates at this stage. The REM-off cells are cient numbers of aminergic REM-off neurons are also excited and begin
located in the locus coeruleus and dorsal raphe nuclei. These cells are to suppress the cholinergic REM-on population. However, these amin-
ergic REM-off neurons then self-suppress, allowing the emergence of
aminergic neurons and are inactive during REM sleep. Histaminergic
the next REM period. C, In a subsequent revision of the RI hypothesis,
neurons in the tuberomammillary region of the posterior hypothal-
mutually excitatory interactions between cholinergic and glutamatergic
amus can also be considered REM-off cells. Thus, the cholinergic neurons underlie the rapidly escalating firing of pontine reticular REM-on
REM-on and aminergic REM-off cells are all located within the tran- neurons during REM sleep and cholinergic REM-on cells both self-excite
sections in the pons. LDT-PPT cholinergic neurons promote REM and self-inhibit via cholinergic autoreceptors. 5-HT, 5-hydroxytryptamine;
sleep through pontine reticular formation (PRF) effector neurons, Ach, Acetylcholine; LC, locus coeruleus; LDT, laterodorsal tegmental;
which in turn send feedback loops to LDT-PPT neurons. Cholinergic mPRF, medial pontine reticular formation; NE, Norepinephrine; NREM,
neurons of the PPT and LDT projecting to the thalamus and basal fore- nonrapid eye movement; PPT, pedunculopontine tegmental; REM, rapid
brain regions, as well as to the PRF, are responsible for activation and eye movement; RN, reticular network. (From Hobson Hobson J.A., Pace-
generation of REM sleep. Aminergic cells seem to play a permissive Schott E.F., Stickgold R., 2000. Dreaming and the brain: Toward a cog-
nitive neuroscience of conscious states. Behav. Brain Sci. 23, 793–842).
role in the appearance of the REM sleep state. In the latest modification
(Hobson et al., 1975; McCarley & Hobson, 1975).
of the reciprocal interaction model, McCarley suggested that in addi-
tion to cholinergic excitation of PRF, a reduction of GABA inhibition
in the PRF also may play a role in REM sleep generation. For example, In the model proposed by Lu and coworkers (2006), there is recip-
GABA levels in the PRF (as measured by microdialysis technique) are rocal interaction between GABA-ergic REM-off neurons in ven-
lowest during REM and intermediate between wakefulness and REM trolateral periaqueductal gray matter (vlPAG) and lateral pontine
and NREM sleep. Also, injection of GABA antagonists (e.g., bicucull- tegmentum and GABA-ergic REM-on neurons in the sublaterodorsal
ine) into rostral PRF produced REM sleep in cats and rats. There is evi- nucleus (SLD; corresponding to the dorsal subcoeruleus or peri-locus
dence of GABA-ergic inhibition of locus coeruleus/dorsal raphe nuclei coeruleus alpha in cats) and a dorsal extension of the SLD termed the
(REM-off neurons). The source of GABA-ergic neurons is probably precoeruleus (PC). These mutually inhibitory neuronal populations (SLD
both local (e.g., a subgroup of PRF GABA-ergic neurons) and distant GABA-ergic REM-on and GABA-ergic REM-off neurons in the vlPAG-
(e.g., GABA-ergic neurons in the ventrolateral periaqueductal gray lateral pontine tegmentum) serve as a flip-flop switch. Ascending gluta-
matter). matergic projections from PC neurons to medial septum are responsible
for EEG hippocampal theta rhythm during REM sleep. Descending glu- Marked impairment of the arousal and cognition systems may result
tamatergic projections from ventral SLD directly to spinal interneurons, in coma or severe sleepiness. The reversibility of this state of awareness
apparently without a relay in the medial medulla, inhibit spinal ventral differentiates sleep from coma. There are also physiological and met-
horns by both glycerinergic and GABA-ergic mechanisms. Cholinergic abolic differences between sleep and coma. Coma is a passive process
and aminergic neurons play a modulatory role and are not part of the (loss of function), whereas sleep is an active state resulting from phys-
flip-flop switch. The question arises as to how two mutually inhibitory iological interactions of various systems in the brainstem and cerebral
neuronal populations (e.g., GABA-ergic REM-on and GABA-ergic cortex. Metabolic depression of the cerebral cortex and brainstem char-
REM-off neurons) stabilize the flip-flop switch permitting NREM-REM acterizes coma and stupor, whereas in sleep, oxygen use and metabolic
cycling. It has been suggested that inhibitory external projections from rhythm remain intact. By disrupting the arousal system or stimulating
extended ventrolateral preoptic neurons (eVLPO) and excitatory pro- the sleep-promoting neurons, focal neurological lesions may also cause
jections from hypocretinergic and aminergic neurons to the REM-off excessive sleepiness. For example, lesions of the brainstem, thalamus,
neurons stabilize the switch, permitting NREM-REM cycling. McCarley hypothalamus, and periaqueductal region may produce excessive sleep-
(2009) suggested that this model is based on C-fos labeling, only with- iness, stupor, and coma. These regions may also affect REM-generating
out electrophysiological recordings. Furthermore, this model does neurons in the pons and cause various REM sleep alterations, so lesions
not address how REM sleep duration progressively increases with the in these structures may cause symptomatic narcolepsy.
progression of the night. A third promising model has recently been
Video 101.1 Circadian Oscillators in the Epithalamus. (From Guilding,
proposed by Luppi et al. (2011, 2013) in which at the onset of REM
C., Hughes, A.T.L., Piggins, H.D., 2010. Neuroscience, 169[4]. Copyright
sleep, SLD glutamatergic REM-on neurons are activated with deac- © 2010 IBRO.)
tivation of REM-off GABA-ergic VLPAG and mesopontine tegmen-
tum. Ventral SLD glutamatergic neurons using both a direct pathway
to the spinal cord and an indirect pathway through the ventromedial
medulla activate glycinergic and GABA-ergic inhibitory interneurons
causing hyperpolarization of motor neurons and REM atonia, a hall-
mark of the REM sleep state. Dorsal SLD sends ascending glutamater-
gic neurons causing cerebral cortical activation through projections to
thalamocortical neurons.
Many important questions regarding the mechanism of sleep
remain unanswered. Why do VLPO neurons fire at sleep onset? What
initiates the cascade of disfacilitation in brainstem wake-promoting
neurons? What initiates activation of LDT neurons and PPT neurons
at REM onset? What causes activation of wake-promoting neurons at
sleep offset? What maintains NREM-REM sleep cycling?
The following speculative summary attempts to answer some of these
questions. VLPO excitation at NREM sleep onset is initiated by adenos-
ine (a sleep-promoting factor in the forebrain region, accumulated during
prolonged wakefulness) and suprachiasmatic nucleus (SCN), as well as by
reciprocal inhibition of aminergic and orexin wake-promoting neurons;
progressive inhibition of aminergic REM-off neurons, causing disinhibition
of REM-on cholinergic neurons and initiating REM sleep; and simultaneous
cascade of disfacilitation of the brainstem arousal system due to decreased
environmental afferent stimuli, culminating in blockades at the thalamic
level. Physiological facilitation (or disinhibition) after a certain period (per-
haps determined in the case of sleep/wake regulation by the SCN regulatory
neurons connected anatomically to sleep/wake neurons) will be followed by
inhibition (or disfacilitation), and thus the cycle will begin again.
Fig. 101.4 Stage N2 Sleep. Unique features of stage N2 sleep include 12- to 14-Hz sleep spindles and bipha-
sic K complexes intermixed with delta waves (0.5–2 Hz) and up to 75 μV in amplitude occupying less than
20% of the epoch. Stage N2 is an intermediate stage of sleep, but it also accounts for the bulk of a typical
polysomnographic recording. It follows stage N1 sleep and initially lasts about 20 minutes. Stage N2 can
begin to be scored if one or more K complexes or sleep spindles are noted during the first half of the epoch
or the last half of the previous epoch. K complexes are biphasic in morphology consisting of negative (upward
deflection) sharp waves followed by a slower positive (downward deflection) component with a total duration
of greater than 500 ms. Sleep spindles are generated in the midline thalamic nuclei, are characterized by 12-
to 14-Hz sinusoidal EEG activity in the central vertex region and must persist for at least 0.5 seconds. Stage
N2 sleep is associated with a relative diminution of physiological bodily functions with attenuation of blood
pressure, brain metabolism, gastrointestinal secretions, and cardiac activity.
human circadian rhythm for entrainment by the light/dark cycle. The (DSPS)—has been uncovered by applying gene sequencing techniques.
melatonin level rises fairly abruptly in the evening and then reaches its ASPS occur due to a mutation of the PER2 gene (a human homolog of
maximum level between 3:00 am and 5:00 am, after which it decreases the period 2 gene in Drosophila) causing advancing of the clock (i.e.,
to low levels during the daytime. Melatonin reciprocally activates the alteration of the circadian timing of sleep propensity). DSPS is due to
SCN at two melatonin receptors (C): melatonin type 1 (MT1) and polymorphism of the PER3 gene.
melatonin type 2 (MT2) receptors. Serotonergic input from the raphe
nucleus modulates the SCN through actions at serotonin (also known Circadian, Homeostatic, and Other Sleep Factors
as 5-hydroxytryptamine; 5-HT) receptor 5-HT2C. Daily activity and Sleep and wakefulness are controlled by both homeostatic and circadian
behaviors likewise influence output from the SCN—the neuronal factors. The duration of prior wakefulness determines the propensity to
master clock for coordinating circadian rhythms—including key sleepiness (homeostatic factor), whereas circadian factors determine the
physiological processes such as the sleep/wake cycle, body tempera- timing, duration, and characteristics of sleep. There are two types of sleep-
ture, and neuroendocrine secretion. The SCN also receives key signals iness: physiological and subjective (Dinges, 1995). Physiological sleepiness is
vital for metabolism (Fig. 101.21) and derives “time of day” infor- the body’s propensity to sleepiness. There are two highly vulnerable peri-
mation from environmental light cues captured by specialized cells ods of sleepiness: 2:00–6:00 am, particularly 3:00–5:00 am, and 2:00–6:00
within the retina. pm, particularly 3:00–5:00 pm. The propensity to physiological sleepiness
Sleep scientists have begun to identify the molecular basis of (e.g., midafternoon and early-morning hours) depends on circadian fac-
the mammalian circadian clock. A total of eight or nine genes (e.g., tors. The highest number of sleep-related accidents have been observed
CLOCK, PER, Bmal) and their protein products have been identified during these periods. Subjective sleepiness is the individual’s perception of
within the circadian clock system; understanding of these is still evolv- sleepiness; it depends on several external factors such as a stimulating envi-
ing (Turek and Vitaterna, 2011). Remarkable progress has been made ronment and ingestion of coffee and other caffeinated beverages.
in the past few years in the key components of the circadian clock in Physiological sleepiness depends on two processes: homeostatic
both fruit flies (Drosophila) and mammals. Dysfunction of circadian factor and circadian phase. Homeostatic factor refers to a prior
rhythm results in some important human sleep disorders. The molec- period of wakefulness and sleep debt. After a prolonged period of
ular mechanism of two human circadian rhythm disorders—advanced wakefulness, there is an increasing tendency to sleep. The recovery
sleep phase syndrome (ASPS) and delayed sleep phase syndrome from sleep debt is aided by an additional amount of sleep, but this
Fig. 101.5 Stage N3 Sleep. Polysomnographic recording of Stage N3, also termed deep sleep, slow-wave
sleep (SWS), or delta sleep. The updated American Academy of Sleep Medicine Sleep (AASM) Sleep Stage
Scoring collectively refers to stage N3 as being comprised of Rechtschaffen and Kales (R & K) sleep scoring
stage 3 and 4 together and does not make a distinction between them as such distinction probably does not
appear to serve clear clinical significance. N3 sleep is marked by high-amplitude slow waves (0.5-to-2 Hz) with
minimum amplitude of 75 microvolts as measured over the frontal regions. Slow-wave activity must be pres-
ent for greater than or equal to 20% of the epoch to be scored stage N3 sleep. No specific criteria for EOG and
EMG exist for stage N3 sleep, but in general, muscle tone is further decreased and there is no eye movement
activity. This stage of sleep has the highest threshold for arousal and is associated with disorders of arousal.
recovery is not linear. Thus, an exact number of hours of sleep are necrosis factor, promote sleep. Other sleep factors increase in concen-
not required to repay sleep debt; rather, the body needs an adequate tration during prolonged wakefulness and infection. It has been shown
amount of slow-wave sleep for restoration. The interaction between the that adenosine in the basal forebrain can fulfill the major criteria for the
circadian and the homeostatic drive producing alertness is depicted in neural sleep factor that mediates the somnogenic effect of prolonged
Fig. 101.22. The circadian factor determines the body’s propensity to wakefulness by acting through adenosine A1 and A2A receptors. Several
maximal sleepiness between 3:00 am and 5:00 am. The second period other endogenous compounds may serve as sleep factors, including delta
of maximal sleepiness (3:00–5:00 pm) is not as strong as the first. Sleep sleep-inducing peptides, muramyl peptides, cholecystokinins, arginine
and wakefulness and the circadian pacemaker have a reciprocal rela- vasotocin, vasoactive intestinal peptides, growth hormone-releasing fac-
tionship: the biological clock can affect sleep and wakefulness, and tors, and somatostatins. Finally, neurologists need to be mindful of how
sleep and wakefulness can affect the clock. There are two variables that the circadian clock regulates how the body responds to an illness, such as
seem to play a role in regulating the timing of sleep. First is the homeo- COVID-19. It is particularly relevant these days to appreciate the role of
static sleep drive, which increases as the day progresses and the longer chronotherapy when matching immunotherpy to the body’s circadian
a person is awake. The second is timing information from the SCN. In rhythm in impacting recovery from illness.
this two-process model, the SCN promotes wakefulness by stimulating
arousal networks. The activity of the circadian system appears to oppose Functions of Sleep
that of the homeostatic sleep drive, and thus the alerting mediated by The function of sleep remains the greatest biological mystery of all
the SCN increases during the day. The propensity to be awake or asleep time. There are several theories about the function of sleep (eBox
at any time is related to the homeostatic sleep drive and the opposing 101.3), but none are satisfactory (Crick and Mitchison, 1995; Kavanau,
SCN alerting signal. At normal bedtime, both the alerting drive and 1997; Mahowald et al., 1997). Sleep deprivation experiments in ani-
the sleep drive are at their highest level. The two melatonin receptors, mals have clearly shown that sleep is necessary for survival, but from
MT1 and MT2 receptor subtypes, are directly involved in the regula- a practical point of view, complete sleep deprivation for a prolonged
tion of sleep and circadian regulation. Stimulation of MT1 receptors is period cannot be conducted in humans. Sleep deprivation studies in
believed to decrease the alerting signal from the SCN, while MT2 stim- humans have shown an impairment of performance, which demon-
ulation is thought to be involved in synchronizing the circadian system. strates the need for sleep. The performance impairment of prolonged
Various sleep factors have been identified, but their role in main- sleep deprivation results from a decreased motivation and frequent
taining homeostasis has not been clearly established (Krueger et al., “microsleeps.” Overall, human sleep deprivation experiments have
2011). Several cytokines, such as interleukin-1, interferon-α, and tumor proven that sleep deprivation causes sleepiness and impairment of
eBOX 101.3 Proposed Biological Functions

of Sleep
a. Facilitation of waste clearance of the central nervous system via the glym-
phatic system
b. Synaptic neuronal network integrity
c. Body and brain tissue restoration
d. Energy conservation
e. Adaptation
f. Memory reinforcement and consolidation
g. Gene expression in sleep/wakefulness
h. Thermoregulation
Fig. 101.6 Stage REM (R) Sleep. Polysomnographic recording of Stage R sleep shows rapid eye movement
(REM) depicting mixed-frequency theta, low-amplitude beta, characteristic sawtooth waves. Chin electromyo-
gram (EMG) shows marked hypotonia. Stage R sleep is also referred to as paradoxical sleep, or active sleep,
typically occurs between 90 and 120 minutes after sleep onset in adults, and occupies between 20% and 25%
of overnight adult sleep. Rapid eye movements are conjugate, irregular, sharply peaked eye movements. Chin
EMG tone should be at the lowest level of any sleep stage. Unlike the progressive relaxation noted during
the NREM sleep stages N1, N2, and N3, physiological activity during REM sleep is significantly higher. Blood
pressure and pulse rate may increase dramatically or may show intermittent fluctuations. Breathing becomes
irregular and brain oxygen consumption increases. If patients are awakened from stage R sleep, they may often
recall dreaming. Pathologically short REM sleep latency may point to a state of acute or cumulative sleep depri-
vation, may be caused by abrupt discontinuation of REM sleep–suppressing agents (such as antidepressants),
central nervous system hypersomnias, and may also suggest a major affective disorder.
performance, vigilance, attention, concentration, and memory. Sleep and luteinizing hormone) and decreased levels of catabolic hormones
deprivation may also cause some metabolic, hormonal, and immu- (e.g., cortisol) during sleep, as well as the subjective feeling of being
nological effects. Sleep deprivation causes immune suppression; even refreshed after sleep, may support the theory of body and brain tissue
partial sleep deprivation reduces cellular immune responses. Studies restoration by sleep. The role of NREM sleep in restoring the body is
from Van Cauter’s (Spiegel et al., 1999) group include a clearly docu- further supported by the presence of increased slow-wave sleep after
mented elevation of cortisol level following even partial sleep loss, sug- sleep deprivation. The critical role of REM sleep for CNS development
gesting an alteration in hypothalamic-pituitary-adrenal axis function. in young organisms and increased protein synthesis in the brain during
This has been confirmed even in chronic sleep deprivation that causes REM sleep may support the theory of restoration of brain function by
impairment of glucose tolerance. Glucose intolerance may contribute REM sleep. Although data remain scant and controversial, studies of
to memory impairment as a result of decreased hippocampal function. brain basal metabolism that suggest an enhanced synthesis of macro-
Chronic sleep deprivation may also cause a decrement of thyrotropin molecules such as nucleic acids and proteins in the brain during sleep
concentration, increased evening cortisol level, and sympathetic hyper- provide an argument in favor of the restorative theory of sleep.
activity, which may serve as risk factors for obesity, hypertension, and The energy conservation theory is somewhat inadequate. The fact that
diabetes mellitus. Further data from the same group demonstrated that animals with a high metabolic rate sleep longer than those with slower
increase in ghrelin levels associated with short sleep reduced leptin. metabolism has been cited in support of this theory. It should, however,
These differences in leptin and ghrelin may induce increased appetite, be noted that during 8 hours of sleep, only 120 calories are conserved.
possibly explaining the increased body mass index (BMI) observed The adaptation theory suggests that sleep is an instinct that allows
with short sleep duration in the study populations. The authors cor- creatures to survive under a variety of environmental conditions.
rectly indicate that in Western societies, where chronic sleep restriction Some recent advances have been made in understanding the molec-
is common and food is ubiquitous, alterations in appetite regulatory ular mechanisms of memory consolidation during sleep (Stickgold and
hormones with sleep curtailment may contribute to obesity. Walker, 2007). Studies have revealed that new memories can be strength-
The restorative theory suggests that sleep is needed to restore cerebral ened by sleep. In other words, sleep can rescue memories that are lost
function after periods of waking. The findings of increased secretion during wakefulness during the daytime, and consolidated memories
of anabolic hormones (e.g., growth hormone, prolactin, testosterone, can be reconsolidated when they are reactivated. Memory is stored in
TABLE 101.2 Key Brain Wave Morphologies, Frequencies, and Landmarks Used in Sleep Staging
EEG Morphology Label Definition
Alpha activity 8- to 13-Hz rhythm, most prominent in occipital loads. Generated by cortex,
possibly via dipole located in layers 4 and 5. Used as a marker for relaxed
wakefulness and CNS arousals.
Theta activity 4- to 8-Hz waves, prominent in central and temporal leads. Sawtooth is a
unique variant of theta activity (containing waveforms with a notched or
Sawtooth waves
sawtooth-shaped appearance) frequently seen during REM sleep.
Vertex sharp waves Sharply contoured, negative-going bursts that stand out from the background
activity and appear most often in central leads placed near the midline.
Sleep spindle A phasic burst of 11- to 16-Hz activity, prominent in central scalp leads; typi-
cally lasting for 0.5–1.5 sec. Spindles are a scalp representation of thalamo-
cortical discharges; the name derives from their shape (which is spindle-like).
K complex An EEG event assuming a biphasic morphology and consisting of a well-delin-
eated negative sharp wave immediately followed by a positive component
standing out from the background EEG with total duration ≥0.5 sec, usually
maximal in amplitude over the frontal regions.
Slow waves High-amplitude (≥75 μvolts) and low-frequency (≤2 Hz) variants of delta (1–4
Hz) activity. Slow waves are the defining characteristics of stage N3 sleep.
REM Rapid eye movements are conjugate saccades occurring during REM sleep
correlated with the dreamer’s attempt to look at the dream sensorium. They
are sharply peaked with an initial deflection usually <0.5 sec in duration.
SEM Slow eye movements are conjugate, usually rhythmic, rolling eye movements
with an initial deflection usually ≥0.5 sec in duration.
CNS, Central nervous system; EEG, electroencephalogram; REM, rapid eye movement.
Modified from Kryger, M.H., Avidan, A., Berry, R., 2013. Atlas of Clinical Sleep Medicine, second ed. Saunders/Elsevier, Philadelphia.
The theory of maintenance of synaptic and neuronal network integ-

TABLE 101.3 Summary of Nonrapid Eye rity is an emerging concept that is concerned with the primary function
Movement and Rapid Eye Movement Sleep of sleep. Intermittent stimulation of neural network synapses is neces-
States sary to preserve CNS function (Kavanau, 1997).
Sleep State % Sleep Time Gene expression (Cirelli and Tononi, 2011) studied by deoxyribo-
nucleic acid (DNA) microarray technique identified sleep- and wake-
NREM sleep 75–80
fulness-related genes (brain transcripts) subserving different functions
N1 3–8
(e.g., energy metabolism, synaptic excitation, long-term potentiation,
N2 45–55
and response to cellular stress during wakefulness and protein synthe-
N3 13–23
sis, memory consolidation, and synaptic downscaling during sleep).
REM sleep (stage R) 20–25
Fig. 101.23 provides a basis for the synaptic homeostasis theory.
Tonic stage Continuous
The top panel of the figure illustrates schematically how a net increase
Phasic stage Intermittent
in synaptic strength occurs during wakefulness when many circuits in the
NREM, Nonrapid eye movement; REM, rapid eye movement. brain become potentiated (red lines in the brain schematic), resulting in
overall cellular and systems costs, followed by synaptic renormalization
during sleep. This is that time when most, if not all, circuits undergo
two stages: short-term memory, which is labile, and long-term memory, synaptic down-selection (green lines). The bottom portion of the figure
which is stable and consolidated, requiring synthesis of new ribonucleic highlights how parameters are used to test SHY. The color gradient in
acid (RNA) and proteins by the neurons. Recent studies have clearly the column labeled “synaptic strength” highlights that while objectively
shown a significant contribution of sleep to memory consolidation. It verifiable indicators of structural and molecular measures were more
has been suggested that memory consolidation occurs during both slow- likely to reveal a state of synaptic strength, electrophysiological mea-
wave and REM sleep. There is a further suggestion that REM-NREM sures such as firing rates and evoked responses can be strongly affected
sleep cycling is also important for memory consolidation. by other factors that modulate intrinsic neuronal excitability, including
100
REM sleep
R 90
NREM sleep
25%
80
NI
N3 5%
15% R 70
N1
N2 60
% of sleep
W
5% W
N3 50
N2
50% 40
30
20
10
Fig. 101.7 Pie Graph Demonstrates Proportion of Time During the
Night That an Adult Spends in Various Sleep Stages. Wakefulness
0
(W) in sleep usually makes up less than 5% of the night. Stage N1 sleep
Newborn 2 wk 6 mo 6 yr
12 yr 20–30 31–50 51–90
generally makes up 2% to 5% of sleep; stage N2, 45% to 55%; stage
yr yr yr
N3, 3% to 15%. Nonrapid eye movement (NREM) sleep therefore usu-
ally makes up 75% to 80% of sleep. Stage rapid eye movement (R) Fig. 101.9 Schematic diagram showing percentages of rapid eye move-
sleep typically makes up between 20% and 25% of total sleep of the ment (REM) and nonrapid eye movement (NREM) sleep at different ages.
night, occurring in three to six discrete episodes. (Modified from Kryger, Note the marked changes in REM sleep in the early years.(Modified and
M.H., Avidan, A., Berry, R., 2013. Atlas of Clinical Sleep Medicine, second adapted from Roffwarg, H.P., Muzzio, J.N., Dement, W.C., 1966. Onto-
ed. Saunders/Elsevier, Philadelphia). genic development of the human sleep-dream cycle. Science 152, 604).
the levels of neuromodulators and the overall balance between excitation Neonatal
and inhibition. However, these cannot be used alone to infer synaptic
strength. In the upper panels (structural and molecular), the red line Background 7-9 Hz 10-11 Hz
activity 6-7 Hz
indicates the axon to spine interface (ASI), and the yellow area outlines 3 Hz
the head of the spine. Excitatory glutamatergic receptors (AMPARs) are Unusual Posterior slow waves
Awake Rolandic µ
shown as squared boxes close to the ASI. Minis = miniature excitatory patterns
Lambda waves
synaptic currents (Cirelli, 2017; Cirelli and Tononi, 2015).
The thermoregulatory function theory is based on the observa- Activation Hyperventilation
tion that thermoregulatory homeostasis is maintained during sleep,
whereas severe thermoregulatory abnormalities follow total sleep Transition Hypnagogic
REM NREM hypersynchrony
deprivation. The preoptic anterior hypothalamic neurons participate
in thermoregulation and NREM sleep. These two processes are closely Figures Vertex spikes
linked by preoptic anterior hypothalamic neurons but are clearly sep- Spindles
Sleep
arate. Thermoregulation is maintained during NREM sleep but is % NREM
suspended during REM sleep. Thermoregulatory responses such as % REM
shivering, piloerection, panting, and sweating are impaired during

REM sleep. There is a loss of thermosensitivity in the preoptic anterior 0 1 3 6 9 1 3 6 12 20
hypothalamic neurons during REM sleep. Months Years
A fascinating new theory proposes a sleep state-dependent Fig. 101.10 Maturation of the Brain Wave Patterns in Sleep. Devel-
enhanced brain flushing as depicted by enhanced CSF flow through a opment, appearance, and disappearance of electroencephalographic
relatively newly discovered drainage system, the so-called glymphatic landmarks from prematurity to 3 months post term to age 20. Sleep
spindles and vertex transients generally appear around 48 weeks of
system (Iliff et al., 2012). In mice, data revealed that enhanced CSF-
conception. NREM, Non rapid eye movement; REM, rapid eye move-
flow, during sleep state, increased the removal of β-amyloid metab- ment. (From Hrachovy, R.A., 2000. Development of normal EEG. In:
olites. The glymphatic system allows for CSF circulation through the Levin, K.H., Luders, H.O. [Eds.], Comprehensive Clinical Neurophysiol-
brain, exchanging fluid allowing for enhanced clearance waste products ogy. WB Saunders, Philadelphia, pp. 387–413).
across the blood–brain barrier into the nearby blood vessels for further
transportation, as illustrated in Fig. 101.24 (Herculano-Houzel, 2013).
Emerging new data shows that the glymphatic (paravascular) system and tauopathies (Larson et al., 2012). The glymphatic fluid transporting
mediates liquid flux through the brain, highlights that the circadian system could provide an additional source of apoE and then delivers it
clock probably plays a critical role in this context, and likely holds new to brain via the periarterial space. By inference, when the glymphatic
research paradigms to further elucidate the role of sleep-state depended fluid flow and interstitial fluid (ISF) clearance system fails in this essen-
CSF-flow in delaying and preventing neurodegenerative disease-asso- tial physiological role, one would presume a high likelihood of apoE
ciated metabolites during sleeping, including alpha-synucleinopathies isoform-specific disorders chronically (Achariyar et al., 2016).
stimuli that act through the ascending reticular activity system (ARAS)
PHYSIOLOGICAL CHANGES IN SLEEP
also act as tonic stimuli to ventilation. Activity decreases in the respi-
A constellation of physiological changes are observed in humans, ratory neurons in the parabrachial and Kölliker-Fuse nuclei in the
which are distinctly different in three states of existence, namely wake- pons, the nucleus tractus solitarious (NTS), nucleus ambiguus, and
fulness, NREM sleep, and REM sleep that are different from those nucleus retroambigualis in the medulla. Respiratory muscle activ-
noted during wakefulness (Chokroverty, 2015b). This section out- ity decreases slightly during NREM sleep but markedly during REM
lines physiological changes observed during NREM and REM sleep in sleep. A marked decrement or even temporary suppression of inter-
somatic and autonomic nervous systems and includes changes in the costal muscle tone occurs during REM sleep, whereas tonic activity of
respiratory, cardiovascular, and gastrointestinal systems; endocrine, the diaphragm diminishes, and phasic activity continues. Muscle tone
renal, and sexual function; and thermoregulation (eTable 101.4). in the upper airway decreases in NREM sleep and disappears in REM
sleep, resulting in an increase in upper airway resistance. The decreased
Somatic Central Nervous System sensitivity of the respiratory neurons to carbon dioxide, inhibition of
Firing rates of many neurons in the CNS decrease during NREM sleep the reticular activating system, and alteration of metabolic control of
but increase during REM sleep. respiratory neurons during sleep result in a decrement of tidal volume,
minute ventilation, and alveolar ventilation. In normal individuals,
Autonomic Nervous System diminished alveolar ventilation causes arterial carbon dioxide tension
During sleep, the autonomic nervous system undergoes several (PaCo2) to rise by 2–8 mm Hg, the arterial oxygen tension (PaO2) to
changes that may have implications for the pathophysiology of auto- decrease by 3–10 mm Hg, and oxygen saturation (SaO2) to decrease by
nomic failure and sleep disorders in humans. Most of the autonomic less than 2% during sleep. These blood gas changes are noted despite
changes involve respiration, circulation, thermoregulation, and the a fall in oxygen consumption and carbon dioxide production during
pupils (e.g., pupilloconstriction during sleep). During NREM sleep, sleep. Both hypercapnic and hypoxic ventilatory responses decrease
there is an overall decrease in sympathetic activity and tonic increase during REM and NREM sleep, with a more marked decrease during
in parasympathetic activity, which increases further during tonic REM REM sleep. These decrements result from a combination of fac-
sleep. In addition, during phasic tonic REM sleep, sympathetic activ- tors: fewer functional medullary respiratory neurons during sleep,
ity decreases. Sympathetic activity, however, during phasic REM sleep, decreased sensitivity of the central chemoreceptors subserving med-
increases intermittently, which results in swings of blood pressure and ullary respiratory neurons, and increased resistance in the upper air-
heart rhythm, causing bradytachyarrhythmias. way. Arousal responses also decrease, particularly during REM sleep.
The voluntary respiratory control system may be active during some
Respiratory Changes portion of REM sleep. Respiration is therefore vulnerable during sleep
Two systems—metabolic (or automatic) and voluntary (or behav- in normal individuals. Mild respiratory irregularity with few apneic
ioral)—control respiration during sleep and wakefulness. Both meta- episodes (apnea index <5) may occur at sleep onset and during REM
bolic and voluntary systems operate during wakefulness, whereas only sleep. In disease states, however, particularly PD and multiple system
the metabolic system operates during NREM sleep. The wakefulness atrophy (Mehanna and Jankovic, 2010), neuromuscular and brainstem
eTABLE 101.4 Physiological Changes during Wakefulness, Nonrapid Eye Movement Sleep,
and Rapid Eye Movement Sleep
Physiology Wakefulness NREM sleep REM sleep
Parasympathetic activity ++ +++ ++++
Sympathetic activity or variable (++) ++ + Decreases
Heart rate Normal sinus rhythm Bradycardia Brady/tachyarrhythmia
Blood pressure Normal Decreases Variable
Cardiac output Normal Decreases Decreases further
Peripheral vascular resistance Normal Normal or decreases slightly Decreases further
Respiratory rate Normal Decreases Variable; apneas may occur
Alveolar ventilation Normal Decreases Decreases further
Upper airway muscle tone ++ + Decreases or absent
Upper airway resistance ++ +++ ++++
Hypoxic and hypercapnic ventilatory Normal Decreases Decreases further
responses
Cerebral blood flow ++ + +++
Thermoregulation ++ + −
Gastric acid secretion Normal Variable Variable
Gastric motility Normal Decreases Decreases
Swallowing Normal Decreases Decreases
Salivary flow Normal Decreases Decreases
Migrating motor complex (a special type Normal Slow velocity Slow velocity
of intestinal motor activity)
Penile or clitoral tumescence Normal Normal Increases markedly
+, Mild; ++, moderate; +++, marked; ++++, very marked; −, absent; NREM, nonrapid eye movement; REM, rapid eye movement.
disorders, and chronic obstructive pulmonary disease (COPD), apneas 100
MLT
may become more frequent, more prolonged, and pathologically more
significant. 0
100
Cardiovascular Changes
ADH
Heart rate, blood pressure, cardiac output, and peripheral vascu- 0
lar resistance decrease during NREM sleep and decrease still further 100
ALD
during REM sleep. During phasic REM, blood pressure and heart rate
are unstable because of phasic vagal inhibition and sympathetic activa- 0
tion caused by alterations in brainstem neural activity. Heart rate and 100
TSH
blood pressure fluctuate during REM sleep. Cerebral blood flow and
cerebral metabolic rate for glucose and oxygen decrease by 5%–23% 0
100
during stages 1–4 of NREM sleep, whereas these values increase by
TES
10%–41% above waking levels during REM sleep. These data indirectly
suggest that NREM sleep is the state of resting brain, with reduced neu- 0
100
ronal activity, decreased synaptic transmission, and depressed cerebral
PRO
metabolism. The data also are consistent with the assumption that REM
sleep represents an active brain state with increased neuronal activity 0
100
and increased brain metabolism. The largest increases during REM
GDH
sleep are noted in the hypothalamus and the brainstem structures, and
0
the smallest increases are in the cerebral cortex and white matter. 100
COR
Because of all the hemodynamic and sympathetic alterations, REM
sleep, which is prominent during the third part of the night’s sleep,
0
could initiate increased platelet aggregation, plaque rupture, and cor- 100
onary artery spasm. These increases may act as triggering mechanisms GH
for thrombotic events, causing myocardial infarction (MI), ventricular 0
arrhythmias, or even sudden cardiac death.
Onset 1 2 3 4 5 6 7 8
Gastrointestinal Changes Hours of sleep
Gastric acid secretion shows a variable response during sleep in normal eFig. 101.25 Endocrine Function During Sleep. Schematic diagram
individuals, but patients with duodenal ulcers show a striking increase showing plasma levels of hormones during 8 hours of sleep in an adult.
ADH, Antidiuretic hormone; ALD, aldosterone; COR, cortisol; GDH,
in acid secretion and no inhibition of secretion during the first 2 hours
gonadotropic hormone; GH, growth hormone; MLT, melatonin; PRO,
of sleep. Swallowing is suppressed during sleep, and there is prolonged prolactin; TES, testosterone; TSH, thyroid-stimulating hormone. Zero
acid clearance; these factors are important in the pathogenesis of indicates lowest secretory episode, and 100 indicates peak secretion.
esophagitis caused by nocturnal gastroesophageal reflux (Orr, 2015). (Reproduced with permission from Chokroverty, S., 1999. Physiological
Esophageal motility is also reduced during sleep. Results of studies of changes in sleep. In: Sleep Disorders Medicine: Basic Science, Techni-
intestinal motility during sleep are contradictory. A special pattern of cal Considerations, and Clinical Aspects, second ed. Butterworth-Heine-
motor activity called the migrating motor complex shows a circadian mann, Boston.)
rhythm in its propagation, with the slowest velocity during sleep.
Endocrine Function Changes Changes in Sexual Function

Profound changes in neuroendocrine secretions are found during sleep The most striking finding is increased penile tumescence in men and
(eFig. 101.25). Growth hormone secretion exhibits a pulsatile increase increased clitoral tumescence in women during REM sleep.
during NREM sleep in the first one-third of the night. Prolactin secre-
tion also rises 30–90 minutes after the onset of sleep. Sleep inhibits Thermoregulation Changes
cortisol secretion. Secretion of thyroid-stimulating hormone reaches a Body temperature has been linked intimately to the sleep-wake cycle,
peak in the evening and then decreases throughout the night. but it follows a circadian rhythm that is independent of the sleep-
Testosterone levels in adult men continue to be highest during wake rhythm. At the onset of sleep, body temperature begins to fall; it
sleep, but no clear relationship has been demonstrated between lev- reaches its lowest point during the third sleep cycle. Thermosensitive
els of gonadotropic hormones and the sleep/wake cycle in children neurons are located within the sleep promoting anterior hypothalamic
or adults. During puberty, gonadotropin levels increase in sleep. preoptic neurons. Warm-sensitive neurons show increased firing rates
Melatonin, which is synthesized and released by the pineal gland and at sleep onset causing peripheral vasodilation, heat loss, fall of body
derived from serotonin, begins to rise in the evening, attaining maxi- temperature, and increased EEG slow-wave activity during sleep.
mal values between 3:00 am and 5:00 am, and decreases to low levels Thermoregulation is maintained during NREM sleep but is nonexis-
during the day. tent in REM sleep, and experimental animals become poikilothermic.
Other endocrine changes include a maximum rise of aldosterone Thus, physiological responses (e.g., shivering, panting, sweating, and
just before awakening in the early hours of the morning and a marked piloerection) to thermal stimuli are depressed or absent during REM
decrease of plasma renin activity during REM sleep. sleep.
Sleep stages in men during normal aging
Wake Stages N1 N2
60
80
% of sleep period
40
60
20
40
0 20
16-25 26-35 36-50 51-60 61-70 71-83 16-25 26-35 36-50 51-60 61-70 71-83
Stage N3 REM sleep
20 20
% of sleep period
10 10
0 0
16-25 26-35 36-50 51-60 61-70 71-83 16-25 26-35 36-50 51-60 61-70 71-83
Age (yr) Age (yr)
Fig. 101.11 Sleep Changes with Age. Age-related changes in sleep stages occur with different chronolo-
gies for slow-wave sleep (stage N3) and rapid eye movement (REM) sleep. From young adulthood to midlife,
deep slow-wave sleep is replaced by lighter stages of sleep without significant changes in sleep fragmenta-
tion or REM sleep. From midlife to late life, sleep is more fragmented at the expense of decreases in both
lighter stages of sleep (N1 + N2) and REM sleep. (Modified from Van Cauter, E., Leproult, R., Plat, L.,2000.
Age-related changes in slow-wave sleep and REM sleep and relationship with growth hormone and cortisol
levels in healthy men. JAMA 284, 861–868. With permission.)
SLEEP DEPRIVATION AND SLEEPINESS sleep apnea, circadian rhythm disorders, and chronic insomnia
are well-known adverse effects of sleep deprivation and sleepiness.
Additional text available at http://expertconsult.inkling.com.
Sleepiness and associated morbidity are worse in night shift workers,
Total Sleep Deprivation older workers, and female shift workers. Recent data indicates that
chronic sleep deprivation is associated with poorer academic perfor-
mance as assessed by grade point average (GPA) (Chen and Chen,
Partial and Selective Sleep Deprivation 2019). The ramifications of chronic sleep loss may also predict the
likelihood of obtaining a college degree. Students who experienced
sleep deprivation from their freshman to senior years had a lower
Consequences of Excessive Daytime Sleepiness chance of graduation than students who were not sleep deprived
The consequences of excessive daytime sleepiness (EDS) presented in (Chen and Chen, 2019).
eBox 101.4 principally affect four key domains: (1) performance and
productivity at work and school, (2) higher cerebral functions, (3)
Higher Cerebral Functions
quality of life and social interactions, and (4) morbidity and mortality Sleepiness interferes with higher cerebral functions, causing impair-
(Roth and Roehrs, 1996). ment of short-term memory, concentration, attention, cognition,
and intellectual performance. Psychometric tests document increased
Performance and Productivity at Work and School reaction time in patients with excessive sleepiness. These individuals
Impaired performance and reduced productivity at work for shift make increasing numbers of errors, and they need increasing time to
workers, reduced performance in class for school and college stu- reach the target in reaction time tests (Dinges, 1995). Sleepiness can
dents, and impaired job performance in patients with narcolepsy, also impair perceptual skills and new learning. Insufficient sleep and
Sleepiness is determined by both circadian and homeostatic factors. Measurements of mood and performance after partial sleep deprivation
The circadian phase is determined by the suprachiasmatic nuclei, and (e.g., restricting sleep to 4.5–5.5 hours for 2–3 months) showed minimal
it works in a biphasic manner. There are two phases when an individ- deficits in performance, which may have been related to decreased moti-
ual has the maximal sleepiness propensity: an intense phase that occurs vation. After selective REM deprivation, PSG studies showed increased
around 3:00–5:00 am and another, which is less intense, around 3:00– REM pressure (i.e., earlier and more common onset of REM sleep during
5:00 pm. In addition, there are two forbidden, or dead, zones when successive nights) and REM rebound (i.e., quantitative increase of REM
the individual is wide awake and unable to sleep, noted around late percentages during recovery sleep). The observation of a psychotic reac-
morning and early evening. Homeostasis refers to a balance between tion after REM deprivation as noted by Dement was proved to be inac-
sleep and wakefulness. After prolonged wakefulness, there is an intense curate in subsequent investigations. Similar to REM deprivation, after
desire to sleep. REM sleep is influenced by the circadian rhythm, sleep deprivation for two consecutive nights, there is an increase in slow-
whereas slow-wave sleep is influenced by homeostasis. Much is known wave sleep during the recovery night. It is more difficult to deprive a
about the physiology of circadian rhythm, but the neurobiology of the person of slow-wave sleep than of REM sleep.
homeostatic influences remains largely unknown. Excessive sleepiness, In summary, these experiments have proven conclusively that
therefore, may result from both circadian dysrhythmia and disruption sleep deprivation causes sleepiness and impairment of performance,
of homeostasis of the body. vigilance, attention, and concentration but does not cause permanent
A large segment of the population working different shifts and memory or other CNS changes.
having irregular sleep/wake schedules is chronically sleep deprived
(Bonnet and Arand, 1995). The at-risk groups include doctors,
nurses, firefighters, interstate truck drivers, police officers, overnight eBOX 101.4 Consequences of Excessive
train drivers, and high school and college students. Comparing a Daytime Sleepiness
survey conducted at the beginning of the last century and another
Impaired performance and productivity
toward the end of the century, modern America is sleep deprived
Impaired short-term memory, attention, conception, and cognition
by approximately 1.5 hours of sleep nightly (Harrison and Horne,
Impaired quality of life
1995). This does not necessarily mean sleep requirement is smaller
Psychological stress
today, it simply means Americans are getting less sleep. However,
Increased morbidity and mortality (i.e., increased likelihood of accidents)
there may have been a sampling error in these two surveys; for
example, 2000 people were sampled in the earlier survey versus 311
in the later one. Increased environmental light and sound, industri-
alization, increasing numbers of people working in various shifts,
and the advent of television and radio are cited as some of the fac-
tors responsible for this reduction of total sleep hours. Harrison and
Horne (1995), however, argued that most people are not chron-
ically sleep deprived but have the capacity to take more sleep. In
one epidemiological study, an average prevalence of sleepiness in
Western society was estimated to be 5%–15% of the total population
(Partinen, 2011).
Experiments have been conducted to study the consequences
of total, partial, and selective sleep deprivation. These experiments
have shown clearly that in animals, sleep is necessary for survival,
but studies of complete sleep deprivation for prolonged periods (e.g.,
weeks to months) cannot be conducted in humans from a practical
point of view. Experiments in rats, using a carousel device, have pro-
vided evidence that sleep is essential for survival. All rats deprived of
sleep for 10–30 days died after having lost weight despite increasing
food intake. The rats also lost temperature control. It took longer
for rats deprived of REM sleep to die than it did those deprived of
slow-wave sleep.
Observational studies focusing on sleep deprivation have revealed

frequent occurrence of “microsleep” episodes (i.e., brief episodes of
NREM sleep) and a decrement of performance that may have been
caused by the loss of motivation. Sleep deprivation increases the day-
time tendency to sleep, as proven by multiple sleep latency tests in
such subjects. The percentage of slow-wave sleep increases consider-
ably during the recovery sleep period after sleep deprivation. The REM
sleep percentages also increase during the recovery sleep after a pro-
longed period of sleep deprivation, but this increment of REM sleep
percentage was not shown after short periods of sleep deprivation for
4 days. These facts might suggest that different mechanisms regulate
NREM and REM sleep.
SLEEP ARCHITECTURE AND AGING at the wheel at some time. Young male drivers are especially susceptible
700 to crashes caused by falling asleep, as documented in a study in North
Carolina in 1990, 1991, and 1992 (e.g., in 55% of the 4333 crashes, the
600 drivers were predominantly male and age 25 or younger). In the October
1995 Gallup poll, 52% of all adults surveyed said that in the past year,
Total sleep time (min)
500 W they had driven a car or other vehicle while feeling drowsy; 31% of adults
admitted dozing off while at the wheel of a car or other vehicle, and 4%
400 N1 reported having had an automobile accident because of tiredness during
R
driving. Sleep deprivation increases morbidity and mortality due to
300
N2 metabolic derangements and accidents. A number of national and inter-
200 national catastrophes involving industrial operations, nuclear power
plants, and all modes of transportation have been related to sleepiness
100 and fatigue (Dinges, 1995). Some of the more infamous examples are
N3 the Exxon Valdez oil spill in Alaska; the nuclear disaster at Chernobyl
0 in the former Soviet Union; the near-nuclear disaster at Three Mile
0 40
10 20
50 60 30 70 80 Island in Pennsylvania; the gas leak disaster in Bhopal, India, resulting
Age (yr) in 25,000 deaths; and the Challenger space shuttle disaster. In postgrad-
Fig. 101.12 Ontogeny of Sleep. Changes in sleep stage in infants, chil- uate medical training, data has repeatedly shown a dose response rela-
dren, adults, and elder adults, demonstrating the evolution of sleep by tionship between average hours of sleep per night and personal stress,
sleep stage. W, wake; R, rapid eye movement (REM) sleep; N1, N2, N3, reports of working while professionally and personally impaired. Studies
stages N1, N2, and N3 NREM sleep, respectively. Compared with early comparing extended call shift with a revised schedule allowing for sleep
life, older adults spend more time awake in bed, less time in R and N3
recovery revealed the rate of diagnostic errors was 5.6 times higher in the
sleep, and more time in lighter stages of sleep.
traditional schedule than the intervention schedule as depicted in Fig.
101.26 (Lockley et al., 2004). These reports among others have catalyzed
excessive sleepiness may cause irritability, anxiety, and depression. the Institute of Medicine (IOM) to proposed new work hours schedules
Learning disabilities and cognitive impairment due to impaired vigi- which were accepted by the Accreditation Council for Graduate Medical
lance have also been described (Roth and Roehrs, 1996). Education (ACGME, 2010) and went into effect in July 2011.
Morbidity and Mortality Causes of Excessive Daytime Sleepiness

Persistent daytime sleepiness causes individuals to have an increased Excessive sleepiness may result from both physiological and patholog-
likelihood of accidents. Estimates by the US National Highway Traffic ical causes (eBox 101.5).
Safety Administration showed that approximately 56,000 police-re-
ported crashes per year resulted from drivers who were “asleep at the Physiological Causes of Sleepiness
wheel.” New York state police estimate that 30% of all fatal crashes It is important to first differentiate sleepiness from fatigue or tired-
along the New York State Thruway occur because the driver fell asleep ness. Based on the behavioral definition, fatigue can be differentiated
at the wheel. Approximately 1 million crashes annually (one-sixth of all by absence of the previously mentioned criteria for the presence of
crashes) are thought to be produced by driver inattention or lapses. Sleep sleep. Fatigue defines a state of sustained lack of energy coupled with
deprivation and fatigue make such lapses more likely to occur. Truck a lack of motivation and drive, but without the behavioral criteria
drivers are especially susceptible to fatigue-related crashes (Lyznicki of sleepiness such as heaviness or drooping of the eyelids, sagging or
et al., 1998). Many truckers drive during the night while they are sleep- nodding of the head, and yawning. In addition, fatigue is often a sec-
iest. Truckers also may have a high prevalence of sleep apnea. The US ondary consequence of sleepiness. Sleep deprivation and sleepiness
Department of Transportation estimates that 200,000 automobile acci- due to lifestyle and habits of going to sleep and waking up at irregular
dents each year may be related to sleepiness. Nearly one-third of all hours can be considered to result from disruption of the normal cir-
trucking accidents that are fatal to the driver are related to sleepiness cadian and homeostatic physiology. Groups who are excessively sleepy
and fatigue. A general population study by Hays and colleagues (1996) because of lifestyle and inadequate sleep include young adults and
involving 3962 elderly individuals reported an increased mortality risk of elderly individuals, workers on irregular shifts, healthcare profession-
1.73 in those with EDS, defined by napping most of the time. als (e.g., physicians, particularly the residents, and nurses), firefighters,
The presence of sleep disorders (see Primary Sleep Disorders police officers, train drivers, pilots and flight attendants, commercial
Associated with Excessive Daytime Sleepiness, later) increases the risk truck drivers, and those individuals with competitive drives to move
of crashes. Individuals with untreated insomnia, sleep apnea, and nar- ahead in life, sacrificing hours of sleep and accumulating sleep debt.
colepsy, as well as shift workers, have more automobile crashes than Among young adults, high school and college students are particularly
other drivers (Costa de Silva et al., 1996). A 1991 Gallup Organization at risk for sleep deprivation and sleepiness. The reasons for excessive
national survey found that individuals with chronic insomnia reported sleepiness in adolescents and young adults include both biological and
2.5 times as many fatigue-related automobile accidents as those with- psychosocial factors. Some of the causes for later bedtimes and sleep
out insomnia. The same 1991 Gallup survey found serious morbidity deprivation in these groups include social interactions with peers;
associated with untreated sleep complaints, as well as impaired abil- homework in the evening; sports, employment, or other extracurric-
ity to concentrate and accomplish daily tasks, impaired memory, and ular activities; early wake-up times to start school; and academic obli-
interpersonal difficulties. Sleep deprivation has an adverse impact on gations requiring additional school or college work at night. Biological
cognition and leads to increases in number of failures to carry out factors may play a role but are not well studied. For example, teenagers
intended actions, which may have severe consequences in safety-criti- may need extra hours of sleep. Also, the circadian timing system may
cal situations (Grundgeiger et al., 2014). change with sleep phase delay in teenagers. EDS associated with shift
A 1994 telephone survey of drivers by the New York State Task Force work has been described (see Primary Sleep Disorders Associated with
estimated that approximately 25% reported that they had fallen asleep Excessive Daytime Sleepiness, later).
Quality of Life and Social Interaction have difficulty with sleeping and sleepiness as a result of insufficient
People complaining of EDS are often under severe psychological stress. sleep and circadian dysrhythmia. Data illustrates the positive effects
They are often wrongly perceived as dull, lazy, and downright stupid. of protecting sleep and preventing sleep deprivation. A study from
Excessive sleepiness may cause severe marital and social problems and 2010 in healthy elderly individuals older than 75 years of age who had
impaired quality of life. Individuals with this problem have serious dif- no sleep complaints demonstrated that allowing more time to sleep
ficulty with interpersonal relationships. (about 7.5 hours nightly) was associated with better maintenance of
Shift workers constitute approximately 20%–25% of the work force physical health-related quality of life and stability of medical illness
in America (i.e., approximately 20 million people). A majority of them burden over 30 months (Reynolds et al., 2010).
eBOX 101.5 Causes of Excessive Daytime Sleepiness

Physiological Causes Acromegaly
Sleep deprivation and sleepiness related to lifestyle and Diabetes mellitus
irregular sleep/wake schedule Hypoglycemia
Hyperglycemia
Pathological Causes
Psychiatric or Psychological Causes
Primary Sleep Disorders Depression
Obstructive sleep apnea syndrome Psychogenic unresponsiveness or sleepiness
Central sleep apnea syndrome
Narcolepsy Neurological Causes
Idiopathic hypersomnia Neurodegenerative disorders
Circadian rhythm sleep disorders: Alzheimer disease
Jet lag Parkinson disease
Delayed sleep phase state Multiple system atrophy
Irregular sleep/wake pattern Myotonic dystrophy and other neuromuscular disorders causing sleepiness
Shift-work sleep disorder CNS space-occupying tumors/lesions (i.e., tumors, demyelinating or vascular
Free-running (non-entrained) type lesions) affecting the diencephalon
Periodic limb movement disorder Post-traumatic hypersomnolence
Restless legs syndrome Encephalitis lethargica and other encephalitides and encephalopathies,
Behaviorally induced insufficient sleep syndrome including Wernicke encephalopathy
Inadequate sleep hygiene Cerebral trypanosomiasis (African sleeping sickness)
Kleine-Levin syndrome (KLS) secondary to sleep apnea
Seasonal affective depression
Occasionally due to insomnia Medication-Related Hypersomnia
Benzodiazepines
General Medical Disorders Nonbenzodiazepine hypnotics (e.g., zolpidem, eszopiclone)
Hepatic failure Sedative antidepressants (e.g., tricyclic antidepressants, trazodone)
Renal failure Antipsychotics
Respiratory failure Nonbenzodiazepine anxiolytics (e.g., buspirone)
Electrolyte disturbances Antihistamines
Cardiac failure Narcotic analgesics
Severe anemia Beta-blockers
Endocrine causes
Hypothyroidism Toxin- and Alcohol-Induced Hypersomnolence
Sleep Duration Recommendations
Infants Children Children Teens Adults Older Adults

4-12 mo 3-5 yr 6-12 yr 13-18 yr 19-65 yr 65 yr+
12-16 10-13 9-12 8-10 7-8 7-8

(including naps) (including naps)
Hours a day
The 2015 Joint Consensus Statement from the American Academy of Sleep Medicine (AASM)
and Sleep Research Society (SRS)
Fig. 101.13 Sleep Duration Recommendations. In 2015, the American Academy of Sleep Medicine (AASM) and
Sleep Research Society (SRS) developed a consensus recommendation for the proper amount of sleep needed
to promote optimal health in adults (From Watson, N.F., Badr, M.S., Belenky, G., et al., 2015. Recommended
amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine
and Sleep Research Society. Sleep. 38 [6], 843–844. Published 2015 Jun 1. https://doi.org/10.5665/sleep.4716.)
Pathological Causes of Sleepiness sclerosis (MS) (Kanbayashi et al., 2009). Narcolepsy-cataplexy has been
Neurological causes of excessive sleepiness may include CNS tumors and described in occasional patients with MS (Nishino and Kanbayashi,
vascular lesions affecting the ARAS and its projections to the posterior 2005) and arteriovenous malformations in the diencephalon.
hypothalamus and thalamus, leading to daytime sleepiness. It should be EDS has been described in association with encephalitis lethargica
noted that lesions of this system often cause coma rather than just sleepi- and other encephalitides, as well as with encephalopathies, including
ness. Brain tumors (e.g., astrocytomas, suprasellar cysts, metastases, lym- Wernicke encephalopathy. It was noted that the lesions of encephali-
phomas, and hamartomas affecting the posterior hypothalamus, pineal tis lethargica described by Von Economo in the beginning of the last
tumors, and astrocytomas of the upper brainstem) may produce excessive century, which severely affected the posterior hypothalamic region
sleepiness. Prolonged hypersomnia may be associated with tumors in the (eFig. 101.27), were associated with the clinical manifestation of
region of the third ventricle. “Secondary” narcolepsy with or without cat- extreme somnolence. These lesions apparently interrupted the ascend-
aplexy with hypocretin deficiency resulting from craniopharyngioma and ing arousal systems projecting to the posterior hypothalamus through a
other tumors of the hypothalamic and pituitary regions has been described. variety of mechanisms including cerebrovascular accidents (Scammell
Cataplexy associated with sleepiness, sleep paralysis, and hypnagogic hal- et al., 2001). While encephalitis lethargica is now extinct, lesions in
lucinations has been described in patients with rostral brainstem gliomas the diencephalon due to CNS and comorbid medial reasons may occa-
with or without infiltration of the walls of the third ventricle. Narcolepsy- sionally be encountered on the neurology wards. Cerebral sarcoidosis,
cataplexy also has been described in a human leukocyte antigen (HLA) Whipple disease, and tumors involving the hypothalamus may cause
DR2-negative patient with a pontine lesion documented by MRI. symptomatic or secondary narcolepsy, which may present with severe
Other neurological causes of EDS include bilateral paramedian tha- hypersomnolence with or without hypothalamic deficiencies.
lamic and sometimes other cortical and subcortical infarcts (Bassetti Cerebral trypanosomiasis, or African sleeping sickness, is transmit-
and Valko, 2006), post-traumatic hypersomnolence, and multiple ted to humans by tsetse flies: Trypanosoma gambiense causes Gambian
Th
a Aq
V3
O
Hy
K.oculomet V4
eFig. 101.27 The Origin of Encephalitis Lethargica or Von Econo-

mo’s Sleeping Sickness. The role of the brain in mediating sleep-wake
behavior was initially proposed in 1916 when Baron Constantine von
Economo performed autopsies on brain tissue recovered from victims
of a viral encephalitis that profoundly disrupted sleep-wake regulation.
Data from Von Economo’s clinico-anatomic studies showed lesions at
the junction of the midbrain and posterior hypothalamus (diagonal hatch-
ing) produced hypersomnolence. In contrast, lesions involving the basal
forebrain and anterior hypothalamus (horizontal hatching) produced pro-
found insomnia. Von Economo documented that lesions between these
two sites (see arrow), which included the lateral hypothalamic area,
caused narcolepsy. Until recently, however, the nature of the circuitry
subserving these putative wake/arousal centers and sleep-promoting
brain regions remained elusive. (From von Economo, C., 1930. Sleep as
a problem of localization. J. Nerv. Ment. Dis. 71, 249–259.)
16 The following question was found to have 94% sensitivity and

87% specificity in detecting RBD: “Have you ever been told, or sus-
14 0 h in bed 4 h in bed pected yourself, that you seem to ‘act out your dreams’ while asleep
12 (for example, punching, flailing your arms in the air, making running
PVT lapses (relative #)
movements, etc.)?” (Postuma et al., 2012).

10 These and other studies provide evidence supporting the notion that
Poor performance
dopamine activity is normally influenced by circadian factors (Rye and
8 6 h in bed Jankovic, 2002). For example, tyrosine hydroxylase levels fall several
6 hours before waking, and their increase correlates with motor activity.
The relationship between hypocretin and sleep disorders associated with
4 PD is of considerable interest especially since recent data has linked deple-
tion of hypothalamic hypocretin/orexin neurons as positively correlating
2
8 h in bed with impaired memory in animal models of PD (Oliveira et al., 2019)
0 Myotonic dystrophy and other neuromuscular disorders may cause EDS
due to associated sleep apnea-hypopnea syndrome and hypoventilation.
BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 In addition, in myotonic dystrophy, there may be involvement of the
Days of nocturnal sleep restriction ARAS as part of the multisystem membrane effects noted in this disease.
Fig. 101.14 Sleep Deprivation and Performance. Data depicting a
Excessive daytime sleepiness associated with general
“dose relationship” between poor performance and the Psychomotor medical disorders. Several systemic diseases such as hepatic, renal,
Vigilance Task (PVT) performance lapses under varying doses of daily or respiratory failure and electrolyte disturbances may cause metabolic
sleep. Displayed are group averages for subjects in the 8-hour (dia- encephalopathies that result in EDS. Patients with severe EDS drift into a
mond), 6-hour (light square), and 4-hour (circle) chronic sleep period coma. The other medical causes for EDS include congestive heart failure
time in bed (TIV) across 2 weeks, and in the 0-hour (dark square) sleep and severe anemia. Hypothyroidism and acromegaly also may cause EDS
condition across 3 days. Subjects were tested every 2 hours each day; due to the associated sleep apnea syndrome. Hypoglycemic episodes in
data points represent the daily average (07:30–23:30) expressed rela- diabetes mellitus and severe hyperglycemia are additional causes of EDS.
tive to baseline (BL). Curves through data points represent statistical Primary sleep disorders associated with excessive daytime
nonlinear, model-based, best-fitting profiles of the response to sleep
sleepiness. A number of primary sleep disorders cause excessive
deprivation for subjects in each of the four experimental conditions.
(Adapted from Van Dongen, H.P., Maislin, G., Mullington, J.M., et al.,
sleepiness (see eBox 101.5). The most common cause of EDS in the
2003. The cumulative cost of additional wakefulness: dose-response general population is behaviorally induced insufficient sleep syndrome
effects on neurobehavioral functions and sleep physiology from chronic which is associated with significant adverse health and social outcomes
sleep restriction and total sleep deprivation. Sleep 26, 117–126.) including association with 7 of the 15 leading causes of death and has
been declared to be a “public health epidemic” (Chattu et al., 2018).
or West African sleeping sickness, and Trypanosoma rhodesiense causes The next most common cause is obstructive sleep apnea syndrome
East African sleeping sickness. (OSAS) followed with narcolepsy and idiopathic hypersomnolence.
Certain neurodegenerative diseases such as Alzheimer disease Most patients with EDS referred to the sleep laboratory have OSAS.
(AD), PD, and multisystem atrophy (MSA) also may cause EDS Other causes of EDS include circadian rhythm sleep disorders, periodic
(Raggi and Ferri, 2010). The causes of EDS in AD include degen- limb movement disorder (PLMD), RLS, and inadequate sleep hygiene
eration of the SCN, resulting in circadian dysrhythmia, associated and certain CNS acting agents.
sleep apnea-hypopnea, and frequent periodic limb movements in Many sedatives and hypnotics cause EDS. In addition to the benzodi-
sleep (PLMS). In PD, excessive sleepiness may be due to the associ- azepine and nonbenzodiazepine hypnotics and sedative antidepressants
ated PLMS, sleep apnea, and depression. EDS in MSA associated with (e.g., tricyclic antidepressants and trazodone), nonbenzodiazepine neu-
cerebellar-parkinsonism or parkinsonian-cerebellar syndrome and roleptics, antihistamines, antipsychotics, most older generation antiepi-
progressive autonomic deficit may be caused by the frequent asso- leptic drugs, and narcotic analgesics including tramadol also cause EDS.
ciation with sleep-related respiratory dysrhythmias, impaired mela- Beta-blockers for treatment of hypertension may occasionally cause
tonin secretion, and possible degeneration of the reticular activating excessive sleepiness.
arousal systems (Cao et al., 2018; Devine, Lee Khemani, and Carter, Toxin and alcohol-related hypersomnolence can occur as well. Many
2019; Nakamura et al., 2018; Rekik et al., 2018; Silvestri, 2018). industrial toxins such as heavy metals and organic toxins (e.g., mercury,
Sleep disorders are being increasingly recognized as a feature of lead, arsenic, and copper) may cause EDS. These may sometimes also
PD and other parkinsonian disorders. Although some studies have cause insomnia. Individuals working in industrial settings using toxic
attributed the excessive daytime drowsiness and irresistible sleep epi- chemicals routinely are at risk. These toxins also may cause systemic dis-
sodes (sleep attacks) to antiparkinsonian medications (Ondo et al., turbances such as alteration of renal, liver, and hematological function.
2001), sleep disturbances are also an integral part of PD (Arnulf et al., There may be an impairment of nerve conduction. Chronic use of alco-
2002). In one study of 303 patients with PD, 21% reported falling asleep hol at bedtime may produce alcohol-dependent sleep disorder. Usually
while driving (Ondo et al., 2002). Several studies also reported a rela- this causes insomnia, but sometimes the patients may have excessive
tively high incidence (10%–20%) of symptoms of restless legs syndrome sleepiness in the daytime. Many of these patients suffer from chronic
(RLS) in patients with PD (Hening et al., 2009; Krishnan et al., 2003; alcoholism. Acute ingestion of alcohol causes transient sleepiness.
Ondo et al., 2002). There is also increasing awareness about the relation-
ship between parkinsonian disorders and REM sleep behavior disorder CLASSIFICATION OF SLEEP DISORDERS
(RBD). RBD as well as its associated PSG biomarker—RSWA—may be
the presenting feature of PD, MSA, and other parkinsonian disorders, International Classification of Sleep Disorders
long before the appearance of the motor manifestations (Boeve, 2010; The latest edition of the International Classification of Sleep Disorders
Boeve et al., 2007; Iranzo et al., 2014; Postuma et al., 2010a; Raggi and (ICSD-III) (AASM, 2014) listed seven broad categories of disor-
Ferri, 2010; McCarter et al., 2019; Nepozitek et al., 2019). dered sleep, along with several subcategories under each category as
Fig. 101.16 Neuroanatomy and Neuromodulators of Wake (blue) and Sleep (red). The brain in the awake
state illustrates important arousal and sleep centers and pathways of neurotransmission. Current models of
wakefulness and sleep hold that wakefulness is maintained by the combined excitatory influence of fore-
brain-projecting noradrenergic (locus coeruleus), histaminergic (tuberomammillary nucleus), serotoninergic
(dorsal raphe), and cholinergic (not shown) cell groups located at or near the mesopontine junction. Sleep, on
the other hand, is initiated and maintained by neurons in the median preoptic (MnPO) and ventrolateral preoptic
(VLPO) nuclei via inhibitory projections to the more rostrally situated wakefulness-promoting cell groups. Hypo-
cretin (orexin) neurons located in the lateral hypothalamus reinforce activity in the brainstem arousal pathways
and also stabilize both sleep and wakefulness. Disruption of the hypocretin system leads to narcolepsy. The
suprachiasmatic nuclei (SCN) determine the timing of the sleep-wake cycle and help to “consolidate” these
behavioral states. The pineal gland, located in the epithalamus, produces melatonin, a hormone thought to func-
tion as a hypnotic signal. The cerebral cortex and medullary brainstem also contain subpopulations of γ-amino
butyric acid (GABA)-ergic sleep-active neurons. (From Biology of Sleep Kryger MH, Avidan, AY, Berry, R. Atlas
of clinical sleep medicine. Second edition. ed. Philadelphia, PA: Elsevier/Saunders; 2013 Chapter 3, 22-64.)
well as Appendices A and B (see eBox 101.6). Appendix A includes into single entity and recurrent hypersomnia into a singly entry with
sleep-related medical and neurological disorders, including sleep-re- a subtype.
lated epilepsy and headache, fatal familial insomnia (FFI), as well as
sleep-related laryngospasm, sleep-related gastroesophageal reflux, Approach to a Patient with Sleep Complaints
and sleep-related myocardial ischemia. Appendix B includes sub- The approach to a patient with a sleep complaint must begin with a clear
stance-induced (e.g., alcohol, opioid, cannabis, sedative, hypnotic understanding of sleep disorders as listed in the International Classification
or anxiolytic, cocaine, other stimulants, hallucinogens, nicotine, of Sleep Disorders (ICSD). Some common sleep complaints are trouble
inhalants, and other psychoactive substances) sleep disorders. The falling asleep and staying asleep (insomnia); falling asleep during the day
seven broad categories consist of insomnia, sleep-related breathing (daytime hypersomnolence); and inability to sleep at the right time (circa-
disorders (SBDs), central disorders of hypersomnolence, circadian dian rhythm sleep disorders). Other common complaints are thrashing and
rhythm sleep disorders, parasomnias, sleep-related movement disor- moving about in bed with repeated leg jerking (parasomnias and other
ders, and other sleep disorders. The ICSD-III reflects a major change abnormal movements, including nocturnal seizures) and RLS.
from the ICSD-II predominantly in simplification of the insomnia Cardinal manifestations in a patient complaining of insomnia
disorders, an expansion of the SBDs, classification of narcolepsy into include all or some of the following: difficulty falling asleep; frequent
type 1 and type 2, consolidating the ICSD-II idiopathic hypersomnias awakenings, including early-morning awakening; insufficient or total
eBOX 101.6 International Classification of Sleep Disorders

The third edition of the International Classification of Sleep Disorders (ICSD-III: Diag- d. Non-24-hour sleep-wake rhythm disorder
nostic and Coding Manual, 2014; American Sleep Disorders Association, Rochester, e. Shift work disorder (SWD)
MN) includes seven major categories of sleep disorders: f. Jet lag disorder
I. Insomnia g. Circadian sleep-wake disorder not otherwise specified (NOS)
II. Sleep-related breathing disorders V. Parasomnias
III. Central disorders of hypersomnolence 1. NREM-related parasomnias
IV. Circadian rhythm sleep-wake disorders a. Disorders of arousal (From NREM Sleep)
V. Parasomnias b. confusional arousals
VI. Sleep-related movement disorders Sexsomnias
VII. Other sleep disorders c. Sleepwalking
I. Insomnia Sleep-related eating disorder
1. Disorders d. Sleep terrors
a. Chronic insomnia disorder 2. REM-related parasomnias
b. Short-term insomnia disorder a. REM sleep behavior disorder (RBD)
c. Other insomnia disorder b. Recurrent isolated sleep paralysis
2. Isolated symptoms and normal variants c. Nightmare disorder
a. Excessive time in bed 3. Other parasomnias
b. Short sleeper a. Exploding head syndrome
II. Sleep-Related Breathing Disorders b. Sleep-related hallucinations
Sleep-related breathing disorders are characterized by abnormal respira- c. Sleep enuresis
tion during sleep; they occur in both adults and children. There are four major d. Parasomnia due to a medical disorder
sleep-related breathing disorders: e. Parasomnia due to a medication or substance
1. Central sleep apnea syndromes f. Parasomnia, unspecified
a. Central sleep apnea with Cheyne-Stokes 4. Isolated symptoms and normal variants
b. Central apnea due a medical disorder without Cheyne-Stokes breathing a. Sleep talking
c. Central sleep apnea due to high altitude periodic breathing VI. Sleep-Related Movement Disorders
d. Central sleep apnea due to a medication or substance a. Restless legs syndrome (RLS)
e. Primary central sleep apnea b. Periodic limb movement disorder (PLMD)
f. Primary sleep apnea of infancy c. Sleep-related leg cramps
g. Primary central sleep apnea of prematurity d. Sleep-related bruxism
h. Treatment-emergent central sleep apnea (previously noted as “Com- e. Sleep-related rhythmic movement disorder
plex sleep apnea”) f. Benign sleep myoclonus of infancy
2. Obstructive sleep apnea syndromesThe obstructive sleep apnea syn- g. Propriospinal myoclonus at sleep onset
dromes include adult obstructive sleep apnea and pediatric obstructive h. Sleep-related movement disorder due to a medical disorder
sleep apnea. i. Sleep-related movement disorder due to a medication or substance
3. Sleep-related hypoventilation disorders j. Sleep-related movement disorder, unspecified
a. Obesity hypoventilation syndrome 1. Isolated symptoms and normal variants
b. Congenital central alveolar hypoventilation syndrome a. Excessive fragmentary myoclonus
c. Late-onset central hypoventilation with hypothalamic dysfunction b. Hypnagogic foot tremor and alternating leg muscle activation
d. Idiopathic central alveolar hypoventilation c. Sleep starts (hypnic jerks)
e. Sleep-related hypoventilation due to a medication or substance VII. Other Sleep Disorders
f. Sleep-related hypoventilation due to a medical disorder This category includes sleep disorders that cannot be appropriately classified
4. Sleep-related hypoxemia disorder: elsewhere in the ICSD-III, either because the disorder overlaps with more than
a. Sleep-related hypoxemia one category or when insufficient data have been collected to firmly establish
5. Isolated symptoms and normal variants another diagnosis.
a. Snoring
b. Catathrenia Isolated Symptoms and Normal Variants
III. Central Disorders of Hypersomnolence: Other sleep-related symptoms or events do not meet the standard definition of a
a. Narcolepsy type 1 (NT1) sleep disorder.
b. Narcolepsy type 2 (HT2)
c. Idiopathic hypersomnia (IH) Appendices
d. Kleine-Levin syndrome (KLS) The third edition of the International Classification of Sleep Disorders (ICSD-III)
e. Hypersomnia due to a medical disorder includes two appendices:
f. Hypersomnia due to a medication or substance Appendix A includes diagnoses that can be classified as medical or neurolog-
g. Hypersomnia associated with a psychiatric disorder ical disorders
h. Insufficient sleep syndrome 1. Disorders
1. Isolated symptoms and normal variants a. Fatal familial insomnia
a. Long sleeper b. Sleep-related epilepsy
IV. Circadian Rhythm Sleep–Wake Disorders c. Sleep-related headaches
a. Delayed sleep-wake phase disorder (DSPD) d. Sleep-related laryngospasm
b. Advanced sleep-wake phase disorder (ASPD) e. Sleep-related gastroesophageal reflux
c. Irregular sleep-wake rhythm disorder (ISWD) f. Sleep-related myocardial ischemia
Appendix B is a guide to ICD-10-CM coding for substance-induced sleep disorders.
Wakefulness Non-REM sleep REM sleep
Hypocretin Thalamus
Hypocretin
BF VLPO PPT PPT REM-on

TMN PPT TMN TMN
SN LDT SN LDT LDT neurons
VTA Raphe LC VTARaphe LC Raphe LC
A B C
Motor neurons
Wakefulness Nonrapid eye movement sleep (non-REM) sleep Rapid eye movement (REM) sleep
Neurochemistry
A B C
BF: Acetylcholine ++++ + ++++
LDT: Acetylcholine ++++ +++ → 0 ++++
Dorsal and median ++++ ++ 0

raphe: Serotonin
Loceus coeruleus : (NE) ++++ ++ 0
TMN: (Histamine) ++++ ++ 0
Posterior/lateral ++++ + +
hypothalamus
(Hypocretin/orexin)
Ventrolateral preoptic + +++ ++++

area (GABA)
Neurophysiology Wakefulness Nonrapid eye movement sleep (non-REM) sleep Rapid eye movement (REM) sleep
Posture Erect, sitting, or recumbent Recumbent Recumbent

Mobility Normal Slightly reduced or immobile; postural shifts Moderately reduced or immobile; myoclonic jerks
Response to stimulation Normal Mildly to moderately reduced Moderately reduced to no response
Level of alertness Alert Unconscious but reversible Unconscious but reversible
Eyelids Open Closed Closed
Eye movements Waking eye movements Slow rolling eye movements Rapid eye movements
EEG Alpha waves; desynchronized Synchronized Theta or sawtooth; desynchronized
EMG (muscle tone) Normal Mildly reduced Moderately to severely reduced or absent
EOG Waking eye movements Slow rolling eye movements Rapid eye movements
Fig. 101.17 Neuroanatomy and Neuromodulators of Wake Nonrapid Eye Movement and Rapid Eye
Movement Sleep. The brain in the awake state illustrates important arousal and sleep centers and path-
ways of neurotransmission. Schematic representation of wake/sleep pathways and localization of strategic
arousal and sleep centers in the brain. Midsagittal view is shown with superimposed schematic representa-
tion of circuits most relevant for wakefulness (A), non-REM sleep (B), and REM sleep (C). A, Mechanism of
Wakefulness (Arousal): Summary: hypocretin/orexin neurons project to, and excite, the other wake-promoting
brainstem nuclei, as well as the basal forebrain, and widely throughout the cortex (red arrows). Cholinergic
input (orange) from the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei project through the
thalamus and facilitate thalamocortical transmission of arousal signals. A second pathway projects through
the hypothalamus to cortical centers and facilitates the processing of thalamocortical inputs that arise from
midbrain centers, including the noradrenergic (blue) locus coeruleus (LC); the serotonergic (purple) dorsal raphe
(Raphe); the histaminergic (pink) tuberomammillary nucleus (TMN); and the dopaminergic (yellow) ventral peri-
aqueductal grey matter (VPAG). This pathway also receives input from the cholinergic (orange) basal fore-
brain (BF) and the peptidergic neurons of the lateral hypothalamus (LH) and perifornical neurons (PeF), which
contain hypocretin or melanin-concentrating hormone (light green). The melatonergic (red) neural network
affects arousal and sleep through regulation of circadian rhythms. This internal biological clock originates in the
suprachiasmatic nucleus (SCN), projects through the dorsomedial hypothalamus (DMH), and sends inhibitory
signals to the γ-aminobutyric acid (GABA)-ergic (grey) ventrolateral preoptic nucleus (VLPO) of the hypothala-
mus. During non-REM sleep, the ventrolateral preoptic nucleus (VLPO) projects to, and inhibits, the wake-pro-
moting nuclei (green lines). During REM sleep, the LDT and PPT cholinergic neurons lack the wake-inhibition
(from hypocretin/orexin, TMN, raphe, and LC), and excite the thalamus (yellow). Medullary interneurons inhibit
motor neurons, causing atonia in REM. BF, Basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmentum;
PPT, pedunculopontine nucleus; SN, substantia nigra; TMN, tuberomammillary nucleus; VLPO, ventrolateral
preoptic nucleus; VTA, ventral tegmental area. (Adapted from Nishino, S., [ed.]. 2013. Basic sleep concepts,
science, deprivation, and mechanisms of neurotransmitters and neuropharmacology of sleep/wake regulations.
Encyclopedia of Sleep. Stanford University School of Medicine, Palo Alto, CA, pp 395–406. With permission.)
Telecephalon & Telecephalon &

Diencephalon Diencephalon
Midbrain Midbrain
Locomoter Locomoter
generators generators
Pons Pre-coeruleus Pre-coeruleus
Pons
Sublaterodorsal Sublaterodorsal
nucleus nucleus
Indirect route Indirect route
Magnocellular Magnocellular
reticular formation reticular formation
Medulla Medulla
Direct route Direct route
Indirect route Indirect route
Spinal interneuron Spinal interneuron
Spinal cord Spinal cord
Spinal motor neuron Spinal motor neuron
A B
Fig. 101.19 Neurophysiology and Neuropathology of Rapid Eye Movement (REM) Sleep Motor Con-
trol. A, Physiology of normal rapid eye movement (REM) sleep muscle atonia: The “REM-on” regions con-
sisting of the pre-coeruleus and sublaterodorsal nucleus (SLD) activate two inhibitory pathways, referred to
as the direct route and indirect route. The SLD nucleus stimulates an inhibitory spinal interneuron via the
direct route and this nucleus in turn inhibits or hyperpolarizes the alpha motor neuron to induce skeletal
muscle atonia. The SLD nucleus activates the medullary magnocellular reticular formation (MCRF) through
the indirect route causing the MCRF to inhibit the motor neuron and thus produce skeletal muscle atonia.
B, Pathophysiology in the setting of REM sleep behavior disorder. Dysfunction of the SLD nucleus and/or
its afferent or efferent neuropathways results in loss of the normally present inhibition of the motor neuron
thus permitting skeletal muscles to become active during REM sleep culminating in augmentation of EMG
tone (RSWA) and dream enactment behavior (DEB) diagnostic of RBD. Rapid eye movement sleep behavior
disorder, chest. (Adapted from Boeve, B.F., Silber, M.H., Saper, C.B., et al., 2007. Pathophysiology of REM
sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130 [Pt 11], 2770–2788.)
lack of sleep; daytime fatigue, tiredness, or sleepiness; lack of concen- (Kleine-Levin syndrome [KLS]). Sometimes a patient with RLS may
tration, irritability, anxiety, and sometimes depression and forgetful- complain of EDS. Abnormal movements and behavior during sleep
ness; and preoccupation with psychosomatic symptoms, such as aches include REM and NREM sleep parasomnias and other abnormal
and pains. movements (e.g., PLMS), some daytime movement disorders that per-
Cardinal manifestations of hypersomnia include EDS, falling asleep sist during sleep, and nocturnal seizures.
in an inappropriate place and under inappropriate circumstances, no The physician must evaluate the patient first on the basis of the
relief of symptoms after additional sleep at night, daytime fatigue, history and physical examination before undertaking laboratory tests,
inability to concentrate, and impairment of motor skills and cognition. which must be determined by the clinical diagnosis. The first step in
Additional symptoms depend on the nature of the underlying sleep the assessment of a sleep-wakefulness disturbance is careful evaluation
disorder (e.g., snoring and apneas during sleep witnessed by a bed of the sleep complaints. The history should include information on the
partner in patients with OSAS; attacks of cataplexy, hypnagogic hal- patient’s entire 24 hours and must include a detailed sleep history, with
lucinations, sleep paralysis, automatic behavior, and disturbed night a sleep questionnaire as well as a sleep log or diary (Fig. 101.28). It must
sleep in patients with narcolepsy). also include psychiatric, neurological, medical, drug-alcohol, and family
Sleeplessness and EDS are symptoms; therefore, every attempt and past histories. The history must be followed by a physical examina-
should be made to find a cause for these complaints. Insomnia may tion to uncover medical or neurological causes of insomnia, hypersom-
be due to a variety of causes. The etiological differential diagnosis for nia, and parasomnias (Avidan, 2018). Physical examination of patients
EDS may include OSAS; central sleep apnea (CSA); narcolepsy; idio- with OSAS may uncover upper airway anatomical abnormalities.
pathic hypersomnia; several psychiatric, neurological, and other med- It is advisable to interview the bed partner, caregiver, or parents
ical illnesses; drug or alcohol abuse; and periodic hypersomnolence of children to get an adequate history, particularly the history during
Organization
Pineal A
gland
C
Retina
Dark +
(Stimulation of +
Melatonin Production) –
+
Raphe
Retina RHT nucleuss NA
B
(GLU)
SCN –
SCG
MT1 , MT2
5-HT2C
+
–
Light receptors
(Inhibition of
Melatonin Production)
Circadian rhythms
(e.g., hormones,
core temperature, Modulation
sleep, appetite) (e.g., mood,
meals, work
sleep, activity)
Fig. 101.20 The Suprachiasmatic Nucleus Sends Timing Information to the Brain and Periphery. The
circadian pacemaker is located in the hypothalamic suprachiasmatic nucleus (SCN). It is responsible for gen-
erating the internal circadian rhythms in gene expression, electrophysiology, and hormone secretion. Direct
projections from the retina carry information about the cycle of light and darkness to the SCN, which in turn
synchronizes a phase of SCN rhythms with the external environment. (From de Bodinat, C., Guardiola-Lemai-
tre, B., Mocaer, E., Renard, P., Munoz, C., Millan, M.J. 2010. Agomelatine, the first melatonergic antidepres-
sant: discovery, characterization and development. Nat. Rev. Drug Discov. 9[8], 628–642.)
sleep at night, which may have an effect on daytime functioning. A phenomena such as cataplexy, hypnagogic hallucinations, sleep paral-
sleep questionnaire containing a list of pertinent questions relating to ysis, and disturbed night sleep in a young adult suggests narcolepsy.
sleep complaints; sleep hygiene; sleep patterns; medical, psychiatric, Nonrefreshing sleep or no benefit from additional sleep may suggest
and neurological disorders; and drug and alcohol use may be filled out sleep apnea syndrome and idiopathic hypersomnia. Identification of
by the patient to save time during the history taking. A sleep log kept an irregular sleep-wake schedule and delayed sleep onset and awaken-
over a 2-week period also is a valuable indicator of sleep-wake-pat- ing and inquiry into the patient’s lifestyle to uncover sleep deprivation
terns and is of fundamental importance in screening for causes of sleep and insufficient sleep are important for the diagnosis of sleepiness. An
deprivation. Such a log should include bedtime, rise time on week- urge to move the limbs in the early evening may suggest RLS. A fam-
days and weekends, daytime naps, amount of time needed to fall sleep, ily history is important in primary sleep disorders such as narcolepsy,
number and duration of nighttime awakenings, total sleep time, and RLS, and advanced/delayed circadian patterns
subjective feelings upon awakening.
Pertinent questions can help diagnose primary sleep disorders. For Subjective Measures of Sleepiness
example, a history of snoring and apneas witnessed during sleep at A variety of scales have been developed to assess the subjec-
night would suggest OSAS. Unusual movements during sleep at night tive degree of sleepiness. The most well-known is the Epworth
may suggest PLM. A history of sleep attacks and REM-sleep intrusion Sleepiness Scale (ESS), which assesses the level of sleepiness (Johns,
Retinohypothalamic tract
to the SCN
Light
SCN
ANS
HPA
Behaviora Via hormones,

l
(eating an stimulus neural signals
apple)
Peripheral
tissues
Muscle
Lung
Heart
Liver
Gut
Fig. 101.21 The suprachiasmatic nucleus (SCN) derives “time of day” information from environmental light
cues captured by specialized cells within the retina. This information is relayed via the retinohypothalamic
tract to the SCN, which conveys timing information to the brain including the paraventricular, arcuate nuclei
subparaventricular zone, medial preoptic area, intergeniculate leaflet, and paraventricular nucleus of the
thalamus. The SCN also provides timing cues to peripheral tissues via the autonomic nervous system and
hormones, which together organize complex behaviors from the sleep/wake to the feeding/fasting rhythm
“peripheral oscillators.” (From Arble, D.M., Sandoval, D.A., 2013. CNS control of glucose metabolism:
response to environmental challenges. Front. Neurosci. 7, 20. https://doi.org/10.3389/fnins.2013.00020.)
1998) in a variety of situations. The patient is rated on eight sit- repeatedly, but normative data do not exist, making it difficult to use
uations with a score of 0–3 (3 being the highest chance of dozing for clinical decision making or comparisons between persons.
off). The maximum score is 24, and a score greater than 10 sug- The Karolinska Sleepiness Scale (KSS) is another subjective mea-
gests the presence of excessive sleepiness (Box 101.7). This scale sure of sleepiness somewhat similar to the SSS measuring responses
has been weakly correlated with multiple sleep latency test (MSLT) on a 9-point scale (1 = very alert to 9 = very sleepy), while scores of 7
scores, which is the gold standard measurement at present for day- or above are considered pathologic. The KSS is useful when evaluating
time sleepiness, and normal values do not necessarily imply the lack sleepiness in drug trials, and fatigue in flight crews. Similarly to the
of clinically significant daytime sleepiness. However, it is high in SSS, it lacks normative data, and diurnal pattern and the impact of
vulnerable population such as people with narcolepsy, sleep apnea, stress, sleep quality, sex, illness, and age (Akerstedt et al., 2017).
and sleep-deprived residents as depicted in Fig. 101.29 (Avidan, Another scale is the visual analog scale of alertness and well-being. In
2013; Lipford et al., 2019; Papp et al., 2004). this scale, subjects are asked to indicate their feelings on an arbitrary line.
The Stanford Sleepiness Scale (SSS) (eBox 101.8) is a seven-point Laboratory tests should be used to confirm the clinical diagnosis
scale that measures subjective sleepiness but may not be reliable in and must be subservient to the clinical history and physical examina-
patients with persistent sleepiness. The scale may detect sleepiness as tion. The tests to uncover suspected sleep disorders are resource inten-
it waxes and wanes over the course of a day. Advantages include its sive and are best planned in consultation with a sleep specialist; they
brevity, its ease of administration, and its ability to be administered are described in later sections of this chapter.
eBOX 101.7 Epworth Sleepiness Scale
Eight Situations Scores*

Sitting and reading __
Watching television __
Sitting in a public place (e.g., a theater or meeting) __
Sitting in car as a passenger for an hour without a break __
Lying down to rest in the afternoon __
Sitting and talking to someone __
Sitting quietly after a lunch without alcohol __
In a car, while stopped for a few minutes in traffic __
*Scale to determine the total scores: 0, would never doze; 1, slight

chance of dozing; 2, moderate chance of dozing; 3, high chance of dozing.
Modified with permission from Johns, M.W., 1991. A new method for measuring day-
time sleepiness: The Epworth sleepiness scale. Sleep 14, 540–545.
eBOX 101.8 Stanford Sleepiness Scale
Scale Rating Degree of Sleepiness

1 Wide awake, active, and alert
2 Awake and able to concentrate but not functioning at peak
3 Relaxed, awake, and responsive but not fully alert
4 Feeling a little foggy
5 Difficulty staying awake
6 Sleepy, prefer to lie down
7 Cannot stay awake; sleep onset is imminent
X Asleep
The SSS is a quick way to assess propensity to sleepiness during the

day, while reminding patients to consider two peaks of alertness during
the day, at about 9 am and 9 pm. Alertness wanes to its lowest point at
around 3 pm; after that it begins to build again. Rate your alertness at
different times during the day. If you go below a three when you should
be feeling alert, this is an indication that you have a serious sleep debt
and you need more sleep.
Modified with permission from Hoddes, E., Zarcone, V., Smythe, H., et al., 1973. Quanti-
fication of sleepiness: A new approach. Psychophysiology 10, 431–436.
Sleep homeostatic CLINICAL PHENOMENOLOGY

Process S drive (sleep load)
In this section, pertinent features of some common primary sleep dis-
Wake orders are described, along with a summary of sleep dysfunction in
neurological, medical, psychiatric, and pediatric disorders.
Insomnia
Alertness level
Insomnia is the most common sleep disorder affecting the population
and the most common disease encountered in the practice of sleep
medicine (Morin and Benca, 2011, 2015). Several population surveys
of adults have determined that approximately 35% of the general pub-
Process C Circadian
alerting signal lic has had insomnia complaints; in 10%, this is a persistent problem
Sleep
(Jaussent et al., 2017; Morin, LeBlanc, et al., 2006; Ohayon, 2002; Roth
and Roehrs, 2003). Insomnia is defined as an inability to initiate, main-
9 AM Day-active 9 PM Night-asleep 9 AM
tain sleep, or early awakening, despite an adequate opportunity for
Fig. 101.22 Circadian Mediation of Sleep and Wakefulness. Sleep sleep, culminating in poor sleep quality associated with a lack of feel-
and wakefulness are regulated by two processes operating simultane-
ing restored and refreshed in the morning, leading to a dissatisfaction
ously: the homeostatic process (Process S) which primarily regulates the
with sleep and poor daytime functioning (AASM, 2014). The ICSD-III
length and depth of sleep, and endogenous circadian rhythms (Process
C: “biological time clocks”), which influence the internal organization of (AASM, 2014) classifies insomnia into three types: short-term insom-
sleep and timing and duration of daily sleep/wake cycles. nia disorder, chronic insomnia disorder, and other insomnia disorder.
Wake Sleep
Net synaptic potentiation Synaptic re-normalization
SYNAPTIC STRENGTH
Energy costs Energy costs TIME

Supplies costs Supplies costs
Saturation Saturation
Wake Sleep
STRUCTURAL
synapse
number / size
MEASURED PARAMETERS
MOLECULAR
synaptic
receptors
(AMPARs)
ELECTRO-
PHYSIOLOGICAL neuromo-
minis dulatory
tone
evoked responses neuronal

excitability
unit firing excitation/

inhibition
Current opinion in neurobiology
Fig. 101.23 Sleep, Synaptic Homeostasis and Neuronal Firing Rates. (From Cirelli, C., 2017. Sleep,
synaptic homeostasis and neuronal firing rates. Curr. Opin. Neurobiol. 44, 72–79. © 2017.)
Blood-CSF barrier
A CSF
Blood Fec
capillary
CPE
TJ
ISF
Blood-brain barrier
B
Perivascular space
Para-arterial space
Paravenous space
Key:
Aquaporin 4 Arterial blood flow
Nutrients Venous blood flow
Waste Perivascular flow
Cellular clocks Paravascular flow
Trends in neurosciences
Fig. 101.24 Glymphatic Waste Clearance System and Relationship to Sleep. A, Representation of the
fluid compartments and barriers of the brain. B, Waste clearance route through the blood–brain barrier with
a paravascular flow (red–blue shaded arrow) from arteries (red) to veins (purple). Astrocytes (green) take up
fluid from the para-arterial space via aquaporin 4 channels and distribute it to neurons (orange) and the inter-
cellular space. Waste loaded fluid is then cleared by astrocytes via aquaporin 4 into the paravenous space
and transported out of the brain. A perivascular flow (yellow arrows) is also hypothesized. CSF, Cerebrospinal
fluid; CPE, choroid plexus epithelial cell; Fec, fenestrated endothelial cell; ISF, interstitial fluid; TJ, tight junc-
tion. (Adapted, with permission, from [41, 55]. Urs Albrecht, Jürgen A. Ripperger, Circadian Clocks and Sleep:
Impact of Rhythmic Metabolism and Waste Clearance on the Brain, Trends in Neurosciences, Volume 41,
Issue 10, 2018, Pages 677–688, ISSN 0166-2236, https://doi.org/10.1016/j.tins.2018.07.007. (http://www.
sciencedirect.com/science/article/pii/S0166223618301905.)
Intern sleep schedule and patient safety outcome

p< .001
136
p=0.03
100.1 99.7
82.5
5X Dx errors
p< .001
18.6
3.3
Serious medical errors - total Serious medication error Serious diagnostic error
Traditional "q3" 24-30 h shifts
Intervention schedule -<16 h scheduled shifts
Fig. 101.26 Intern Sleep Schedule and Patient Safety Outcome. Twenty interns studied under two
conditions: a “traditional on-call schedule” with 30-hour shifts scheduled every other shift and an “inter-
vention schedule” in which shifts were limited to 16 hours. Sleep times were collected from sleep
logs and, during ICU shifts, the logs were supplemented by continuous ambulatory polysomnographic
recordings. Objectively verifiable indicators of attentional failures included periods of slow rolling eye
movements intruding during wakefulness. Failures were documented in a subgroup of recordings from
between 11 pm and 7 am. The number of attentional failures during the night in the traditional condition
was more than twice the number of attentional failures in the intervention condition. Medical errors
were determined by direct observation of interns and chart review, voluntary repor ts, and computerized
event-detection monitoring and reported as errors per 1000 pt days. Errors consisted of procedural,
medication, and diagnostic errors. The study included 2203 patient days, 634 admissions, and 5888
hours of direct observation. Interns made 35.9% more serious errors during the traditional schedule than
during the intervention schedule. The rate of diagnostic errors was 5.6 times higher in the traditional
schedule than the intervention schedule.
The perception of insomnia does not necessarily depend on total hours include psychiatric, medical, primary sleep-related (i.e., OSAS),
of sleep obtained, because there is considerable individual variation in neurological disorders, pain syndrome, or drug and alcohol abuse.
sleep requirement. There is an increasing association of insomnia with eBox 101.10 lists the causes of chronic insomnia. These comor-
age, female sex, low socioeconomic status, divorce, widowhood, sep- bid insomnias were classified as secondary insomnia in the past,
aration, recent stress and depression, and drug or alcohol abuse, with but this signifies causation; no definite evidence exists that these
higher predilection among women (Martikainen et al., 2003). conditions are responsible for insomnia (National Institutes of
Health, 2005).
Short-Term Insomnia Disorder (Acute Insomnia) In addition to short-term effects of disturbed sleep and inade-
This type of insomnia is characterized by short-term difficulty in ini- quate daytime functioning, people with insomnia report impaired
tiating or maintaining sleep that results in general sleep dissatisfaction work performance and productivity, reduced social and physical
and is accompanied by daytime distress about the poor sleep quality functioning, reduced overall quality of life, and a two- to fivefold
or impairment in social, family, occupational, academic, or other increased risk for developing subsequent depression associated
important areas of functioning. The disorder and its associated symp- with significant suicidal behavior. There are also suggestions of
toms occur despite having adequate time and circumstances to obtain increased mortality and morbidity from coronary artery disease,
necessary sufficient sleep (AASM, 2014). In many cases of short-term hypertension, obesity, and diabetes mellitus (Ayas et al., 2003a,
insomnia lasting less than 3 months, there is an identifiable cause that 2003b; Knutson and Turek, 2006). A longitudinal sleep laboratory
serves as the precipitant. In other cases, insomnia occurs episodically, follow-up study for 14 years, however, found increased mortality in
often coincident to daytime stressors that account for the insomnia men with chronic insomnia with objectively measured short sleep
(AASM, 2014). Once the stressful event is removed and the patient duration that could not be explained by comorbid type 2 diabetes
adjusts to the event, the sleep disturbance resolves. Causes of acute mellitus or hypertension (Vgontzas et al., 2010). The clinically sig-
insomnia are listed in Box 101.9. nificant consequences (both short-term and long-term) of insomnia
most typically develop when sleep difficulties occur at least three
Chronic Insomnia times per week and persist for at least 3 months. Hence those fre-
Most cases of insomnia are chronic and comorbid with other con- quency and duration criteria must be met for a diagnosis of chronic
ditions (Morin and Benca, 2015, 2011). Common comorbidities insomnia disorder (AASM, 2014).
Two-week sleep diary

Instructions:
1. Write the date, day of the week, and type of day: work, school, day off, or vacation.
2. Put the letter "C" in a box when you have coffee, tea, cola, or anything else with caffeine. Put "M" in a box when you take any medicine.
Put "A" in a box when you drink alcohol. Put "E" in a box when you exercise.
3. Put a downward arrow to show when you go to bed. Shade in the box when you think you fell asleep.
4. Shade in all the boxes that show when you are asleep at night or when you take a nap during the day.
5. Put an upward arrow to indicate when you got out of bed.
6. Leave boxes unshaded to show when you are awake at night and during the day.
Sample entry below: On a monday when I worked, I jogged on my lunch break at 1:00 pm, had a glass of wine with dinner at 6:00 pm, fell
asleep watching television from 7:00-8:00 pm, went to bed at 10:30 pm, fell asleep around midnight, woke up and stayed awake between
4:00-5:0O am, went back to sleep between 5:00-7:00 am, and had coffee and breakfast and took medicine at 7:00 am.
Today’s Day Type of day 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11
Noon
Midnight
date of the (work, PM PM AM AM AM
week school,
vacation)
Sample Mon. Work E C
A ↓ ↑
M
↓ ↑
↓ ↑
↓ ↑
Week 1
↓ ↑
↓ ↑
↓ ↑
↓ ↑
↓ ↑
↓ ↑
↓ ↑
Week 2
↓ ↑
↓ ↑
↓ ↑
↓ ↑
Adapted with permission from: The American Academy of Sleep Medicine.
Form available at: http://sleepeducation.org/docs/default-document-library/sleep-diary.pdf.
Fig. 101.28 Sample Sleep Log (Sleep Diary). A sleep log is a record of an individual’s sleeping and waking
times, usually tabulated over a period of several weeks. The patient is instructed to record the following data:
Time required to fall asleep; time he/she thinks they fell as leep; number, time, and length of any nocturnal
awakenings; time he/she woke up; time he/she got out of bed; time he/she wanted to wake up; a comment
on how he/she felt during the day; start and end times of any daytime naps; potential medications used.
(Adapted with permission from The American Academy of Medicine. Available at: http://sleepeducation.org/
docs/default-document-library/sleep-diary.pdf.)
Proposed Mechanism and Physiological Profiles of Patient • I ncreased 24-hour and evening cortisol levels and increased
with Insomnia 24-hour corticotropin levels (indicating abnormal hypothalamic–
The proposed basis and evolution of insomnia as a disorder of hyper- pituitary–adrenal axis)
arousal (Fig. 101.30) and its evolution during early life to adulthood • Increased brain glucose metabolism
and from acute to chronic forms is summarized in Fig. 101.31, as it • Increased EMG activity, as noted in the frontalis muscle
transforms to chronic insomnia. Patients suffering from insomnia • EEG spectral analysis showing increased beta activity
may suffer from a general disorder of hyperarousal due to a func- • Decreased nocturnal melatonin and increased diurnal melatonin levels
tional alteration in the anatomical substrates for sleep/wake states con- • Increased latencies on MSLT, despite disturbed nocturnal sleep
ferred by hyperactivity of wake-promoting neurons or hypoactivity of • Neuroimaging findings of subcortical (ARAS) hyperarousal. The
sleep-generating neurons that is genetically determined. Evidence of data support that in people with insomnia, during transition from
hyperarousal is provided by the following observations in these patients waking to sleep, there is a state of increased cerebral metabolism
(Morin and Benca, 2011, 2015) and is highlighted in Fig. 101.31: due to a lack of a reduction in activity in subcortical structures
• Increased heart rate compared to people without insomnia (Nofzinger et al., 2004).
• Elevated sympathetic and decreased parasympathetic tone (as mea- Hyperarousal dysfunction is supported by functional neuro-
sured by spectral analysis to show heart rate variability) anatomy, where PET imaging designed to measure regional brain
20 comorbidities are provided in Boxes 101.11 and 101.12 at http://

expertconsult.inkling.com.
15 The section below covers insomnia subtypes of described in the
ICSD-III (AASM, 2014).
ESS score
10
Idiopathic and Psychophysiological Insomnia
The onset of idiopathic insomnia occurs in early childhood, as high-
5
lighted in Fig.101.31 and contributing to a “Predisposition” to develop
insomnia Fig. 101.33, as demarcated by the red column. Patients gen-
0
Normal Insomnia Sleep apnea Residents Narcolepsy erally have lifelong difficulty with initiating or maintaining sleep, or
Mean 5.90 2.20 9.50 14.70 17.50 both, resulting in poor daytime functioning. Diagnosis depends on the
Fig. 101.29 The Epworth Sleepiness Scale (ESS) Across Popula- exclusion of concomitant comorbid medical, neurological, psychiat-
tions. The diagram highlights ESS for normal subjects and patients with ric, or psychological disturbances. Psychophysiological insomnia may
representative sleep disorders (insomnia, obstructive sleep apnea, and transpire during young adulthood, and the symptoms may persist for
narcolepsy) as well as medical residents. Sleepiness in medical residents decades. This is chronic insomnia is characterized by hypervigilance
is equivalent to that found in patients with serious sleep disorders such and hyperarousal and it is fueled by learned sleep-preventing associa-
as narcolepsy. The ESS is an 8-item self-report which asks respondents tions. Patients are overconcerned on sleep problems, but they may not
to rate their likelihood of “dozing” under several specified conditions. have generalized anxiety or any other psychiatric disorders. Sometimes
The individual rates each situation from 0 to 3, with 3 indicating the high- a family history exists. The development of conditioned responses
est likelihood. The highest possible score is 24. The generally accepted
incompatible with sleep is the predominant feature of psychophysi-
value for the upper limit of “normal” is 11. Values between 11 and 13
ological insomnia. Insomnia is an event precipitated or initiated by a
are considered mild, 14 and 17 moderate, and greater than 17 severe.
stressor such as acute life events such as a new job, death of a loved
one, COVID19 and surgery, but it persists even after that initial stress
BOX 101.9 Causes of Acute Insomnia is gone (see Fig.101.33, demarcated by the yellow column). Factors
contributing to negative conditioning in the setting of insomnia are
Internal Acute medical or surgical illnesses (including intensive “perpetuating” factors include excessive fear and frustration about
(patient-related care unit stays) being unable to initiate and maintain sleep, and the identification of
factors) Stimulant medications (e.g., theophylline, beta-blockers, the bedroom as an arousal sign and environmental and disadvantages
corticosteroids, thyroxine, bronchodilators, or withdrawal life-style factors that perpetuate the insomnia Fig. 101.33, blue col-
of central nervous system depressant medications) umn including alcohol , caffeine, artificial and excessive blue light
exposure from light exposure, television and electronics high
External A change of sleeping environment (most common cause
temperatures and excessive environmental noise . Patients generally
(environmental of transient insomnia, the so-called first night effect)
sleep poorly during nocturnal polysomnogram, a phenomena referred
factors) Jet lag
to as “the first night effect”, although occasionally patients sleep better
Unpleasant sleep environment (excessively hot/cold
because they are removed from their usual sleep environment (reverse
room temperature)
first-night effect). Patients with psychophysiological insomnia confine
Excessive environmental noise (living close to the motor
anxiety to sleep-related issues, which differentiates them from patients
way/train track/airport)
with generalized anxiety disorders. New data provide good evidence to
Excessive environmental light exposure
support the view that primary psychophysiological insomnia is a true
conflict between the sleep system and inappropriate activation of CNS
(Riemann, 2010).
BOX 101.10 Chronic Insomnia Phenotypes
Paradoxical Insomnia
Idiopathic or primary insomnia
Paradoxical insomnia is a sleep state misperception characterized by
Psychophysiological insomnia
subjective complaints of sleeplessness without objective evidence (e.g.,
Paradoxical insomnia (sleep state misperception)
PSG evidence of insomnia). Patients often complain of severe sleep
Inadequate sleep hygiene
disturbance but lack supportive objective evidence to corroborate
Insomnia comorbid with psychiatric disorders
the degree of sleep disturbance claimed. (AASM, 2014). There is an
Insomnia comorbid with general medical disorder
increased propensity for these patients to underestimate the amount of
Insomnia comorbid with neurological disorder
sleep they are actually getting. In essence, they are thought to perceive
Insomnia due to drug or other substance abuse
much of the time they actually sleep as wakefulness. Actigraphy (an
accelerometer which measures sleep/wake activities) or PSG recording
metabolism demonstrates that patients with insomnia show increased documents normal sleep patterns in such patients.
activity during the transition from waking to sleep onset as compared
to healthy subjects, suggesting that there is an overall cortical hyper- Inadequate Sleep Hygiene
arousal in insomnia (eFig. 101.32). Furthermore, patients with insom- Patients with inadequate sleep hygiene negate the good sleep measures
nia have less reduction of activation from waking to NREM sleep in that promote sleep. Such measures include avoidance of caffeinated
the ARAS, hypothalamus, insular cortex, amygdala, hippocampus, beverages, alcohol, and tobacco in the evening; avoidance of intense
anterior cingulate, and medial prefrontal cortices, as illustrated in the mental activities close to bedtime (this has been seriously questioned in
figure (Nofzinger et al., 2004; Nofzinger et al., 2006). recent literature); avoidance of daytime naps and excessive time spent
Additional insomnia subtypes mentioned in the ICSD-II are proin bed awake; and adherence to a regular sleep/wake schedule.
vided for historical reasons. This outline as well as insomnia criteria Insomnia commonly coexists or precedes the development of a
from the ICSD-III along with a listing of medical and neurological number of psychiatric illnesses. Surveys have shown that individuals
Mesial temporal cortex ARAS

ARAS Hypothalamus Thalamus
A
ARAS Hypothalamus Mesial temporal cortex
Cingulate Insular cortex
B
Pontine ACC, medial Thalamus Diffuse
brainstem prefrontal cortex thalamocortical network
eFig. 101.32 Neuroimaging in the Setting of Insomnia Disorders. A,
Insomnia is characterized by failure of brain structures that are involved
in sleep onset and maintenance to demonstrate appropriate decrease in
metabolic rate from transitioning from wakefulness to sleep. All regions
shown reach statistical significance at the P < .05, corrected, level
of significance in relation to healthy sleeper control subjects. ARAS,
Ascending reticular activating system. B, Brain structures in which
metabolism during nonrapid eye movement sleep correlates with wake-
fulness after sleep onset in insomniac patients. ACC, Anterior cingu-
late cortex. (From Nofzinger, E.A., Nissen, C., Germain, A., et al., 2006.
Regional cerebral metabolic correlates of WASO during NREM sleep in
insomnia. J. Clin. Sleep Med. 2, 316–322; and Nofzinger, E.A., Buysse,
D.J., Germain, A., et al., 2004. Functional neuroimaging evidence for
hyperarousal in insomnia. Am. J. Psychiatry 161, 2126–2131.)
with insomnia are more likely to develop new psychiatric disorders, hypocretin measurement. Hypocretin levels are generally normal if the
particularly major depression, within 6–12 months. Anxiety disorders, patient is HLA-negative, unless the patient has a diencephalic lesion
depression, and schizophrenia are some of the major psychiatric disor- that explains the CNS hypersomnia (narcolepsy type due to a medical
ders associated with insomnia. condition) (AASM, 2014).
Medical and neurological disorders comorbid with insomnia are Pathogenesis of narcolepsy-cataplexy syndrome. The most
listed in eBoxes 101.11 and 101.12. RLS, PLMD, and circadian rhythm exciting recent development in sleep medicine is the pathogenetic
disorders are some of the other causes of chronic insomnia. In some role played by the recently discovered hypocretin (orexin) peptidergic
patients, insomnia may coexist with sleep apnea. systems in the lateral hypothalamus. Reports of mutation of the
hypocretin receptor 2 gene (HCRTR2) in dogs (Lin et al., 1999) and
Mechanism of Insomnia in Neurological Diseases pre-prohypocretin knockout mice (Chemelli et al., 1999) producing
Insomnia in neurological disorders may result from the following sug- the phenotype of human narcolepsy brought narcolepsy research
gested mechanisms: to the forefront of the molecular neurobiology field. Most cases of
• Hypofunction (metabolic or structural) of the hypothalamic VLPO human narcolepsy and cataplexy have decreased hypocretin 1 in the
neurons or the lower brainstem hypnogenic neurons in the region cerebrospinal fluid (CSF) (Bourgin et al., 2008; Fronczek et al., 2009;
of the NTS and dysfunction of thalamus may alter the balance Nishino, 2007). Hypocretins are noted to be depleted in narcoleptic
between the waking and sleeping brain, causing sleeplessness. brains at autopsy, as can be seen in Fig. 101.34 (Thannickal et al., 2000)
• Neurological disorders may cause pain, agitation and confusion, with a proposed mechanism involving an environmental trigger which
alteration of the sensory-motor system, and abnormal movements produces an autoimmune response in genetically venerable individuals
during sleep, which may interfere with normal progression and (Overeem et al., 2008). In addition, mutation of the pre-prohypocretin
cycling of NREM-REM sleep. gene has been identified in one child with severe narcolepsy (Peyron
• Medications used to treat neurological illnesses (e.g., corticoste- et al., 2000). Therefore, the contemporary theory for the pathogenesis
roids, antiepileptic drugs such as lamotrigine, zonisamide, and of narcolepsy-cataplexy syndrome suggests that the condition results
levetiracetam, dopaminergic medications, decongestants) may from a depletion (degeneration or autoimmune disorder) of the
cause insomnia. hypocretin neurons in the lateral and perifornical region of the
• Certain neurological disorders may alter circadian rhythm in the hypothalamus, as can be appreciated in Fig. 101.35. Narcolepsy-
SCN causing insomnia. (This is particularly true in the case of Alz- cataplexy syndrome thus can be considered a hypocretin (orexin)
heimer dementia, but also PD and traumatic brain injury [TBI].) deficiency syndrome, which is how the condition is being referred to in
• Neurological illnesses have a bidirectional relationship with psychi- the updated version of the ICSD-III (AASM, 2014). The possibility of
atric conditions, particularly depression and anxiety, which proan autoimmune disorder has been raised because of the association of
mote sleeplessness. narcolepsy with HLA-DQB1*0602 haplotype; however, all attempts to
• Neurological disorders such as MSA, MS and neuromuscular dis- find evidence of autoimmune disorder in narcolepsy have so far failed
orders such as myotonic dystrophy type 2 have strong association (Overeem et al., 2008). There is no evidence of inflammatory processes
with primary sleep disorders such as SDB, resulting in sleep frag- or immune abnormalities, presence of classical autoantibodies, or an
mentation, excessive sleepiness impaired quality of life. increase of oligoclonal bands in the CSF in these patients. Erythrocyte
sedimentation rate, serum immunoglobulin levels, C-reactive protein,
Central Disorders of Hypersomnolence complement levels, and lymphocyte subset ratio are all found to be
Since the French physician Gelineau used the term narcolepsy in 1880 normal in these patients, pointing against an autoimmune disorder.
to describe irresistible sleep attacks and astasia, which includes all the On the other hand, increased levels of streptococcal antibodies in
features of cataplexy, there have been many reports of patients with narcoleptic patients in some reports and evidence of gliosis in the
narcolepsy-cataplexy syndrome (Nishino, 2007; Nishino and Mignot, lateral hypothalamus by Thannickal and colleagues (2000) indicate
2011; Scammell, 2003). The prevalence of narcolepsy is estimated to be that further exploration for possible immune-related dysfunction
approximately 1 in 2000 individuals in the United States, 1 in 600 peo- in narcolepsy is needed. Finally, the presence of autoantibodies
ple in Japan, and 1 in 500,000 individuals in Israel. Reports of adequate (patient serum binding to rat hypocretin neurons) in one out of nine
epidemiological studies in different parts of the world are, however, narcolepsy-cataplexy patients keeps the autoimmune theory very much
lacking (Video 101.2). in the forefront (Knudsen et al., 2007). Environmental considerations
such as streptococcal infection, seasonal influenza, and more recent
Genetics of Narcolepsy reports implicating the 2009 influenza pandemic A/H1N1 raise even
Most cases of human narcolepsy are sporadic, but some are dominant. stronger concerns for an immunological mechanism for narcolepsy.
There is, however, a 10–40 times greater prevalence of narcolepsy in Proposed immunological mechanisms that could trigger specific
families than in the general population. For example, approximately destruction and subsequent elimination of hypocretin producing
one or two first-degree relatives of narcoleptic patients, compared with neurons include molecular mimicry or bystander activation and are
0.02%–0.18% in the general population, manifest the illness. Twin likely a combination of genetic and environmental factors, such as
studies show that the majority of monozygotic twins are discordant, upper airway infections (Mahlios et al., 2013).
and only 25%–31% are concordant, suggesting an influence of envi- In the summer of 2010 concerns were raised in Scandinavia about
ronmental factors in the etiology of narcolepsy. From 95% to 100% of a possible association between narcolepsy and ASO3 adjuvanted A/
white and Japanese patients carry the HLA. It has been established that H1N1 2009 pandemic vaccine following observation of a potential
HLA-DQB1*0602 is a marker for narcolepsy on chromosome 6 across temporal association by clinicians in sleep centers in these countries. A
all ethnic groups. However, cases of narcolepsy not carrying HLA-DR2 follow-up study of children in England depicted a comparable associa-
or HLA-DQ1 antigens have been reported. In addition, 12%–38% tion of increased risk (Miller et al., 2013). The earlier data from Finland
of the general population carries the same HLA alleles, but narco- described a 13-fold increased risk of narcolepsy following vaccination
lepsy is present in only 0.02%–0.18% of the population. Clinically, of patients aged 4–19, the majority of whom developed narcolepsy
HLA-DQB1*0602 typing may be indicated when considering a CSF symptoms within 3 months after vaccination (Fig. 101.36) and almost
eBOX 101.11 Medical Disorders Comorbid eBOX 101.12 Neurological Disorders

with Insomnia Comorbid with Insomnia
Ischemic heart disease Neurodegenerative diseases:
Nocturnal angina Parkinson disease
Congestive cardiac failure Alzheimer disease
Chronic obstructive pulmonary disease Other degenerative dementias
Bronchial asthma Progressive supranuclear palsy
Peptic ulcer disease Multiple system atrophy
Gastroesophageal reflux disease Huntington disease
Rheumatic disorders, including: Torsion dystonia
Fibromyalgia Tourette syndrome
Rheumatoid arthritis Brain tumors
Osteoarthritis Cerebral hemispheric and brainstem strokes
Ankylosing spondylitis Traumatic brain injury causing post-traumatic insomnia
Sjögren syndrome Headache syndrome (e.g., migraine, cluster and hypnic headaches, exploding
Acquired immunodeficiency syndrome (AIDS) head syndrome)
Chronic fatigue syndrome Fatal familial insomnia (rare prion disease)
Lyme disease Propriospinal myoclonus at sleep onset
Dermatological disorders (e.g., nocturnal pruritus)
Systemic cancer
Video 101.2 Thirty-Five Years of Undiagnosed Narcolepsy. Patients

with classic narcolepsy frequently go undiagnosed for decades, as did
this patient. (From Kryger MH, Avidan, AY, Berry, R. Atlas of clinical
sleep medicine. Second edition. ed. Philadelphia, PA: Elsevier/Saun-
ders; 2013)
Hallmarks of Hyperarousal
Brain
EEG fast frequencies
during sleep
Number of arousals
during REM sleep
Daytime Systemic
sleep-onset latency
Metabolic rate
Sleep duration
Body temperature
Heart
Pituitary- Heart rate
Adrenal Axis Altered heart rate
variability
Activity
Fig 101.30 Indicators of Hyperarousal in Insomnia. Insomnia disorder is characterized by physiological

hyperarousal consisting of increased activity of the hypothalamic–pituitary–adrenal axis. Such activity is sup-
ported by increased levels of cortisol and amplification of sympathetic autonomic nervous system activity
demarcated by an increased resting heart rate, metabolic rate, and increased body temperature. Quantified
sleep electroencephalography (EEG) and polysomnographic data demonstrate reduction in sleep duration
and efficiency, arousals, and is supported by an increased sleep-onset latency during daytime investigations
of sleepiness utilizing the Multiple Sleep Latency Test (MSLT). This is also consistent with the lowest ESS
score observed among patients with insomnia in figure 101.29. REM, Rapid eye movement.
Exposure to and
Persistence of Sleep
Disturbances in Early Life
PRE-NATAL
EARLY LIFE STRESS
• Environmental
• Genetic
• Epigenetic
• Neuroendocrine
factors
• Hyperactivation of the Alterations in

Stress-System
synaptic plasticity,
• Epigenetic Shaping of the • Attachment
strength, pruning
HPA Axis • Character
• Temperament
• Stress System Sleep and

Sensitization Alteration in brain
Circadian Rhythm
• Alterations development
Disturbances
in Stress Reactivity
Increased Susceptibility & Vulnerability to Insomnia & Mood Disorders Later in Life
Contributes to “Predisposition” in Spielman’s 3P Model, Figure 101-21
Fig 101.31 Indicators of Hyperarousal in Insomnia Developmental Pathways toward Insomnia and Mood disorders in Adult Life. Sleep
disturbances and pathways to chronic insomnia and mood disorders in adult life. The model of chronic insomnia in the setting of mental disorders
emerges initially in early-prenatal/early life stress occurs within the framework of the complex-genetic –and environmental predisposition that is
mediated through exposure to stress. Programming may occur in prenatal and postnatal periods, which constitute highly sensitive periods during the
development of an individual and may subserve the basis of predisposition to insomnia and mental health pathologies later in life possibly through
epigenetic mechanisms. Since disturbed sleep is one of the key consequences of early life stress it is hypothesized that disturbed sleep due to prena-
tal early life stress, possibly mediated by epigenetic processes, may re-shape the individual’s stress system contributing to an increased vulnerability
to stress-related disorders, particularly insomnia and depression prospectively.
all within 6 months (Nohynek et al., 2012; Wijnans et al., 2013). New Clinical Manifestations of Narcolepsy
data from Stanford University implicated a small epitope of pH1N1 The onset of the disorder in most cases is in adolescents and young
that resembles hypocretin and is likely involved in molecular mimicry adults, with a peak incidence between ages 15 and 30. However, rare
(De la Herran-Arita et al., 2013). Fig. 101.37 highlights a few patho- cases have been described in children younger than age 5 and adults
physiological mechanisms for narcolepsy which points toward selec- older than age 50. The ICSD-III divides narcolepsy into two types:
tive venerability (conferred through HLA positivity), a trigger, and a narcolepsy type 1 (with cataplexy, or low hypocretin levels), and nar-
reaction leading to destruction of the vulnerable populations of orexin colepsy type 2 (without cataplexy, and with normal hypocretin levels)
neurons. It is believed that the underlying pathology of narcolepsy is (AASM, 2014) eTable 101.6. Secondary narcolepsy due to a known
related to genetic, environmental, and acute triggering factors. The underlying CNS disorder is referred to as narcolepsy type 1 due to a
implications of genetic factors (specifically HL A-DQB1*06:02 positiv- medical condition (when hypocretin levels are low) or narcolepsy type
ity) are a strong predisposition to narcolepsy. The first clinical marker 2 due to a medical condition (when hypocretin levels are normal).
of such a predisposition is a short sleep latency period before onset of Diseases impacting the major clinical manifestations of narcolepsy
REM sleep. Environmental exposures to bacterial and viral pathogens include sleep attacks (100%), cataplexy (60%–70%), sleep paralysis
in early life might alter immune system development. (25%–50%), hypnagogic hallucinations (20%–40%), disturbed night
eTABLE 101.6 Comorbid Conditions with

Narcolepsy
Sleep apnea Up to 30%
Periodic limb movements in 10%–60%
sleep
REM sleep behavior disorder Up to 36%
Eating disorder (craving for High prevalence, but exact percentage
food) unknown, including night eating syn-
drome not related to obesity
Increased BMI or obesity Up to 30%, higher in children diagnosed
with narcolepsy (50%)
Increased prevalence of type 2 Up to 10%
diabetes mellitus
BMI, Body mass index; REM, rapid eye movement.
Spielman’s 3P Model of Insomnia
70%
60%
Clinical
50% insomnia
threshold
40%
30%
20%
10%
0%
Baseline Acute Early Chronic
Perpetuating Precipitating Predisposing

Fig. 101.33 3-P Model of Insomnia Etiology. The 3-P Model of Insomnia Etiology explains that all express a
certain vulnerability to express insomnia (Predisposing Factors, 1st P). Insomnia disorder occurs when a pre-
cipitating event pushes patients above the insomnia threshold (2nd P). When the precipitating factor ★ dimin-
ishes, the insomnia is kept above threshold when patients develop behavioral conditioned arousal response
associated with the bedroom environment that perpetuates the insomnia. These perpetuating (3rd P) factors
are shown in the figure by alcohol too close to bedtime, caffeine too late during the day, excessive light, TV,
light-emitting electronic devices).
9
<11 yr
8
11–16 yr
7
17–19 yr
6
20 yr and older
Incidence of 5
narcolepsy
per 100,000 4
3
2
1
2002 2003 2004 2005 2006 2007 2008 2009 2010

Year
H1N1 influenza vacine (brand

with potent ASO3 adjuvant)
Fig. 101.36 Narcolepsy Incidence Following Administration of the H1N1 Vaccine. Epidemiological data
following vaccination of children in Finland and Sweden with a monovalent 2009 H1N1 influenza vaccine
(brand with potent ASO3 adjuvant). The data demonstrate 8- to 12-fold increase in narcolepsy following
vaccination as demarcated by the arrow. The Centers for Disease Control (CDC) in the United States did
not find any association between US-licensed H1N1 or seasonal influenza vaccine and narcolepsy following
review of data collected by the Vaccine Adverse Event Reporting System (VAERS). (Data from Nohynek, H.,
Jokinen, J., Partinen, M., et al., 2012. As03 adjuvanted AH1N1 vaccine associated with an abrupt increase
in the incidence of childhood narcolepsy in Finland. PLoS ONE 7 [3], e33536.; Wijnans, L., Lecomte, C., de
Vries, C., et al., 2013. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)
pdm09 pandemic and vaccination campaigns. Vaccine 31 [8], 1246–1254.)
Orexin neurons
Predisposing
A Genetic factors
Blood-brain
barrier
Induction Phase Effector Phase
B Environmental factors
Viral infection
Bacterial infection
C Triggering events MHC

class I
MHC
Infection class II
Vaccination Damaged
neuron
D Clinical symptoms Cataplexy E
EDS Lymph node
Hypothalamus
Viral/bacterial antigen
B cell CD4 T cell CD8 T cell Dendritic cell
Fig. 101.37 Plausible Disease Mechanism in Narcolepsy. It is believed that the underlying pathology of
narcolepsy is related to genetic, environmental, and acute triggering factors. The implications of genetic
factors (specifically HL A-DQB1*06:02 positivity) are a strong predisposition to narcolepsy A. The first
clinical marker of such a predisposition is a short sleep latency period before onset of rapid eye move-
ment (REM) sleep. B, Environmental exposures to bacterial and viral pathogens in early life might alter
immune system development in susceptible individuals and predispose these individuals to narcolepsy
later in life. One hypothesis implicates these changes directly or indirectly cause the loss of some orexin
neurons. An alternative explanation is that these genetic and environmental factors might only increase
the vulnerability of these neurons. C, Triggering events could include vaccinations and infections by
viruses such as influenza type A (H1N1) and bacteria such as Streptococcus spp. induce or reactivate
the immune response, leading to the selective destruction of venerable orexin neurons (induction phase)
resulting in the clinical manifestation of narcolepsy (D).
Fig. 101.37, cont’d D, The clinical symptoms of narcolepsy progress over days to weeks and perhaps even
years, as an increasing number of orexin neurons is destroyed or silenced, causing an imbalance in brainstem
sleep and wake pathways (effector phase) that leads to full-spectrum narcolepsy with cataplexy. E, The exact
sequence of events leading to the selective and preferential destruction of orexin neurons in the hypothala-
mus is still under investigation, but presumed inflammatory cytokines and activated immune cells (dendritic
cells, antigen-specific CD4+ T cells, and cytotoxic CD8+ T cells), which eventually cross the blood–brain bar-
rier, are thought to be involved. Antibodies can cross a disrupted blood–brain barrier and might also contribute
to neuronal destruction. EDS, Excessive daytime sleepiness; MB, mammillary body; OT, optic tract. (From
Bassetti, C.L.A., Adamantidis, A., Burdakov, D. et al., 2019. Narcolepsy—clinical spectrum, aetiopathophysi-
ology, diagnosis and treatment. Nat. Rev. Neurol. 15, 519–539. https://doi.org/10.1038/s41582-019-0226-9.)
TABLE 101.5 Major Clinical Features of is based on activation, during awake state, of brainstem neuronal cir-
cuitry that normally induces skeletal muscle atonia during REM sleep.
Narcolepsy
During cataplexy, muscle weakness is generated by decreased exci-
MAJOR MANIFESTATIONS tation of noradrenergic neurons and increased inhibition of skeletal
Excessive sleepiness 100% motor neurons by GABA-releasing or glycinergic neurons (Dauvilliers
Cataplexy 70% et al., 2014) (Bassetti et al., 2019). The medial prefrontal cortex and
Sleep paralysis 25%–50% amygdala contain neural networks through which positive emotions
Hypnagogic/hypnopompic hallucinations 20%–40% conceivably trigger cataplectic attacks (Dauvilliers et al., 2014).
Disturbed night sleep 70%–80% Sleep paralysis occurs in approximately 25%–50% of patients and
Automatic behavior 20%–40% is generally noted months to years after the onset of narcoleptic sleep
attacks. The sudden apparent paralysis of one or both sides of the body
or one limb occurs either during sleep onset (hypnagogic) or on awak-
sleep (70%–80%), and automatic behavior (20%–40%) (Nishino, ening (hypnopompic) in the morning. The patient is unable to move
2007; Nishino and Mignot, 2011; Overeem et al., 2001) (Table 101.5). or speak and is frightened, although he or she retains consciousness.
The classic narcoleptic sleep attack is an irresistible desire to fall The attacks last from a few minutes to 15–20 minutes.
asleep in inappropriate circumstances and at inappropriate places Hypnagogic hallucinations are found in 20%–40% of narcolep-
(e.g., while talking, driving, eating, playing, or when involved in bor- tic patients. They occur either at sleep onset or on awakening in the
ing or monotonous circumstances) as illustrated in Fig. 101.38. These morning and generally appear months to years after the onset of sleep
spells last from a few minutes to as long as 20–30 minutes, and the attacks. Hallucinations are most commonly vivid and visual (and often
patient generally feels refreshed on waking. There are wide variations fear-inducing) but are sometimes auditory, vestibular, or somesthetic
in frequency of attacks—anywhere from daily, weekly, monthly, or in nature. In 30% of patients, three of the four major manifestations
every few weeks to months. Attacks generally persist throughout the of the narcoleptic tetrad (sleep attacks, cataplexy, sleep paralysis, and
patient’s lifetime, although fluctuations and rare temporary remissions hypnagogic hallucinations) occur together, and in about 10% of cases,
may occur. Patients often show a decline in performance at school and all four major features occur together.
work and encounter psychosocial and socioeconomic difficulties as a Disturbed night sleep and automatic behavior. Disturbed night
result of sleep attacks and EDS. sleep is commonly noted in 70% to 80% of patients. In approximately
Cataplexy is defined as a sudden loss of tone in all voluntary muscles 20%–40% of cases, automatic behavior characterized by repeated
with the exception of the respiratory and ocular muscles. By definition, performance of a single function such as speaking or writing in a
cataplexy is universally preceded by a prodromal of emotion leading to meaningless manner, driving on the wrong side of the road, or driving
a transient episode of muscle weakness. The typical emotions that trig- to a strange place without recalling the episode is noted. These episodes
ger cataplexy are positive phenomena and include laughter and excite- of automatic behavior may result from partial sleep episodes, frequent
ment, rage, or anger more than 95% of the time. The attacks may be lapses, or microsleeps.
complete or partial but are rarely unilateral. Most commonly, patients The clinical presentation of narcolepsy with cataplexy in children
momentarily have head nodding, sagging of the jaw, buckling of the may be different from that of adults (AASM, 2014). Children may
knees, dropping of objects from the hands, dysarthria, or loss of voice, present with prolonged nocturnal sleep or paradoxically may pres-
but sometimes they may slump or fall forward to the ground for a few ent with hyperactive behavior, insomnia, and bizarre hallucinations.
seconds. The duration is usually a few seconds to a minute or two, and Children may present with characteristic cataplectic facies (facial
consciousness is retained completely during the attack. During brief weakness with tongue protrusion) not associated with emotion,
cataplectic spells, neurological examination reveals flaccidity of the or cataplexy may be manifested with perioral dystonic movements
muscles and absence or markedly reduced muscle stretch reflexes. H (Fig. 101.40) (Postiglione et al., 2018).
reflex and F responses are decreased or absent. Generally, cataplectic Comorbid conditions. In addition to the major manifestations,
spells occur months to years after the onset of sleep attacks, but occa- patients with narcolepsy may also have several important comorbid
sionally cataplexy is the initial manifestation. It is a lifelong condition conditions (see eTable 101.6): sleep apnea, PLMS, and RBD. Sleep
but is generally less severe and may even disappear in old age. Rarely, apnea is noted in approximately 30% of narcoleptic patients; most
status cataplecticus occurs, particularly after withdrawal of anticata- commonly central apnea is seen, but obstructive or mixed apnea is
plectic medications. An EEG recording shows evidence of wakeful- also reported. Associated sleep apnea may aggravate sleep attacks. It is
ness during brief cataplectic spells, but if the attack lasts longer than important to diagnose obstructive sleep apnea (OSA) in these patients
1 to 2 minutes, the EEG shows REM sleep. A potential pathogenetic because treatment with continuous positive airway pressure (CPAP)
mechanism postulated for cataplexy is illustrated in Fig. 101.39 and will relieve apnea, with curtailment of EDS. RBD generally occurs in
Sleep attack episode
Loss of
Orexin
Acetycholine
Histamine
Serotonin
Noradrenaline
Acetycholine
Sleep paralysis
Inconsistent release of
Momentary paralysis Excessive sleepiness
neurotransmitters that
on awakening, lasting and lapses into sleep
promote wakefulness
seconds to minutes B
A
Sleep Stages
MTT
e
Wake
REMM
1
S1
2
S2
3
S3
4
S4
9:25 9:30 9:35 9:40

Time
C
Fig. 101.38 Narcolepsy Symptom Spectrum. Narcolepsy symptoms include severe unremitting hyper-
somnolence with sleep attacks in virtually all patients, cataplexy in the majority, as well as sleep paraly-
sis, hypnagogic hallucinations, disturbed night sleep, and automatic behavior. The underlying mechanism
of excessive daytime sleepiness has recently been linked to loss of orexin neurons. This pathology reduces
excitatory input to the cortex, thalamus, and wake-promoting neurotransmitter systems in multiple brain
regions, resulting in persistent sleepiness throughout the day. A, Sleep episode/involuntary nap during quiet
reading. B, The specific loss of orexin-producing neurons in patients with narcolepsy accompanied by cata-
plexy leads to erratic firing of the brainstem neurons responsible for arousal. This change results in excessive
daytime sleepiness and a predisposition to lapses into sleep. C, A neurophysiological recording made during a
multiple sleep latency test (MSLT) documents the transition from wakefulness into sleep. A shortened sleep
latency period is evident, and a so-called sleep-onset rapid eye movement (REM) period (SOREMP) occurs
within 15 min. In patients with narcolepsy accompanied by cataplexy, SOREMPs occur in ∼50% of sleep epi-
sodes (detected by MSLT or night-time polysomnography). (A, B, C Adapted from Bassetti, C.L.A., Adaman-
tidis, A., Burdakov, D. et al. Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment.
Nat. Rev. Neurol. 15, 519–539 (2019). https://doi.org/10.1038/s41582-019-0226-9. With permission.)
men with narcolepsy—in up to 36% of all patients with the disorder. prevalence (exact percentage is not known in limited studies) of both
Mostly commonly, the stimulants and tricyclic antidepressants eating disorder (Droogleever-Fortuyn et al., 2008) and increased BMI
or selective serotonin reuptake inhibitors (SSRIs) used to treat (Schuld et al., 2002) not related to each other in narcoleptic patients,
narcolepsy-cataplexy syndrome may induce or exacerbate RBD. PLMS as well as anxiety disorders, depression, and fatigue which is distinct
have been noted in 10%–60% of narcoleptic patients. There is a high from sleepiness.
Sudden positive
Excitatory emotions
Inhibitory
Loss of
Reduced Orexin
activity
Medial
prefrontal
Medial cortex
prefrontal
cortex
Orexin
Amygdala
Reduced actvity in Increased actvity in
NE,5-HT
brain regions that neurons promoting
inhibit REM sleep REM sleep atonia
SLD B Motor neurons

inhibited Cataplexy
Amygdala Cataplexy attack
v/PAG/
LPT Spinal interneuron
MM
Motor neuron
Normal
muscle tone
Cataplexy attack
EOG 1
EOG 2
Chin-EMG
C3-A2
C4-A1
O1-A2
O2-A1
Tibial EMG r
Tibial EMG l
A Sudden loss of muscular-postural tone
with laughter or fright C
Fig. 101.39 Cataplexy in the Setting of Narcolepsy Type 1. The patient with cataplexy attack depicts a
fairly rapidly progressive bilateral loss of skeletal muscle tone, ptosis, loss of control of facial muscles, and
loss of tone of the neck and upper extremity muscles during laughter triggered by tickling. Consciousness
is preserved, and mild muscle twitching or face grimacing can occur. B, Sudden, positive emotions activate
neurons in the vicinity of the medial prefrontal cortex that excite orexin neurons in the lateral hypothalamus
and the central amygdala. The absence of orexin, however, leads to reduced activity of GABAergic neurons
in the periaqueductal grey area that inhibit rapid eye movement (REM) sleep and enhances the activity of glu-
tamatergic neurons in the sublaterodorsal tegmental nucleus involved in REM atonia. The imbalance in this
pathway results in the activation of descending pathways that inhibit spinal motor neurons and eventually to
cataplexy. Pathways shown in blue are excitatory, while those in red are inhibitory. Open circles indicate neu-
ron-cell bodies. Dotted lines indicate reduced activity. C, An electromyography (EMG) recording during a cata-
plexy episode (shaded area) documents a loss of muscle tone in multiple channels with superimposed bursts
of increased muscle phasic activity (which present clinically as motor phenomena such as muscle twitching
and face grimacing). EOG, Electro-oculography channel; l, left; r, right. (Adapted from Bassetti, C.L.A., Ada-
mantidis, A., Burdakov, D. et al., 2019. Narcolepsy—clinical spectrum, aetiopathophysiology, diagnosis and
treatment. Nat. Rev. Neurol. 15, 519–539. https://doi.org/10.1038/s41582-019-0226-9. With permission.)
E
Fig. 101.40 Cataplectic Facies Phenotype. Unique facial aspects (cataplectic facies) and complex move-
ments of cataplectic attacks close to disease onset. A, Facial weakness, ptosis with onward head and trunk
flexion with active shoulder raising; (B) head drop and opposing neck hyperextension viewing (when looking
at something); (C) perioral movement with mouth opening and tongue protrusion; (D) bilateral ptosis with
active eyebrow raising and head swaying; (E) generalized facial hypotonia with bilateral ptosis, asymmetrical
facial contraction. (From Postiglione, E., et al., 2018. The clinical spectrum of childhood narcolepsy. Sleep
Med. Rev. 38, 70e85. © 2017 Elsevier Ltd. All rights reserved.)
Differential Diagnosis of Narcolepsy-Related Sleep Attacks BOX 101.13 Differential Diagnosis of

The most common conditions that should be differentiated from Narcoleptic Sleep Attacks
narcoleptic sleep attacks are illustrated in Box 101.13 and Table
101.7. Narcolepsy-related sleep attacks should be differentiated from Obstructive sleep apnea syndrome
other causes of EDS. These include sleep deprivation and insufficient Sleep deprivation
sleep syndrome, OSAS, alcohol- and drug-related hypersomnolence, Insufficient sleep syndrome
idiopathic hypersomnia (Aldrich, 1996), circadian rhythm sleep dis- Alcohol/drug-related hypersomnolence
orders, and other medical, neurological, and psychiatric disorders Periodic hypersomnolence
causing hypersomnolence. OSAS (which will be reviewed later in the Medical, neurological, and psychiatric disorders causing hypersomnolence
chapter) is the most common cause of EDS in patients referred to a Idiopathic hypersomnia
sleep laboratory for evaluation. It is characterized by repeated epi- Circadian rhythm sleep disorders
sodes of obstructive and mixed apneas during NREM and REM sleep
in overnight PSG recordings. These patients have prolonged daytime
sleep episodes followed by fatigue and drowsiness on awakening, Idiopathic hypersomnia (see later discussion) closely resembles
which contrasts with a fresh feeling in narcoleptic patients on awak- narcolepsy syndrome. In contrast to narcolepsy, the sleep episodes in
ening from brief sleep attacks. All patients with hypersomnolence can idiopathic hypersomnia are prolonged, and the sleep is not refresh-
be excluded after careful history and physical examination and over- ing. PSG recordings and MSLT scores do not show sleep-onset REM
night PSG recording. sleep but do show pathological sleepiness. There is no disturbance of
eTABLE 101.7 Narcolepsy/Cataplexy Differential diagnosis

OBJECTIVE VERIFIABLE INDICATORS
Narcoleptic Confounding
Mimics Overlapping Features Clinical Clues Laboratory/Neuroimaging Neurophysiology
Neuromuscular Hypotonia Additional neurological findings Elevated CPK, aldolase, LDH, Altered EMG/NCV pattern
diseases Hyporeflexia (weakness, worsening with abnormal muscle biopsy imaging/
exercise, etc.) histology
Epileptic attacks Head drops Loss of consciousness, rapid Increased CPK after generalized Critical epileptic EEG
Axial drops onset, post ictal confusion, episodes discharges,
Falls tongue biting, incontinence Unique metabolic abnormalities Inter-ictal EEG epileptic
Negative/positive myoclonus related to different etiologies abnormalities.
Neuroimaging abnormalities
Cerebellar ataxias Unstable gait, slurred speech, Persistent condition (although Different biochemical/genetic
hypotonia and hyporeflexia fluctuating), absence of abnormalities according to
emotional triggers, additional different underlying diseases
neurological findings (e.g., Neuroimaging abnormalities
nystagmus, appendicular
ataxia) frequent involvement
of other CNS structures
Choreic disorders Dyskinesia with prominent facial Presence of piano-playing Evidence of recurrent streptococcal Active bursts on EMG
involvement and choreiform movements, infections coupled with clinical leads
psychiatric comorbidities, recent systemic involvement worsening (vs. hypotonia in NT1)
streptococcal infection, and/or Different biochemical and genetic
elevated streptococcal findings may occur in different
antibodies titer choreic conditions
Encephalitis Acute onset of sleep disturbance, Impaired consciousness, Serological autoimmune/ EEG abnormalities
abnormal movements (orofacial severe psychosis or catatonia, paraneoplastic markers (e.g., potential
dyskinesias, stereotyped frequent seizures, autonomic Altered CSF findings occurrence of epileptic
movements), psychiatric/ dysfunction, and severe (e.g., altered brain blood barrier) activity)
behavioral changes cognitive impairment
ADHD Hyperactivity, lack of attention, Lack of pathological EDS
decreased school performances,
fidgeting
ADHD, Attention-deficit/hyperactive disorder; CNS, central nervous system; CPK, creatine phosphokinase; EDS, excessive daytime sleepiness; EEG,
electroencephalogram; EMG, electromyography; LDH, lactic dehydrogenase; NT1, narcolepsy type 1; CSF, cerebrospinal fluid.
From The clinical spectrum of childhood narcolepsy; NCV, nerve conduction velocity; CRP, C-reactive protein.
REM-NREM organization on PSG recordings. Some patients with

BOX 101.14 Differential Diagnosis of
idiopathic hypersomnia may have a positive family history.
Cataplexy
Differential Diagnosis of Cataplexy and Other Features of Partial complex seizure
Narcolepsy Absence spell
Cataplectic attacks may be mistaken for partial complex seizures, Atonic seizure
absence spells, atonic seizures (as well as gelastic-atonic seizures char- Drop attack
acterized by laughing followed by loss of muscle tone), drop attacks, Syncope
basilar migraines, vertebrobasilar insufficiency, syncope, and pseudocat- Vertebrobasilar insufficiency
aplexy (Box 101.14). Pseudocataplexy is a functional disorder, often seen Basilar migraines
in patients with cataplexy, in which there are negative thoughts rather Pseudocataplexy
than laughter, the typical precipitant of true cataplexy, and characterized
by spells extending over minutes to hours rather than the seconds to
minute/s characteristic of bona fide cataplexy (Plazzi et al., 2010; Shankar ICSD-III classification (AASM, 2014) of three major central disorders
et al., 2010). A partial complex seizure, however, is characterized by an of hypersomnolence and their differentiating features. Supportive fea-
altered state of consciousness, unlike cataplexy. In addition, patients tures also include profound sleep inertia, known as sleep drunkenness
with seizures may have generalized tonic-clonic movements, postictal (elucidated as prolonged difficulty waking up accompanied by irrita-
confusion, and epileptiform discharges on EEG. Absence spells are char- bility and repeated returns to sleep), mental fatigability, dependence
acterized by staring with vacant expression lasting up to 30 seconds, with on other people for awakening them, and long (>1 hour) unrefreshing
an altered state of alertness associated with characteristic 3-Hz spike- naps (AASM, 2014; Vernet et al., 2010). Because of EDS, the condition
and-wave patterns in the EEG. Atonic seizures are accompanied by tran- may be mistaken for sleep apnea. However, the patient does not give a
sient loss of consciousness and EEG evidence of slow spike-and-wave history of cataplexy, snoring, or repeated awakenings throughout the
discharges or multiple spike-and-wave discharges. night. As part of the sleep drunkenness spectrum, some patients may
Sleep paralysis, in the context of narcolepsy, should be differenti- have automatic behavior with amnesia for the events. Physical exam-
ated from isolated physiological and familial sleep paralysis in which ination uncovers no abnormal neurological findings. This disabling
other manifestations of narcolepsy are absent. Automatic behavior and lifelong condition should be differentiated from other causes of
should be differentiated from the automatisms observed in partial EDS (see eBox 101.5). Some recent data propose that IH may be a
complex seizures and psychogenic fugue. The clinical history, pre/ dysfunction of the autonomic nervous system as patients sometimes
post event triggers/confusion, physical examination, and EEG should present with perception of temperature dysregulation, orthostatic
be helpful in differentiating these conditions. Differential diagnosis of disturbance, headache, and peripheral vascular complaints (Raynaud-
narcolepsy and cataplexy are summarized in Table 101.7 (Postiglione type phenomena with cold hands and feet) (AASM, 2014; Bruck and
et al., 2018). Parkes, 1996). Sleep paralysis and hypnagogic hallucinations may also
“Symptomatic narcolepsy” or “secondary narcolepsy” is the pre- be reported, but the frequency is uncertain (4%–40% in different
viously used term to describe narcolepsy associated with underlying series). Finally, there is no clear association between idiopathic hyper-
structural, genetic, inflammatory, or vascular abnormality impact- somnia and HLA.
ing the hypothalamus and leading to severe CNS hypersomno-
lence with or without cataplexy or abnormal CSF hypocretin levels. Kleine-Levin Syndrome (aka Recurrent Hypersomnia, Periodic
Depending on the presence of cataplexy/reduced CSF hypocretin Hypersomnolence)
levels, narcolepsy type 1 and 2 may be found. Leading CNS causes KLS is a form of recurrent hypersomnia associated with symptoms of
include diencephalic and midbrain tumors, MS, strokes, cysts, vascu- hyperphagia and megaphagia, cognitive impairment, and hypersexu-
lar malformations, encephalitis, cerebral trauma, and paraneoplastic ality affecting mostly adolescent patients (males > females) (Arnone
syndrome with anti-Ma2 antibodies and it may present with narco- and Conti, 2016; Arnulf, 2015; Miglis and Guilleminault, 2016; Sum-
leptic-like sleep attacks and other manifestations (Nishino, 2007; Ping and Guilleminault, 2016). During the episodic sleep attacks, the
Nishino and Mignot, 2011; Clavelou et al., 1995). Cataplexy may patient sleeps for 16–18 hours a day or more and upon awakening
develop in children affected with Niemann-Pick disease type C. Fig. eats voraciously. Other behavioral disturbances during the episodes
101.41 illustrates a scenario from the authors’ practice of a gentleman include hyperorality, memory impairment, confusion, hallucinations,
with a history of neurosarcoid of the diencephalon and hypocretin and polydipsia. The ICSD-III requires that there be at least two epi-
deficiency illustrating a case of secondary/symptomatic narcolepsy sodes of excessive sleepiness lasting between 2 days and 5 weeks in
(Panossian and Avidan, 2016). duration, more frequent than once a year and once every 18 months,
with periods of normalcy between episodes (normal alertness, cog-
Idiopathic Hypersomnia nition, and mood) (AASM, 2014). During candidate periods, KLS is
Idiopathic hypersomnia (IH) is characterized by a greater than likely when at least one of the following is present: disinhibited behav-
3-month duration of EDS and an irrepressible need to sleep or daytime ior (e.g., hypersexuality), cognitive impairment, altered perception,
lapses into sleep in the absence, and after correction, of sleep depriva- eating abnormality, so long as the hypersomnia is not better explained
tion (AASM, 2014). by another disorder, especially bipolar disorder (AASM, 2014).
The onset of the disease is generally around the same age as narco- Sleep studies in KLS reveal normal sleep cycling and MSLTs
lepsy (15–30 years). The sleep pattern, however, is different from that show pathological sleepiness without sleep-onset REM. The cause
of narcolepsy. The patient generally sleeps for hours, and the sleep is of the condition is undetermined; a limbic-hypothalamic dysfunc-
not refreshing. Total 24-hour sleep time is 660 minutes or more (typ- tion has been suspected but not proven. Reports of thalamic and
ically 12–14 hours) on 24-hour PSG monitoring or wrist actigraphy hypothalamic hypoperfusion on SPECT study, as seen in eFig.
recording. The MSLT shows a mean sleep onset latency of 8 minutes or 101.42, support this hypothesis (Hong et al., 2006; Huang et al.,
less, with less than two sleep-onset REM sleep periods. Table 101.7 lists 2005). While no evidence-based treatments are currently available
R
8
Hypothalamus
A P
A B F
Other 1% Multiple 9%
Inherited Posterior fossa 6%

disorders Tumor 29%
34% CA SOREMP Frontal lobe 3%
Temporal lobe 3%
SOREMP CA
Brainstem 9%
CA CA
CA Vascular 5%
SOREMP CA
Hypothalamus
CA Encephalopathy 3%
70%
Degeneration 3%
Head trauma 16%
Demyelinating 9%
C D
Fig. 101.41 Secondary or “Symptomatic” Narcolepsy. Secondary narcolepsy is caused by diencephalic
injury in the setting of neurosarcoidosis. A, The location of the diencephalon, where the wake-stabilizing
hypocretin-producing cells are localized. B, Brain MRI indicated sarcoid involvement of the hypothalamus,
showing postcontrast hyperintensity within the anterior hypothalamus. The patient did not experience any
brainstem involvement, nor were any appreciable lesions found in the locus coeruleus or raphe nuclei. C and
D, Neurological diseases and location of brain lesions in 113 cases of secondary narcolepsy. C, Neurological
diseases are shown by category reported as secondary narcolepsy. Reported here are tumors, inherited
disorders, and head trauma, which are the 3 most frequent causes. The percentage of cataplexy (CA) or
sleep-onset REM periods (SOREMP) is denoted in each category with a dashed line. D, Location of brain
lesions in symptomatic patients with narcolepsy associated with brain tumor; the hypothalamus and adjacent
structures are the most common location. Included are 113 symptomatic cases of narcolepsy. (A, Copyright
© Alon Y. Avidan, MD, MPH; B, Copyright © Alon Y. Avidan, MD, MPH; C, D, Modified from Kanbayashi, T.,
Sagawa, T., Takemura, F., et al., 2011. The pathophysiologic basis of secondary narcolepsy and hypersomnia.
Curr. Neurol. Neurosci. Rep. 11 [2], 235–241.)
for KLS, lithium treatment has been found to be effective (Oliveira the upper airway. In CSAS, the problem lies in the ventilatory control
et al., 2013, Sveinsson, 2014) and recent reports also suggest pos- mechanism in the CNS.
sible treatment intervention with clarithromycin and flumazenil Upper airway OSA-hypopnea syndrome remains undiagnosed
(Kelty et al., 2014; Rezvanian and Watson, 2013; Trotti et al., 2014) or underdiagnosed because of insufficient knowledge and aware-
(Video 101.3). ness of serious consequences resulting from this disorder. OSAS
causes significant morbidity and mortality and is often associated
Sleep Apnea Syndrome with a variety of comorbid conditions (Banno and Kryger, 2007;
Sleep apnea syndrome is broadly divided into two types: upper air- Korson and Guilleminault, 2015). Cardinal features of OSAS
way OSAS and central sleep apnea syndrome (CSAS), depending on include habitual loud snoring, witnessed apneas during sleep, and
pathophysiological mechanisms. OSAS is the most common sleep dis- daytime hypersomnolence as well as hyperactivity and nocturnal
order referred to sleep laboratories for PSG recordings. Two groups enuresis, particularly in children. OSAS is characterized by repet-
of neurologists, Gastaut, Tassinari and Duron from France (Gastaut itive episodes of complete (apnea) or partial (hypopnea) upper
et al., 1965), and Jung and Kuhlo from Germany, in 1965 (Jung and airway obstruction during sleep, resulting in arterial oxygen desat-
Kuhlo, 1965) independently located the site of obstruction in OSAS in uration and arousal from sleep.
A B
R L
R L
255
Cingulate
Thalamus gyrus
C 155
112
41
0
Hypothalamus
eFig. 101.42 Neuroimaging in Kleine-Levin syndrome (KLS) demonstrating episodic limbic-hypothalamic dysfunction, The hypoperfusion on single-
photon emission computed tomography (SPECT) depicts episodic hypofunction, demarcated in the following regions: (A) Brain SPECT during to
symptomatic phase demonstrating hypoperfusion in the bilateral frontal and temporal lobes and diencephalic structures (thalami and hypothalamus).
B, Brain SPECT during the convalescent phase depicting recovery in the hypofunction shown in A, with the exception of the right mesial temporal
period. C, Subtraction of brain SPECT images between A and B revealed profound hypoperfusion in the diencephalic structures (bilateral thalami, left
hypothalamus), basal ganglia, bilateral medial and dorsolateral frontal regions, and left temporal areas during the period of active KLS disease state.
L, Left side; R, right side. (From Hong, S.B., Joo, E.Y., Tae, W.S., et al., 2006. Episodic diencephalic hypoperfusion in Kleine-Levin syndrome. Sleep
29, 1091–1093; with permission.)
Video 101.3 Diagnosis, Disease Course, and Management of patient’s chair and speaks incoherently in a loud voice about horses.
Patients With Kleine-Levin Syndrome Adolescent boy aged 18 years He makes repetitive stamping movements to mimic a horse’s rhythm.
during and after a Kleine-Levin episode. During the episode the patient These stereotypical manifestations recur when he speaks about food.
displayed disinhibited, stereotyped behavior that suggests frontal-lobe (From Rico, I., Thomas, J.B.S., Mignot, E., Prof. Lancet Neurology, The,
involvement. The patient sits on the physician’s chair instead of the 2012-10-01, 11[10], 918–928, Copyright © 2012 Elsevier Ltd.)
Sleep-Disordered Breathing Terminology breathing is characterized by movements of the thorax and abdomen
The spectrum of SDB includes a variety of breathing patterns based in opposite directions, indicating increased upper airway resistance
on analysis during overnight PSG recordings. Fig. 101.43 schematically and upper airway obstruction (see Fig. 101.43, B). Repeated arous-
shows some patterns of SDB. Apnea or cessation of breathing consists als temporally related to paradoxical breathing (Fig. 101.44) and at
of three types: obstructive, central, and mixed. Cessation of airflow times crescendo snoring which result in sleep fragmentation signifies
with no respiratory effort defines central apnea, during which both the presence of upper airway resistance which is an important factor
diaphragmatic and intercostal muscle activities as well as gas exchange causing EDS (Berry, 2012). Upper airway resistance syndrome (UARS)
through the nose or mouth are absent (see Fig. 101.43, C). In contrast, is characterized by repeated abnormal respiratory efforts during sleep
during obstructive apnea, airflow stops while the effort continues (see without apnea, accompanied by recurrent arousals and EDS. The
Fig. 101.43, B); in mixed apnea, there is an initial cessation of airflow Respiratory Disturbance Index (RDI) includes all these abnormal
with no respiratory effort (central apnea) followed by a period of upper breathing events, including respiratory effort-related arousal. Cheyne-
airway OSA (see Fig. 101.43, D). Stokes breathing is a unique form of SDB characterized by cyclical and
There are two separate rules for scoring hypopnea in the recent periodic breathing changes in breathing with a crescendo-decrescendo
AASM Scoring Manual (Iber et al., 2007). The rule requires a reduc- sequence separated by central apneas or hypopneas (Fig. 101.45)
tion of the signal by 30% or more of the baseline for at least 10 seconds (Abraham et al., 2015) (Video 101.4).
accompanied by oxygen desaturation of 3% or more, or the event is Dysrhythmic breathing (Fig. 101.46, I) is characterized by non-
associated with an arousal within 3 seconds of the event. The “alter- rhythmical respiration of irregular rate, rhythm, and amplitude that
nate” rule requires a reduction of nasal pressure or the alternative air- becomes worse during sleep. This type of breathing may result from
flow sensor signal by 30% or more of the baseline amplitude for at least an abnormality in the automatic respiratory pattern generator in the
10 seconds accompanied by oxygen desaturation of 4% or more from brainstem. Apneustic breathing (see Fig. 101.46, L) is characterized by
the pre-event baseline. In both these rules the amplitude reduction prolonged inspiration with an increase in the ratio of inspiratory to
must be present for at least 90% of the event’s duration. expiratory time. This type of breathing may result from a neurologi-
To be clinically significant, the number of apneas and hypopneas cal lesion in the caudal pons disconnecting the apneustic center in the
per hour of sleep (Apnea-Hypopnea Index, or AHI) must be at least lower pons from the pneumotaxic center in the upper pons. Inspiratory
5. Most clinicians, however, use this index in the context of the clin- gasp (see Fig. 101.46, K) is characterized by short inspiratory time and a
ical presentation (severe sleepiness, impairment of function) as well relatively prolonged expiration and has been noted in association with
as underlying comorbidities (such as atrial fibrillation, recent stroke, a lesion in the medulla. Ataxic breathing (see Fig. 101.46, H) is char-
neuromuscular disorder) when deciding on clinical significance and acterized by clusters of cyclic breathing followed by recurrent periods
management. An arousal is defined as either a transient return of alpha of apnea (the apnea length is greater than the ventilatory phase). Biot
activities (8–13 Hz) or beta rhythms (>13 Hz) or a change from delta breathing (see Fig. 101.46, J) is a variant of ataxic breathing character-
to theta activities in the EEG lasting from 3 to 14 seconds. Paradoxical ized by two to three breaths of nearly equal volume separated by long
NORMAL MIXED APNEA
Airflow
Airflow
Effort Effort
A D
UPPER AIRWAY OBSTRUCTIVE APNEA PARADOXICAL BREATHING
Airflow
Flow
Thor
effort
Effort
Abd
effort
B E
CENTRAL APNEA CHEYNE-STOKES RESPIRATION
Airflow
Airflow
Effort
Effort
C F
Fig. 101.43 Schematic Diagram Showing Different Types of Breathing Patterns in Neurological Ill-
nesses (Part 1). A, Normal breathing pattern. B, Upper airway obstructive apnea. C, Central apnea. D, Mixed
apnea (initial central followed by obstructive apnea). E, Paradoxical breathing. F, Cheyne-Stokes breathing.
(From Chokroverty, S., 2009. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical
Aspects, third ed. Saunders, Philadelphia, Fig. 29.6.)
Arousal
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
19 sec
NP
Thermal Air Flow
Chest
Abdomen
SpO2
96%
1 sec
eFig. 101.44 Upper Airway Resistance. This polysomnographic tracing illustrates respiratory effort–related
arousals (RERAs) suggestive of upper airway resistance. Note the 19-second flattening (flow limitation) on
the nasal cannula pressure signal (NP) associated with increasing inspiratory efforts culminating with an
electroencephalogram arousal at the termination of the RERA events.(Berry, 2012). (From Berry, R.B., 2012.
Fundamentals of sleep medicine. Saunders, Philadelphia, p. 130.)
Video 101.4 Cheyne-Stokes Respiration and Obstructive Sleep and pathology. (From Kryger, M.H., Avidan, A.Y., Berry, R., 2013. Atlas
Apnea with Heart Failure This patient with obstructive sleep apnea of clinical sleep medicine, Second ed. Philadelphia, PA: Elsevier/
developed heart failure, which led to Cheyne-Stokes breathing. Thus, Saunders)
the patient had evidence of two types of abnormal breathing patterns
A No airflow
A Crescendo-decrescendo
(Cheyne-Stokes) breathing
C
No respiratory effort
C
No respiratory effort
Decrease in oxygen saturation

following apneic episode
D
Fig. 101.45 Cheyne-Stokes Breathing (CSB) Crescendo-Decrescendo Pattern from an Overnight Poly-
somnographic (PSG). The CSA breathing morphology is uniquely characterized by cycles of deep, rapid,
crescendo-decrescendo breathing pattern (A), punctuated by periods of slower, shallower breathing or no
breathing at all (B) with no respiratory effort in between (C), with some delay due to chemoreceptor signal
processing and circulatory delay (D), with resumption of breathing and recovery of the arterial O2 saturation
(SpO2). “D” is pathologically protracted in patients with congestive heart failure and a prolonged circulation
time. Each individual episode contributes a discrete hypoxic episode and a release of norepinephrine and
continued insults accelerate the downward cycle toward heart failure. (From Abraham, W. T., et al., 2015.
Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. 3 [5], 360–369.)
CHEYNE-STOKES VARIANT BIOT BREATHING
Airflow
Effort
A D
INSPIRATORY GASP ATAXIC BREATHING
Airflow
Airflow
Effort Effort
B E
DYSRHYTHYMIC BREATHING APNEUSTIC BREATHING
Airflow
Airflow
Effort
Effort
C F
Fig. 101.46 Schematic Diagram Showing Different Types of Breathing Patterns in Neurological Illnesses (Part II). A, Cheyne-Stokes variant pattern.
B, Inspiratory gasp. C, Dysrhythmic breathing. D, Biot breathing, a special type of ataxic breathing characterized by 2 to 3 breaths of nearly equal
volume followed by a long period of apnea. E, Ataxic breathing. F, Apneustic breathing. (From Chokroverty, S., 2009. Sleep Disorders Medicine: Basic
Science, Technical Considerations, and Clinical Aspects, third ed. Saunders, Philadelphia, Fig. 29.6.)
periods of apnea. Ataxic (including Biot) breathing is often noted in patients. There is an increased prevalence of OSAS in those with
medullary lesions. a thick neck and large abdomen. Men with a neck circumference
Hypoventilation is illustrated in Fig. 101.47 I , II and refers to a reduc- measuring more than 17 inches and women with a neck measuring
tion of alveolar ventilation accompanied by hypoxemia and hypercap- more than 16 inches are at risk for OSAS. Fig. 101.48 demonstrates
nia without any apnea or hypopnea; it may be noted in patients with the compromised retroglossal airspace in the setting of sleep apnea
neuromuscular disorders and kyphoscoliosis and those with underly- and the anatomical sites that might participate in the pathology of
ing lung or chest-wall abnormalities that impair gas exchange during OSA: The normal airspace (green) is severely compromised because
wakefulness. During sleep hypoventilation, the partial pressure of arte- of restriction of the upper airway, intranasal space, and retropalatal
rial carbon dioxide (Paco2) rises at least 10 mm above the supine awake and the retroglossal spaces.
values (Iber et al., 2007; Pepin et al., 2016). Race may be a factor, given that a high prevalence of SDB is noted
in Pacific Islanders, Mexican Americans, and African Americans.
Epidemiology of Obstructive Sleep Apnea Syndrome There are also family aggregates of OSAS. Other factors with a high
No study has been specifically designed to determine the incidence association are alcohol, smoking, and drug use. Other risk factors
of OSAS in a previously healthy population. Based on a definition include nasal allergies or congestion, endocrine diseases (e.g., hypo-
of 15 or more apneas or hypopneas per hour of sleep accompanied thyroidism, acromegaly), disorders with autonomic failure or those
by EDS, the recent Wisconsin sleep cohort study data listed prev- associated with craniofacial abnormalities (e.g., Marfan, Down, and
alence figures of moderate to severe OSAS at 10% in men and 3% Pierre-Robin syndromes). The risk factors associated with OSAS are
in women aged 30–49 years but 17% in men and 9% in women listed in eBox 101.15.
aged 50–70 years. There is a strong association between OSAS and
male gender, increasing age, and obesity. The condition is com- Evaluation and Assessment
mon in men older than age 40, and among women the incidence of Detailed sleep history as well as the daytime history, and careful physical
OSAS is greater after menopause. Approximately 85% of patients examination should be focused on specific associated and risk factors,
with OSAS are men, and obesity is present in about 70% of OSAS specifically BMI, cardiopulmonary examination, and an examination
Obesity Obesity hypoventilation syndrome
Fat tissue surrounding upper airway Upper airway collapse Respiratory Work of
drive breathing
Upper airway narrowing
Low respiratory drive
Adipose tissue in the abdomen

TLC TLC and surrounding chest walls
Reduced lung
volume, muscle
weakness
FRC
ERV Impeded diaphragm FRC Ventilation-perfusion mismatching
ERV
motion, atelectasis Low PaO2
RV REM sleep
RV
Airway closure: PEEPi
A Hypoventilation
Fig. 101.47 Hypoventilation Syndrome in the Setting of Obesity. I: Obesity-related alterations in the
respiratory system, respiratory drive, and in breathing during sleep. ERV, Expiratory reserve volume; PEEPi,
intrinsic positive end-expiratory pressure; REM, rapid eye movements; RV, residual volume; TLC, total lung
capacity;. II: (A) Evolution of nocturnal transcutaneous CO2 in a typical patient with obesity hypoventilation
syndrome. Panel A shows a hypnogram (PSG attributes vs. time) during wakefulness reference TcPCO2.
Panel B depicts increase in TcPCO2 due to long-lasting apneas and hypopneas. Panel C highlights the increase
in PtCO2 corresponding to REM sleep hypoventilation (red circles).
eBOX 101.15 Risk Factors for Obstructive

Sleep Apnea Syndrome
Male gender
Increasing age
Menopause (women)
Body mass index (≥25 is considered overweight, and ≥30 is considered obese)
Increasing neck circumference (>17 inches in men and >16 inches in women)
Race (increased prevalence in Pacific Islanders, Mexican Americans, and
African Americans)
Alcohol
Smoking
Increasing drug use
Familial aggregates
Nasal allergies or congestion
Endocrine diseases
Dysautonomia
Disorders with craniofacial abnormalities
Fig. 101.47 cont’d (B) Polysomnographic pattern of obesity hypoventilation syndrome phenotype with
long-lasting apneas as the main contributor to daytime hypercapnia. The insufficient post-event ventilatory
compensation leads to a progressive hypercapnia (CO2 overload) across the night contributing to the patho-
genesis of diurnal hypoventilation via alteration of ventilatory drive. ABD=abdominal movements. Cz, Electro-
encephalography; DEB, flow; JMB1, leg movements; PTT, pulse transit time; SaO2, oxygen blood saturation;
SAT, SpO2; THER, oronasal thermistor; THO, thoracic movements. (From Pepin, J.L., et al., 2016. Prevention
and care of respiratory failure in obese patients. Lancet Respir. Med. 4 [5], 407–418.)
Normal inferior turbinate

Normal intranasal space
Diminished
Normally intranasal space
positioned maxilla
Diminished
Normal retropalatal space
retropalatal
space Enlarged Enlarged
soft palate/ inferior turbinate
Normal soft
uvula Normally positioned
palate/uvula
Excess fat maxilla
Normal in pharyngeal
tongue Displaced
Normally wall tongue
position
Normal positioned Diminished Normally positioned
retroglossal mandible retroglossal mandible
space space
Excess fat in
submental triangle
Excess
supraplatysma fat
Vocal fold
A B
Fig. 101.48 The Airway Anatomy in Sleep Apnea: The Perfect Storm. Normal and abnormal airway
anatomy. A, this illustrated midline sagittal cross-section of the head and neck depicts the normal upper
airway and maxillofacial spaces and anatomy of a healthy, normal-weight 20-year-old man. The patient has
a normal upper and lower facial skeleton and normal soft tissue indicators (soft palate, tongue, tonsils,
and adenoids), without any compromise of the intranasal cavity. B, with increasing age and weight gain,
the same individual three decades later has an elevated body mass index. Although the anatomy of the
upper and lower facial skeleton remains fixed without any changes, fatty tissue consisting of adipose cells
has expanded and infiltrated the crevices and space in the upper airway. Particularly compromised are the
retropharyngeal and the lateral pharyngeal tissues, the soft palate, and the floor of the mouth, culminating
in restricted airflow. At age 20 years, the patient had normal upper airway space (the intranasal, retropal-
atal, and the retroglossal sites were all well visualized and with appropriate space for air flow to proceed
smoothly and unimpeded. At age 50 years, he has developed obstructive sleep apnea: The normal airspace
(green) is severely compromised because of restriction of the upper airway, intranasal space, and retropal-
atal and the retroglossal spaces. A perfect storm indeed. (From Posnick, J.C., 2014. Obstructive sleep
apnea: evaluation and treatment. In: Posnick, J.C. [ed.]. Orthognathic Surgery: Principles and Practice.
Elsevier, Philadelphia:, pp. 992–1058.)
of the upper airways (neck circumference, airway size, as highlighted symptoms include habitual loud snoring, choking during sleep, ces-
in Fig. 101.49) (Myers et al., 2013). The Modified Mallampati and ton- sation of breathing, and abnormal motor activities during sleep (e.g.,
sillar size classification are useful in evaluating patient airway size and jerking and shaking movements, confusional arousals, or sleep walk-
gauging the possible risk for OSA (Fig. 101.40 New) (Friedman et al., ing), severe sleep disruption, gastroesophageal reflux causing heart-
2013; Waters and Cheng, 2009) The laboratory assessment and man- burn, nocturnal enuresis (noted mostly in children), and profuse
agement are described in this chapter, under Laboratory Assessment sweating at night. The daytime symptoms include EDS characterized
of Sleep Disorders. by sleep episodes lasting 0.5–2 hours and occurring mostly when the
Physical examination may reveal obesity in approximately 70% of patient is relaxing. The prolonged duration and the unrefreshing
the cases, with increased BMI and increased neck circumference, in nature of these sleep attacks in OSAS differentiate these from nar-
addition to upper airway anatomical abnormalities causing reduction coleptic sleep attacks. The other daytime symptoms include impair-
of the upper airway space (e.g., low-hanging soft palate, large edema- ment of memory and motor skills, irritability, morning headache in
tous uvula, large tonsils and adenoids, especially in children, retrog- some patients, automatic behavior, retrograde amnesia, and hyper-
nathia, and micrognathia) as is highlighted in Fig. 101.50 (Avidan, activity (in children). Erectile dysfunction in men is often associated
2018; Myers et al., 2013). In severe cases physical examination may with severe and long-standing OSAS.
reveal evidence of congestive heart failure, cardiac arrhythmias, hyper- OSAS is associated with increased morbidity and mortality as a result
tension, and polycythemia. of both short-term (Strohl et al., 2013) consequences (impairment of
quality of life and increasing traffic and work-related accidents) and
Clinical Manifestations of Obstructive Sleep Apnea Syndrome long-term consequences resulting from associated and comorbid condi-
The symptoms of OSAS can be divided into two groups (Flemons, tions such as hypertension, heart failure, MI, cardiac arrhythmias, stroke
2002; Korson and Guilleminault, 2015): those occurring during sleep due to both supratentorial and infratentorial infarctions, and transient
and those occurring during waking hours (eBox 101.16). Nocturnal ischemic attacks as well as cognitive dysfunction, depression, and
eBOX 101.16 Symptoms and Signs in

Obstructive Sleep Apnea Syndrome
Nocturnal Symptoms During Sleep
Loud snoring (often with a long history)
Choking during sleep
Cessation of breathing (apneas witnessed by bed partner)
Sitting up or fighting for breath
Abnormal motor activities (e.g., thrashing about in bed)
Severe sleep disruption
Gastroesophageal reflux causing heartburn
Nocturia and nocturnal enuresis (mostly in children)
Insomnia (in some patients)
Excessive nocturnal sweating (in some patients)
Daytime Symptoms
Excessive daytime somnolence
Forgetfulness
Personality changes
Decreased libido and impotence in men
Dryness of mouth on awakening
Morning headache (in some patients)
Automatic behavior with retrograde amnesia
Hyperactivity in children
Hearing impairment (in some patients)
Physical Findings
Obesity in the majority of patients (70%)
Increased body mass index (body weight in kg/height in m2): overweight
≥25–29; obese ≥30
Increased neck circumference (>17 inches in men and >16 inches in women)
In some patients:
Large edematous uvula
Low-hanging soft palate
Large tonsils and adenoids (especially in children)
Retrognathia
Micrognathia
Hypertension
Cardiac arrhythmias
Evidence of congestive heart failure
Normal occlusion
Nasion (N)
Neck circumference
measured below
Thyromental Mentum (M) thyroid notch
plane Thyroid notch (T)
Gnathion (G)
Thyromental angle Malocclusion

Cricoid cartilage (C) (retrognathia and overjet)
Soft tissue plane

of anterior of neck N
Upper
incisor
M M Lower
Thyromental incisor Retrognathia
distance T G
Overjet >0.5 cm retroposition of
Cricomental space C >3-mm distance gnathion relative to nasion
(measured as the
perpendicular distance from the Dental occlusion
midpoint of the M-C line to the skin)
Anatomy and measurements

Fig. 101.49 Anatomy and Surface Measurements in the Assessment of a Patient with Suspected Obstruc-
tive Sleep Apnea. Retrognathia, overjet, and reduced cricomental space are key craniofacial properties that are
predictive of obstructive sleep apnea. (From Myers, K.A., Mrkobrada, M., Simel, D.L., 2013. Does this patient
have obstructive sleep apnea? The rational clinical examination systematic review. JAMA 310, 731−741.)
insomnia as summarized in Fig. 101.51. (Gaspar et al., 2017; Banno and cardiac death have been attributed to OSAS. Heart failure, mostly sys-
Kryger, 2007; Cordero-Guevara et al., 2011; Flemons, 2002; Kendzerska tolic heart failure but also diastolic heart failure (in which the studies are
et al., 2014; Kohler et al., 2013; Korson and Guilleminault, 2015; Marin limited), is associated with both obstructive and CSAs, but more CSAs,
et al., 2005; Redline et al., 2010; Somers et al., 2008; Vlachantoni et al., including Cheyne-Stokes breathing, than obstructive apneas (Arias
2013; Zamarion et al., 2013). Several prospective longitudinal studies et al., 2007; Javaheri, 2006; Javaheri and Somers, 2011; Kendzerska et al.,
(Nieto et al., 2000; Peppard et al., 2000; Young et al., 1997) have shown a 2014; Levy et al., 2013; McNicholas et al., 2007; Randerath and Javaheri,
clear association between OSAS and systemic hypertension, which may 2015; Somers et al., 2008). The presence of central apnea, including
be noted in approximately 50% of patients with OSAS. The factors that Cheyne-Stokes breathing, increases the mortality in patients with heart
cause hypertension in OSAS include repeated hypoxemias during sleep failure. Cognitive dysfunction, which is noted in moderately severe to
at night causing an increased sympathetic activity. OSAS is frequently severe OSAS patients (Lim and Pack, 2014), shows improvement after
noted in about 30% of cases of essential hypertension. Several studies satisfactory treatment with CPAP titration (Atwood and Strollo, 2015).
have shown improvement of hypertension or reduction of need for anti- Recently awareness about the presence of depression and insomnia in
hypertensive medications after effective treatment of OSAS with CPAP patients with OSAS has grown, but adequate studies have not been con-
titration (Banno and Kryger, 2007; Faccenda et al., 2001; Hla et al., ducted to find the prevalence and impact of these conditions on OSAS
2002; Kendzerska et al., 2014; Kohler et al., 2013; Pepperell et al., 2002; (Glidewell, 2013). There has been an increased association between
Vlachantoni et al., 2013; Zamarion et al., 2013). Pulmonary hyperten- OSAS and impaired quality of life, metabolic syndrome, hypertension,
sion is also noted in approximately 15%–20% of cases. Cardiac arrhyth- increased risk for metabolic disease, (increased insulin resistance with
mias in the form of premature ventricular contractions, ventricular type 2 diabetes, hypertriglyceridemia, and obesity), depression, cogni-
tachycardia, sinus pauses, and third-degree heart block as well as sudden tive decline, drowsy driving and motor vehicle accidents, and cognitive
(Modified Mallapati)
Position I Position II Position III Position IV

Allows visualization of the Allows visualization of the Allows visualization of the Allows visualization of
entire uvula and tonsils/pillars uvula but not the tonsils soft palate but not the uvula the hard palate only
Grade 1 Grade 2 Grade 3 Grade 4

Within tonsillar fauces Outside tonsillar fauces, Outside tonsillar fauces, Outside tonsillar fauces,
up to 50% of airway to midline up to 75% of the distance > 75% of the lateral
to the midline airway dimension
Fig. 101.50 New Sleep Medicine Examination. A, The Modified Mallampati classification describes tongue
size relative to oropharyngeal size. The test is conducted with the patient in the sitting position, the head
held in a natural position, the mouth wide open and relaxed and with the tongue inside the mouth without
any protrusion or phonation. The subsequent classification is assigned based upon the pharyngeal structures
that are visible. Class I = visualization of the soft palate, fauces, uvula, anterior and posterior pillars. Class II
= visualization of the soft palate, fauces, and uvula. Class III = visualization of the soft palate and the base of
the uvula. Class IV = soft palate is not visible at all. If the patient phonates, this falsely improves the view. If
the patient arches his or her tongue, the uvula is falsely obscured. The test was initially adapted to predict
ease of intubation but can be used to predict the potential severity of obstructive sleep apnea. B, Clinical of
tonsillar size is based on the following scheme. Grade 1: within tonsillar fauces; Grade 2: outside tonsillar
fauces, up to 50% of the airway to the midline; Grade 3: outside tonsillar fauces and up to 75% of the dis-
tance to the midline; and Grade 4: >75% of the lateral airway dimension. (Modified from Mallampati, S.R.,
Gatt, S.P., Gugino, L.D., et al., 1985. A clinical sign to predict difficult tracheal intubation: a prospective study.
Can. Anaesth. Soc. J. 32, 429–434.)
decline. The mechanisms accounting for OSA include hypoxia, sleep plus ventilatory duration) is more than 45 seconds in Cheyne-Stokes
fragmentation, and systemic inflammation (Dumortier and Bricout, breathing and less than 45 seconds in primary CSA.
2019; Walia, 2019). (a combination of) (Oyama et al., 2012; Sharma
et al., 2011; Zamarion et al., 2013). However, CPAP treatment did not Restless Legs Syndrome
significantly improve glycemia control or insulin resistance in patients Clinical Manifestations
with type 2 diabetes and OSAS. Recent studies have also shown an asso- RLS is the most common movement disorder but is uncommonly
ciation of OSAS to an increased risk of cancer and cancer mortality recognized and treated despite a lucid description of the entity in
(Martinez-Garcia et al., 2014). the middle of the last century (Hening et al., 2009; Wijemanne and
Jankovic, 2015). Diagnosis is based on clinical grounds and is based
Pathogenesis of Obstructive Sleep Apnea Syndrome on the International Restless Legs Syndrome Study Group (IRLSSG)
The factors contributing to the pathogenesis of OSAS include local criteria first established in 1995 (Walters, 1995) and modified slightly
anatomical, neurological, and vascular factors as well as familial predis- in 2003 (Allen et al., 2003), and modified again in 2012 (Allen
position (Banno and Kryger, 2007; Dempsey et al., 2010; Joosten et al., et al., 2014). These criteria include five essential diagnostic criteria
2014; Korson and Guilleminault, 2015). Collapse of the pharyngeal (Box 101.17). In addition, there are supportive clinical features as
airway is the fundamental factor in OSA. During sleep, muscle tone well as specifiers for clinical significance and clinical course of RLS
decreases, including that of the upper airway dilator muscles, which (Box 101.18). The IRLSSG diagnostic criteria are consensus criteria
maintain upper airway patency. As a result of this decreased tone, established by the international experts in RLS after careful deliber-
these muscles relax, causing increased upper airway resistance and ation. It is notable that these differ from the AASM (2014) and the
narrowing of the upper airway space. Defective upper airway reflexes Diagnostic and Statistical Manual (DSM-V) diagnostic criteria. The
may also play a role. Increasing familial occurrence of OSAS in some AASM criteria must include the specifier for clinical significance (see
patients may be related to abnormal craniofacial features. In children, Box 101.18), whereas DSM-V (2013) criteria require a frequency of
adenotonsillar enlargement and craniofacial dysostosis causing narrow at least three times a week and a duration of at least 3 months for
upper airway space are important factors. Neurological factors include symptoms. This division into three different requirements amongst
reduced medullary respiratory neuronal output and ventilatory control three groups of physicians is unfortunate but it is hoped that in
instability which may create excessive response to respiratory muscles future these three groups would merge the criteria into uniform and
(high loop gain) promoting upper airway collapse and obstruction in consistent diagnostic criteria to avoid confusion among physicians in
susceptible individuals. Other neurological factors include autonomic different specialties (Video 101.5).
activation during sleep-related breathing events, contributing toward RLS is a lifelong sensory-motor neurological disorder (Earley,
development of hypertension and cardiac arrhythmias. Vascular fac- 2003; Patel et al., 2014) that often begins at a very young age but
tors contributing to the pathogenesis and long-term adverse conse- is mostly diagnosed in the middle or later years. Prevalence of RLS
quences (Banno and Kryger, 2007; Javaheri and Somers, 2011) include increases with age and plateaus for some unknown reason around age
increased endothelin 1 (a vasoconstrictor), reduced nitric oxide (a 85 to 90 (Allen et al., 2001; Earley, 2003; Earley et al., 2011). All five
known vasodilator), and increased serum levels of vascular endothe- essential diagnostic criteria (see Box 101.17) are needed for establish-
lial growth factor (glycoprotein responsible for vascular remodeling the diagnosis. The overall prevalence of RLS has been estimated
ing and atherosclerosis). It has been shown that after effective CPAP at about 7.2% for all adult populations when severity was not con-
titration, these vascular abnormalities are reversed. Thus, a complex sidered, but at 2.7% for moderate to severe cases, particularly those
interaction of peripheral upper airway anatomical, central neural, in North American and European populations (Allen et al., 2005;
vascular, and genetic factors contributes to the syndrome of upper Chokroverty, 2014). The prevalence appears to be much less in some
airway OSAS. surveys from Asia (<1%–3%), suggesting the possibility of ethnic,
racial, and environmental influence in susceptibility to disease. In
Upper Airway Resistance Syndrome most surveys, the prevalence is greater in women than in men, and the
Additional text and eFig. 101.34 are available at http://expertconsult. disease is gradually progressing (Hening et al., 2004). Family studies
inkling.com. of RLS suggest an increased incidence (≈40%–50%) in first-degree
Central sleep apnea syndrome. Additional text is available at relatives of idiopathic cases. A high concordance (83%) in monozy-
http://expertconsult.inkling.com. gotic twins and complex segregation analysis suggest an autosomal
dominant mode of inheritance (Hening et al., 2009). Linkage analy-
Central Sleep Apnea Syndrome sis documented significant linkage to at least five different chromo-
CSAS includes primary CSA, CSA with Cheyne-Stokes breathing, CSA somes (12q, 14q, 9p, 2q, and 20p). Recent genome-wide association
due to high altitude periodic breathing, CSA due to a medical disorder and linkage analysis have documented common variations in certain
without Cheyne-Stokes breathing, CSA due to drug or substance abuse genomic regions, conferring more than 50% increase in risk to RLS-
(e.g., use of opiates) (Javaheri and Randerath, 2014), primary CSA of PLMS (Stefansson et al., 2007; Winkelmann et al., 2007). Four allelic
infancy, primary CSA of prematurity, and treatment emergent CSA variations in different genes have been identified on chromosomes
(ICSD-III; AASM, 2014). Primary CSAS is rare, and the patient may 2p, 6p, 15q, and 12q. Recent review of the genetics of RLS can be
present with EDS and frequent awakenings due to repeated episodes of reviewed elsewhere (Jimenez-Jimenez et al., 2018; Khan et al., 2017;
central apnea followed by arousals. The patient may also present with Rye, 2015; Winkelmann et al., 2017).
insomnia. Cheyne-Stokes breathing as previously highlighted in Fig. The sensory manifestations of RLS include intense disagreeable
101.44 noted in patients with congestive heart failure (Javaheri, 2006; feelings described as creeping, crawling, tingling, burning, aching,
Javaheri and Somers, 2011; Javaheri and Dempsey, 2013) and some- cramping, knifelike, or itching sensations. These creeping sensa-
times in renal failure. The presence of Cheyne-Stokes breathing in car- tions occur mostly between the knees and ankles, causing an intense
diac failure increases mortality. Patients with primary CSA usually are urge to move the limbs to relieve these feelings. Sometimes, simi-
normocapnic or hypocapnic, with Paco2 of 40 mm Hg or lower. The lar symptoms occur in the arms or other parts of the body, particu-
other important point of differentiation is that the cycle length (apnea larly in advanced stages of the disease or when the patient develops
NUMBER OF HYPOCRETIN NEURONS
90000
80000
70000
Number of neurons
60000
50000
40000
30000
20000
10000
A 0
Narcolepsy Normal
Environmental
factor (s)
Number of hypocretin cells
predisposition
(e.g. HLA)
Onset of
Genetic
Damage to
hypocretin producing symptoms
neurons
B Time
eFig. 101.34 Hypocretin Deficiency in Narcolepsy and Proposed Mechanism. A, Hypocretin Loss in Narcolepsy: The number of hypocretin
neurons is severely depleted in patients with narcolepsy and cataplexy within the red frame. Theoretical model to support the pathophysiology of nar-
colepsy is based on an environmental trigger which produces an autoimmune response such as seen in type I diabetes. A specific HLA genetic risk
factor is a key attribute to conferring the risk necessary to develop narcolepsy (much like fair skin is a risk for skin cancer). B, The disease process is
initiated resulting in an irreversible and progressive damage to the hypocretin neurons. At some point, the number of remaining neurons has reached
a critical threshold resulting in the full expression of overt narcolepsy along with its clinical symptoms. (A, Adapted from Thannickal, T., Moore, R.,
Nienhuis, R., et al., 2000. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 27, 469–474l; B, From Overeem, S., Black, J. L., 3rd,
Lammers, G.J., 2008. Narcolepsy: immunological aspects. Sleep Med. Rev. 12 [2], 95–107. https://doi.org/10.1016/j.smrv.2007.07.010).
Since UARS was described by Guilleminault and colleagues in by repeated arousals during sleep at night. This subtle airflow limita-
1993, there has been controversy about this entity. Some investigation cannot be identified by the usual recording of respiration using
tors have rejected it as a distinct clinical entity, whereas others have an oronasal thermistor. Nasal pressure monitoring with a nasal can-
accepted it as such. One controversy concerns whether UARS can be nula is more sensitive than use of a thermistor in detecting airflow
considered as the initial stage, with progressive evolution into full- limitation and increased upper airway resistance (Ayappa et al., 2000).
blown upper airway OSAS. In the only longitudinal study performed Intraesophageal balloon recording, however, is the standard method
in approximately 94 UARS subjects by Guilleminault and colleagues for detecting upper airway resistance and reveals increasing efforts
(2006a) it was noted that about 5% of subjects had developed OSAS with increasing intraesophageal pressure leading to arousal but with-
4.5 years later. In the majority of patients with UARS, symptoms do out any apnea or hypopnea (eFig. 101.35). These patients may or may
not evolve into full-blown OSAS. Many patients have a multitude not snore; they may have EDS and all its consequences, as seen in
of symptoms of a somatic, psychiatric, or psychosomatic nature, OSAS. Adult patients are more likely to complain of fatigue rather
whereas others are associated with attention-deficit/hyperactivity than sleepiness. Chronic insomnia is more commonly seen in UARS
disorder (ADHD), fibromyalgia, and chronic insomnia. UARS thus than in OSAS. UARS can sometimes be mistaken for chronic fatigue
appears to be a heterogeneous syndrome and could be part of a spec- syndrome, fibromyalgia, ADHD, depression, and other psychiatric
trum, with OSAS and obstructive hypoventilation at the far end of the disorders. CPAP titration is widely used as the first line of therapy,
spectrum and snoring at the other end. Some patients may fit with the but not all patients improve on CPAP. Recently, it has been shown
spectrum, but the majority do not. Patients with UARS show subtle that cognitive behavioral therapy in addition to CPAP may be helpful
airflow limitations due to increased upper airway resistance followed for patients with chronic insomnia.
CEREBROSPINAL FLUID LATERAL HYPOTHALAMIC BRAIN TISSUE
A B
600
(pg/mL)
400
200
f f
0
1 cm 1 cm f; fornix
Narcolepsy Neurologic Control
(n = 38) controls (n = 15) Narcoleptic Control
(n = 19)
eFig. 101.35 Hypocretin Loss in Narcolepsy: Cerebrospinal Fluid and Brain Tissue Findings. Cerebro-
spinal fluid (CSF) hypocretin is depicted on the left panel comparing patients with narcolepsy with those with
other neurological conditions and with control patients. Right panel demonstrates lateral hypothalamic brain
tissue staining in narcoleptic (A) versus control (B) patients. Studies show consistent reduction of CSF levels
and brain tissue staining for hypocretin. (From Nishino, S., Ripley, B., Overeem, S., et al., 2000. Hypocretin
(orexin) deficiency in human narcolepsy. Lancet 355, 39–40; and From Peyron, C., Faraco, J., Rogers, W.,
et al., 2000. A mutation in a case of early-onset narcolepsy and a generalized absence of hypocretin peptides
in human narcoleptic brains. Nat. Med. 6, 991–997. Courtesy Stanford Center for Narcolepsy.)
Video 101.5 Middle-Aged Woman with Restless Legs Syndrome (From Kryger, M.H., Avidan, A.Y., Berry, R., 2013. Atlas of clinical sleep
Different people use different terms to discuss the sensation of rest- medicine, Second ed. Philadelphia, PA: Elsevier/Saunders)
less legs. This patient said it felt like “insects crawling” under her skin.
Stroke
Metabolic
diseases Depression
Increased risk for

Cancer
Cardiovascular
diseases
A
Obstructive sleep apnea Neurodegenerative
Hypertension diseases
D
Airflow
Intermittent
hypoxia
O2 saturation
Systemic blood and Oxidative stress

Pressure
arterial pulmonary inflammation
pressure
bursts
endothelial dysfunction
SNA changes in circulating factors
SNA
overactivity
EEG
Sleep C
fragmentation
B
Time
Trends in Molecular Medicine

Fig. 101.51 Consequences of Untreated Obstructive Sleep Apnea. Pathophysiological Mechanisms and
Outcomes of Obstructive Sleep Apnea (OSA). Representative scheme of the pathophysiological mecha-
nisms of OSA and associated consequences: (A) OSA is characterized by recurrent episodes of complete
(apnea, represented in this figure) or partial (hypopnea) obstruction of the upper airway during sleep. (B)
Apnea episodes (between red broken lines) result in cessation of the airflow, often accompanied by reduced
oxygen (O2) saturation and increased systemic blood and arterial pulmonary pressure. As a result, sympa-
thetic neural activity (SNA) increases and apnea episodes end with an arousal of the central nervous system
to restore upper airway patency, marked by an increased electroencephalogram (EEG) wave frequency. Thus,
repetitive obstruction episodes while sleeping culminate in cyclical deoxygenation–reoxygenation (intermit-
tent hypoxia; IH), overactivation of SNA, bursts in systemic blood and arterial pulmonary pressures, and
several arousals and microarousals that result in sleep fragmentation (SF). (C) As a result, OSA is associated
with oxidative stress, inflammation, endothelial dysfunction, and changes in circulating factors. (D) Untreated
OSA has been associated with an increased predisposition for several impairments and diseases, including
hypertension, cardiovascular diseases, metabolic disorders, stroke, depression, cancer, and neurodegenera-
tive diseases (From Gaspar, L.S., Alvaro, A.R., Moita, J., Cavadas, C. 2017.Obstructive sleep apnea and Hall-
marks of aging. Trends Mol. Med. 23 [8], 675–692. https://doi.org/10.1016/j.molmed.2017.06.006. Copyright
© 2017 Elsevier Ltd.)
augmentation (a hypermotor syndrome with symptoms occurring at The condition may have a profound impact on sleep. Patients often
least 2 hours earlier than the initial period, with intensification and seek medical attention for sleep disturbance—generally a problem of
spread to other body parts) resulting from long-standing dopami- initiation, although difficulty maintaining sleep owing to associated
nergic medications (Allen et al., 2003, 2014; Garcia-Borreguero et al., PLMS can occur. Neurological examination is generally normal in
2007; Garcia-Borreguero and Williams, 2010). Up to 30%–50% of the idiopathic form. As stated earlier, RLS often begins in childhood,
RLS/WED patients complain of actual pain (more of an ache rather but diagnosis of childhood RLS may be difficult based on the National
than a sharp burning pain) and not just uncomfortable sensation Institutes of Health (NIH) consensus conference criteria established
(Allen et al., 2014). Most of the movements, particularly in the early in 2002 (Allen et al., 2003) and updated recently (Picchietti et al.,
stages, are noted in the evening while the patients are resting in bed. 2013). To make a correct diagnosis, RLS must be differentiated from
In severe cases, however, movements may be noted in the daytime conditions mimicking RLS (Box 101.19) or those associated (comor-
while subjects are sitting or lying down. At least 80% of RLS patients bid) with RLS (Chokroverty, 2009b) (eBoxes 101.20 and 101.21). An
have PLMS, and many also have periodic limb movements in wake- important and often difficult condition to differentiate from RLS is
fulness (Video 101.6). akathisia (see eBox 101.21).
eBOX 101.20 Causes of Symptomatic or eBOX 101.21 Pertinent Features of

Comorbid Restless Legs Syndrome Akathisia That Differentiate It From Restless
Neurological Disorders
Legs Syndrome
Polyneuropathies Inner restlessness, fidgetiness with jittery feelings, or generalized restless-
Lumbosacral radiculopathies ness.
Amyotrophic lateral sclerosis Common side effect of neuroleptic drugs.
Myelopathies Can be acute, chronic, or tardive.
Multiple sclerosis Characteristic motor restlessness consists of swaying or rocking movements
Parkinson disease of the body; marching in place; crossing and uncrossing of the legs; shifting
Poliomyelitis body positions in chair; inability to sit still; rhythmic or nonrhythmical, syn-
Isaacs syndrome chronous or asynchronous, symmetrical or asymmetrical limb movements;
Hyperekplexia (startle disease) movements resemble chorea rather than the voluntary movements of rest-
less legs syndrome.
Medical Disorders Motor restlessness presents mostly during the day but may be worse when
Anemia: iron and folate deficiency sitting or standing in one place for a long time.
Diabetes mellitus Polysomnography study shows no distinctive features and rarely may show
Amyloidosis evidence of mild sleep disturbance and periodic limb movements in sleep.
Uremia No relevant family history.
Gastrectomy Neurological examination reveals evidence of akathisia and sometimes
Cancer drug-induced extrapyramidal manifestations.
Chronic obstructive pulmonary disease Involuntary movements (e.g., myoclonic jerks) are uncommon and not a prom-
Peripheral vascular (arterial or venous) disorder inent feature.
Rheumatoid arthritis Best treated with anticholinergics or α-adrenergic antagonists.
Hypothyroidism
Drugs and Chemicals

Caffeine
Neuroleptics
Withdrawal from sedatives or narcotics
Lithium
Calcium channel antagonists (e.g., nifedipine)
Video 101.6 Restless Legs Syndrome with Periodic Limb Move-

ments During Sleep (x25) This patient with RLS was originally referred
for sleep apnea. Her problem was a movement disorder caused by iron
deficiency (her ferritin level was 12 ng/mL). Note that she keeps her
feet exposed in this video, which is sped up by a factor of 25 to show
PLMS. (From Kryger, M.H., Avidan, A.Y., Berry, R., 2013. Atlas of clinical
sleep medicine, Second ed. Philadelphia, PA: Elsevier/Saunders)
BOX 101.17 Five Essential Diagnostic Pathophysiology

Criteria for Restless Legs Syndrome The pathophysiology and the site of CNS dysfunction in idiopathic
or primary RLS remain unclear (Allen et al., 2013; Earley et al., 2011;
Criterion 1. An urge to move the legs, usually but not always accompanied by Trenkwalder and Paulus, 2004; Trenkwalder and Winkelman, 2003).
uncomfortable sensations in the legs.* Contemporary thinking in the pathophysiology of RLS suggests abnor-
Criterion 2. The urge to move the legs with any accompanying unpleasant malities in the body’s use and storage of iron and dopamine dysfunction,
sensations begins or worsens during periods of inactivity or quiescence which could involve changes in dopamine receptors or dopamine uptake
such as lying down or sitting. (Earley et al., 2011; Hening et al., 2009). Iron is a necessary cofactor for
Criterion 3. The urge to move the legs with any accompanying unpleasant tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis,
sensations is partially or totally relieved by movement, such as walking or and iron deficiency may decrease the number of dopamine D2 receptor
stretching, as long as the activity continues. binding sites, so the most exciting and current research focus is centered
Criterion 4. The urge to move the legs with any accompanying unpleasant on iron-dopamine dysfunction. Electrophysiological (blink reflex excit-
sensations during rest or inactivity only occurs or is worse in the evening or ability, back-averaging technique, EEG beta oscillations) and magnetic
night than during the day. brain stimulation studies using the paired stimulation technique show
Criterion 5. The above features are not accounted for by another medical increased cortical excitability and decreased subcortical inhibition, sug-
or behavioral condition (e.g., myalgia, arthritis, venous stasis, leg cramps, gesting the site of the CNS dysfunction in RLS in the subcortical loci
positional discomfort, or habitual foot tapping). (Earley et al., 2011; Hening et al., 2009). One study suggested a possi-
* The adult and the pediatric diagnostic criteria are merged together ble spinal mechanism, based on a flexor reflex study showing increased
except that the description of these symptoms in criterion 1 should be flexor reflex excitability during sleep compared to waking, in contrast
in the child’s own words. to decreased excitability in control subjects (Bara-Jimenez et al., 2000).
From Allen, R.P., Picchietti, D.L., Garcia-Borreguero, D., et al., 2014. A spinal mechanism may explain PLMS (Clemens et al., 2006) but does
Restless legs syndrome/Willis Ekbom disease diagnostic criteria: not explain the entire RLS symptomatology. Functional MRI (fMRI)
Updated International Restless Legs Syndrome Study Group (IRLSSG) points to locations in the brainstem, cerebellum, and thalamus (Bucher
consensus criteria e history, rationale, description, and significance. et al., 1997). PET and SPECT studies gave contradictory reports regard-
Sleep Med 15, 860e73. (Marelli et al., 2015). ing presynaptic and postsynaptic dopaminergic dysfunction (Earley
et al., 2011; Hening et al., 2009). CSF analysis, special MRI, and neuro-
pathological studies demonstrate reduction in CNS iron or ferritin or
BOX 101.18 Supportive Features and both, as can be seen in Fig. 101.52 (Allen and Earley, 2001; Earley et al.,
Specifiers for Clinical Significance and Clinical 2011; Hening et al., 2009). In summary, currently there are multiple and
Course of Restless Legs Syndrome inconsistent theories challenging researchers seeking to make advances
in treatment, for example, the most plausible iron-dopamine connec-
• Following features (not essential for diagnosis) will support the diagnosis
tion theory in a subset of patients, an alternative neurotransmitter or
of restless legs syndrome (RLS) in case of some doubt about diagnostic
neuronal pathway (e.g., the activation of thalamic glutamate or hypoxic
certainty:
pathway, both central and peripheral), opioid pathway, reduced thalam-
1. Periodic limb movements in sleep (PLMS) or wakefulness (PLMW) at a
ocortical connectivity coupled with genetic predisposition (Allen et al.,
frequency or intensity greater than expected for age
2013; Ku et al., 2014; Jimenez-Jimenez et al., 2018; Khan et al., 2017; Rye,
2. Response to dopaminergic treatment at least initially
2015; Winkelmann et al., 2017).
3. Positive family history of RLS among first-degree relatives
4. Lack of profound daytime sleepiness
• Specifier for clinical significance:
Periodic Limb Movements in Sleep
RLS symptoms cause significant distress in social, occupational, educa- PLMS (AASM, 2014) is a PSG finding (Fig. 101.53) characterized
tional, or other important areas of functioning by impacting sleep, energy/ by periodically recurring stereotyped limb movements, particu-
vitality, activities of daily living, behavior, cognition, or mood. larly dorsiflexion of the ankles and sometimes flexion of the knees
• Specifier for clinical course (these criteria do not apply to pediatric age and hips at an average interval of 20–40 seconds (range, 5–90 sec-
group pregnancy, or drug-induced RLS): onds), a duration of 0.5–10 seconds during predominantly NREM
1. Intermittent RLS: symptoms occur on average less than twice per week sleep, and occurring for at least four consecutive movements (Box
with at least five lifetime events. 101.22). PLMS appears most commonly in RLS but may also occur
2. Chronic-persistent RLS symptoms occurring on average at least twice in a large number of other medical, neurological, and sleep disor-
weekly for the past year. ders and with ingestion of medications (e.g., SSRIs, tricyclic anti-
depressants) and even in normal individuals, particularly in those
older than age 65. In the current ICSD-III (AASM, 2014), PLMD
In the differential diagnosis, it is important to look for clues includ- characterized by PSG findings of PLMS with a frequency of greater
ing subtle signs based on history and physical findings that point to than 5/hour in children or greater than 15/hour in adults without
the correct diagnosis. The history should include a detailed description associated RLS causing repeated awakenings and sleep fragmen-
of the present complaint, duration and nature of the sensory-motor tations associated with impaired daytime functioning which can-
complaints, as well as past, family, psychiatric, and drug histories. For not be explained by another medical, neurological, psychiatric, or
the diagnosis of RLS, five IRLSSG essential criteria must be met (see other sleep disorder is listed as a separate entity. There is a growing
Box 101.17), with or without the supportive features. For the diagnosis body of evidence that PLMS may simply be a PSG observation and
of mimicries and conditions associated with RLS, characteristic clini- may have no specific clinical significance except its presence in the
cal features of the particular condition should help in arriving at the majority of patients with RLS (Mahowald, 2002; Montplaisir et al.,
correct diagnosis. 2000; Video 101.7).
Video 101.7 Periodic Limb Movements in Sleep (From Richard B.,

Mary W.H. Sleep Medicine Pearls, third ed, Copyright © 2015, 2003,
1999 by Saunders, an imprint of Elsevier Inc.)
BOX 101.19 Conditions That Mimic Restless Legs Syndrome

Presenting with Excess Restlessness Positional discomfort Often comes on with prolonged sitting or lying
Restless legs syndrome Symptoms occur during wakefulness but with in the same position but usually relieved by a
a specific demonstratable circadian pattern simple change in position as opposed to ongoing
predilection to manifest during the evening time. movement, unlike RLS.
Diagnosis made by clinical history, often based Neuroleptic induced Usually generalized as opposed to limb-predom-
on description of an urge to move described as akathisia inant. No pronounced circadian pattern, and
an uncomfortable creepy-crawling sensation often no relief with movement. Should have
brought on at time of inactivity or rest (sitting history of specific medication exposure.
and lying). Movement of symptomatic limb leads Spasticity An involuntary, velocity-dependent, increase
to partial or complete relief. Symptomatic relief in muscle tone secondary to central nervous
is persistent as long as movement continues. system damage that results in resistance to
Demonstrates presence of circadian pattern. movement.
PLMD (periodic limb move- Polysomnographic manifestation of leg move- Akathisia:

ment disorder) ments. Diagnosis made by sleep study. Does Neuroleptic induced
not include sensory symptoms such as an urge Antidepressant induced
to move as in restless legs syndrome (RLS). Related to central nervous system
Patients may endorse sleep disturbance and Degenerative disease
complaints of daytime fatigue and sleepiness. Disorders of abnormal muscular activity
Must exclude other causes of PLMS, including Myokymia
sleep disorder breathing. Hypnic jerks
Nocturnal leg cramps Painful muscular contraction in the back of the Essential myoclonus
legs readily differentiates this condition from Orthostatic tremor
RLS, e.g., cramps or “Charlie horse cramps” are Anxiety/depression
a common experience. Though symptoms may Periodic limb movement disorder
occur at night and relief may be achieved with Restlessness due to orthostatic hypotension
stretching, unlike RLS, cramps are experienced Attention-deficit hyperactivity disorder
as a usually painful muscular contraction.
Neuropathic pain Commonly reported as numbness, burning, Presenting with Nocturnal Leg Discomfort
tingling, and pain—descriptors not as commonly “Growing pains”
seen in RLS. Although the sensory symptoms Small-fiber neuropathies
may become more noticeable at night, the symp- Claudication
toms are usually also present throughout the Venous stasis/varicose veins
day. Unlike RLS, significant relief is not obtained Myalgias
with walking or during sustained movement. Arthritis
Hypotensive akathisias Feeling of restlessness, often localized to the Radiculopathies
legs, brought on by sitting still. Should not occur Delusional parasitosis
while lying down but might be relieved with
movement. Occurs in individuals with orthostatic Presenting with Unusual Motor Activity Combined with Leg
hypotension. Discomfort
Arthritis lower limb Discomfort centered more in joints, does not Painful muscle cramps including nocturnal leg cramps
usually have prominent circadian pattern as Syndrome of painful legs and moving toes
seen in RLS. Variant of painless legs and moving toes
Volitional movements, foot Occurs in individuals who fidget, especially when Causalgia-dystonia syndrome
tapping, leg rocking bored or anxious, but usually do not experience Muscular pain-fasciculation syndrome
associated sensory symptoms, discomfort,
or conscious urge to move. Usually lacks a
circadian pattern.
Reproduced with permission from Chokroverty, S., 2009. Differential diagnosis of restless legs syndrome. In: Hening, W.A., Allen, R.P., Chokrov-
erty, S., et al. (Eds.), Restless Legs Syndrome. Saunders, Philadelphia, p. 111.
Circadian Rhythm Sleep Disorders desynchronization between their internal circadian rhythms and exter-
Circadian rhythm sleep disorders result from a mismatch between nal time. The most common circadian rhythm sleep disorders are jet
the body’s internal clock and the geophysical environment, either as a lag (associated with high-speed air travel across several times zones)
result of malfunction of the biological clock or a shift in the environ- and shift work sleep disorder (seen in patients who work nonstandard
ment causing this to be out of phase (ICSD-III; Abbot and Zee, 2015; shifts). A schematic reorientation of the various circadian derange-
Reid and Zee, 2011). The patients have difficulty sleeping as a result of ments is provided in Fig. 101. 54 (Chokroverty and Thomas, 2014).
R2* (sec–1)
30
A B
0
Fig. 101.52 Reduced brain iron tissue concentrations on MRI. R2* images in a 70-year-old restless legs
syndrome (RLS) patient (A) and a 71-year-old control (B). Much lower R2* relaxation rates are apparent in the
RLS case in both red nucleus and substantia nigra. (From Earley, C.J., Barker, P.B., Horská, A., et al., 2006.
MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep
Med 7, 458–461.)
Fig. 101.53 Periodic Leg Movements of Sleep (PLMS). A 2-minute sleep epoch from a diagnostic poly-
somnogram of a patient with PLMS associated with an irresistible urge to move her legs. Her husband
reports that she has frequent nighttime kicking and jerking movements that disrupt his sleep. A succession
of 5 periodic limb movements are shown (circled in purple), occurring in the right and left legs (anterior tibialis
muscles). According to the American Academy of Sleep Medicine, periodic leg movements are diagnosed
when more than 15 leg movements per hour of sleep are captured. Four or more consecutive movements
are required and the interval between movements is typically 20 to 40 seconds. The movements should
appear at sequence of 4 or more separated by an interval of more than 5 and less than 90 seconds and have
an amplitude of greater than or equal to 25% of toe dorsiflexion during the calibration. Reference electrodes
(F4, C4, O2) are referenced to mastoid electrode (M1) or average (AVG). ABD, Abdominal respiratory effort;
CHEST, chest respiratory effort; Chin, Chin electromyogram; EKG, electrocardiogram; L, left; LOC, left elec-
tro-oculogram; PTAF, nasal pressure; R, right; R LEG, right anterior tibias surface electromyogram; ROC, right
electro-oculogram; SNORE, snore sensor air flow, nasal and oral airflow; SpO2, pulse oximetry. (From Rama,
A.N. Zachariah, R., Kushida, C.A., 2009. Sleep Med. Clin. 4 [3], 361–372.)
Jet Lag gastrointestinal symptoms, increasing chances of being involved in

The experience of jet lag follows eastward or westward jet travel that traffic accidents, and making errors on the job. Adjustment of the
crosses several time zones, disrupting synchronization between the work time schedule rarely improves the symptoms of shift-work sleep
body’s inner clock and external cues; north-south travel does not evoke disorder.
this disorder. Jet lag symptoms include difficulty maintaining sleep, fre-
Delayed Sleep Phase State
quent arousals, and EDS, typically resolving within a few days to 2 weeks.
In DSPS the patient’s major sleep episode is delayed in relation to
Shift-Work Sleep Disorder desired clock time, causing sleep-onset insomnia or difficulty awaken-
Shift-work sleep disorders may affect up to 5 million workers in ing at the desired time (ICSD-III). A typical schedule consists of going
the United States. Symptoms include sleep disruption, fatigue, to sleep late between 2:00 am and 6:00 am, and waking up during the
late morning between 10:00 am and 2:00 pm. These patients have great
difficulty functioning adequately during daytime hours if they must
BOX 101.22 Features of Periodic Limb wake up early in the morning to go to school or work. They cannot
Movements in Sleep function normally in society due to their disturbed sleep schedule;
however, their sleep architecture is generally normal if these individu-
1. Repetitive, often stereotyped movements during NREM sleep
als are allowed to follow their own uninterrupted sleep schedule. Onset
2. Usually noted in legs and consisting of extension of great toe, dorsiflexion
generally occurs during childhood or adolescence. Sometimes a his-
of ankle, and flexion of knee and hip; sometimes seen in arms
tory of DSPS in other family members exists, and some patients may
3. Periodic or quasi-periodic at an average interval of 20–40 sec (range, 5–90
complain of depression. An unusually long intrinsic period owing to
sec) with a duration of 0.5–10 sec and as part of at least 4 consecutive
an abnormality in the biological clock in the SCN is the fundamental
movements
problem.
4. Occurs at any age, but prevalence increases with age
5. May occur as an isolated condition or may be associated with a large num- Advanced Sleep Phase State
ber of other medical, neurological, or sleep disorders and medications
Advanced sleep phase state is the converse of DSPS (ICSD-III). Patients
6. Seen in at least 80% of patients with restless legs syndrome
go to sleep early in the evening and wake up early in the morning. The
7. Occurs predominantly during NREM, nonrapid eye movement. Appearance
patient experiences sleep disruption and daytime sleepiness when not
of PLMS during REM raises suspicion for narcolepsy.
going to sleep at early hours. The condition is often seen in patients
NREM, Nonrapid eye movement; PLMS, periodic limb movements in with depression and in normal elderly individuals. Familial ASPS has
sleep; REM, rapid eye movement. been ascribed to mutation in the HPER2 gene (Jones et al., 2013).
4 PM 8 PM 12 AM 4 AM 8 AM 12 PM 4 PM
Conventional
sleep time
Delayed
sleep phase
disorder
Advanced
sleep phase
disorder
Non–24 hour
circadian
rhythm
disorder
Irregular
sleep-wake
disorder
Night shift
Shift work Night shift
disorder Night shift
Jet lag Flight

disorder
Fig. 101.54 Schematic Representation of the Circadian Rhythm Sleep Disorders. Circadian rhythm sleep
disorders occur due to a misalignment between an individual’s behavioral sleep and wake patterns and endoge-
nous biological circadian rhythms timing system or from misalignment between circadian phase and. Disruption
of circadian timing results in insomnia, excessive daytime sleepiness, and impaired performance. Symptoms may
cause disruption in social, occupational, and other areas of function. Blue rectangles denote sleep time. Green
triangles denote the dim-light melatonin onset, which occurs 2 hours before biological sleep-onset time. Red
triangles denote the core body temperature nadir. (From Malkani, R., Zee, P.C., 2014. Basic Circadian Rhythms
and Circadian Sleep Disorders. Atlas of Sleep Medicine. Chokroverty & Thomas, pp. 119-126, Chapter 5.)
Free-Running Circadian Rhythm Disorder Effect of sleep on epilepsy. Certain types of seizures are
Circadian rhythm sleep disorder, free-running type (nonentrained type characteristically observed during sleep, including nocturnal frontal
or non-24-hour sleep-wake syndrome) is characterized by a patient’s lobe epilepsy, tonic seizure as a component of Lennox-Gastaut
inability to maintain a regular bedtime and sleep onset that occurs at syndrome, benign focal epilepsy of childhood with rolandic spikes,
irregular hours (ICSD-III). The patient displays increasing delay of juvenile myoclonic epilepsy, early- or late-onset childhood occipital
sleep onset by approximately 1 hour during each 24-hour sleep-wake epilepsy, benign focal epilepsy with occipital paroxysms in EEG,
cycle, causing an eventual progression of sleep onset through the day- generalized tonic-clonic seizures on awakening, nocturnal temporal
time hours into the evening. There is no entrainment or synchroniza- lobe epilepsy (a subgroup of partial complex seizures), Landau-
tion with the usual time cues such as sunlight or social activities. This Kleffner syndrome, and continuous spike-and-wave discharges during
disorder is most often seen in blind people. NREM sleep (AASM, 2014).
The tonic seizures of Lennox-Gastaut syndrome are typically acti-
Irregular Sleep/Wake Circadian Rhythm Disorder vated by sleep, are much more frequent during NREM sleep than
Circadian rhythm sleep disorder, irregular sleep-wake type (irreg- during wakefulness, and are never seen during REM sleep. The typical
ular sleep-wake rhythm) is characterized by a lack of clearly defined EEG finding consists of trains of fast spikes intermixed with slow spike-
circadian rhythm of sleep and wake. Patients are seen to be napping and-wave discharges at 2–2.5 Hz.
throughout the 24-hour period, but total sleep time is normal. This Benign focal epilepsy of childhood with rolandic spikes is characterized
condition may be seen in patients with degenerative neurological by focal clonic facial twitchings, often preceded by perioral numbness,
disorders such as dementia and children with mental retardation. seen most frequently during drowsiness and sleep. The EEG shows
Actigraphy recordings are useful in diagnosing any of the circadian centrotemporal or rolandic spikes or sharp waves. These discharges are
rhythm sleep disorders. present throughout the night in all stages of sleep.
Continuous spike-and-wave is a disease of childhood characterized
Neurological Disorders and Sleep Disturbance by generalized continuous slow spike-and-wave discharges seen during
Neurological disorders may affect sleep/wake-generating neurons, at least 85% of NREM sleep and suppressed during REM sleep.
causing profound sleep disturbances that may include insomnia, Juvenile myoclonic epilepsy is characterized by massive bilaterally
hypersomnia, parasomnia, circadian rhythm disorders, and abnormal synchronous myoclonic jerks which are most frequently noted on
movements in sleep at night. These sleep disturbances may adversely awakening. It commonly occurs in young adults aged 13–19 years. A
affect the natural course of the neurological illness. Neurological causes typical EEG shows synchronous and symmetrical multiple spikes and
of insomnia are described elsewhere in this chapter, and neurological spike-and-wave discharges.
disorders causing EDS or hypersomnia are listed in eBox 101.5. EDS Sleep-related epilepsy (Formerly Nocturnal frontal lobe epilepsy)
can result from tumors and vascular lesions affecting the ARAS and its includes nocturnal paroxysmal dystonia, paroxysmal arousals and
projections to the posterior hypothalamus and thalamus. Other causes awakenings, episodic nocturnal wanderings, and autosomal domi-
of EDS include astrocytomas, suprasellar cysts, metastatic tumors, nant nocturnal frontal lobe epilepsy (Chokroverty and Nobili, 2015;
lymphomas and hamartomas affecting the posterior hypothalamus, Derry et al., 2009; Derry and Duncan, 2013; Ferini-Strambi et al., 2012;
pinealomas, and astrocytoma of the brainstem. Symptomatic nar- Foldvary-Schaeffer and Alsheikhtaha, 2013; Nobili et al., 2007; Tinuper
colepsy may occasionally result from craniopharyngioma and other et al., 2005; di Corcia et al., 2005). All these disorders share common
tumors of the hypothalamic and pituitary regions, rostral brainstem features of abnormal paroxysmal motor activities during sleep. Most
gliomas, MS, arteriovenous malformations of the diencephalon, and cases respond favorably to antiepileptic medications, but more than a
cerebral sarcoidosis involving the hypothalamus. Neuromuscular dis- third of cases, particularly those with complex forms, are resistant to
orders, neurodegenerative diseases, encephalitis, and encephalopathies such treatment. These seizures most likely represent partial seizures
may also cause EDS. arising from discharging foci in the deeper regions of the brain, par-
ticularly the frontal cortex, without any concomitant scalp evidence of
Sleep and Epilepsy epileptiform activities. The onset is anywhere from infancy to middle
There is a reciprocal relationship between sleep and epilepsy (Gibbon, age. Nocturnal frontal lobe epilepsy occurs exclusively during sleep
Maccormac, and Gringras, 2019). Sleep affects epilepsy and epilepsy, at night, but other types of frontal lobe seizures may be both diur-
in turn, affects sleep. Sleep increases interictal epileptiform discharges, nal and nocturnal. The episodes are characterized by sudden onset of
causing repeated arousals and sleep fragmentation resulting in EDS, ballismic, choreoathetoid, or dystonic movements, as well as bipedal,
which again triggers seizures and epileptiform discharges, thus repeating bimanual, and bicycling complex movements with motor and sexual
the cycle. Most of the time, seizures are triggered during stages N1 and automatisms occurring in NREM sleep with sudden termination (Box
N2 sleep; occasionally, however, they are triggered during slow-wave 101.23). The duration is mostly less than 1 minute but sometimes may
sleep. In epileptic patients, NREM sleep acts as a convulsant, causing be 1–2 minutes with brief postictal confusion. The spells often occur
excessive synchronization and activation of seizures in an already hyperin clusters. Ictal and interictal EEGs may remain normal, but some-
excitable cortex. In contrast, in REM sleep, there is desynchronization times interictal EEG may show spikes; occasionally, depth recording is
of EEG coupled with an inhibition of interhemispheric transfer of needed for a diagnosis.
impulses, causing an attenuation of epileptiform discharges and lim- Effect of epilepsy on sleep. A variety of sleep abnormalities are
itation of propagation of generalized epileptic discharges to a focal area noted in the PSG recording and include increased sleep-onset latency,
(Fig. 101.55). Sleep deprivation is another important seizure-triggering increased number and duration of awakenings after sleep onset,
factor. Sleep deprivation increases epileptiform discharges by causing reduced sleep efficiency, reduced sleep spindles and K complexes,
sleepiness as well as by increasing cortical excitability. Seizures may reduced REM sleep, increased stage shifts, abnormal sleep cycling,
occur predominantly during sleep (nocturnal seizure), in the daytime and sleep state instability, making classification of staging difficult
(diurnal), or during both sleep at night and daytime (diffuse epilepsy). or impossible. Epileptic patients may present with EDS as well as
Approximately 10% of epileptic patients experience nocturnal seizures. insomnia. The various factors responsible for EDS in epileptics
NREM SLEEP REM SLEEP
“Seizure promotor” “Seizure protector”

NREM Sleep: REM Sleep:
Synchrony of thalamo-cortical synaptic activity Desynchronized neuronal discharge patterns
Greater tendency for propagation of epileptiform Relative resistance to propagation of EEG potentials
discharges Skeletal muscle paralysis
SYNCHRONIZED SLEEP DESYNCHRONIZED SLEEP

Excessive diffuse cortical synchronization Inhibition of thalamocortical synchronization,
Enhancement in interhemispheric impulse traffic tonic reduction in interhemispheric impulse traffic
Fig. 101.55 Sleep State and Epileptogenicity. EEG, Electroencephalogram; NREM, nonrapid eye move-
ment; REM, rapid eye movement.
hypnic jerks, drug-induced nocturnal dyskinesias, jerking

BOX 101.23 Features of Sleep-Related
movements of sleep apnea, and other parasomnias such as bruxism,
Epilepsy benign neonatal sleep myoclonus, and rhythmic movement
Sporadic, occasionally familial (dominant) disorders. There is probably an increased prevalence of sleep apnea
Oftentimes exclusively nocturnal in epilepsy, as reported by scattered case reports, but systematic
Sudden onset in nonrapid eye movement sleep with sudden termination study to determine the true prevalence of sleep apnea has not been
Duration: mostly less than 1 min, sometimes 1–2 min with short postictal con- undertaken (Chokroverty et al., 2006). It is, however, important
fusion to recognize the coexistence of epilepsy and sleep apnea, because
Often occur in clusters treatment of sleep apnea by CPAP titration may improve seizure
Semiology: Stereotyped, tonic, clonic, bipedal, bimanual, and bicycling, ballis- control (Video 101.8).
mic and choreoathetoid movements; motor and sexual automatisms; con-
tralateral dystonic posturing or arm abduction with or without eye deviation Degenerative Dementia and Sleep Dysfunction
Ictal EEG may be normal; interictal EEG may show spikes; sometimes depth Sleep and neurodegeneration: General perspectives. Dementia
recording is needed is characterized by progressive deterioration of memory and cognition
followed by language dysfunction, hallucinations, other psychotic
EEG, Electroencephalogram.
features, depression, and sleep disturbance. In advanced stages, the patient
becomes bedridden, mute, and incontinent. Sleep dysfunction with or
include clinical seizures, particularly nocturnal seizures, frequent ictal without abnormal motor activity during sleep is increasingly recognized
epileptiform discharges, antiepileptic medications, associated primary in patients with irreversible chronic dementing illnesses (Chokroverty,
sleep disorders, and depression. Insomnia in epileptics may be related 2009a; Chokroverty et al., 2015; McCurry and Ancoli-Israel, 2003;
to frequent arousals and sleep fragmentation resulting from nocturnal MacKenzie, 2000). AD is the most common cause of chronic dementia,
seizures and interictal epileptiform discharges, depression, anxiety, accounting for at least 60% of all cases. It is estimated that by 2025 more
associated primary sleep disorders, and a specific effect of some than 10 million and by 2050 about 20 million cases of AD will be present
antiepileptic medications (e.g., lamotrigine). in the United States. Other conditions include diffuse Lewy body disease
Sudden unexpected death in epilepsy (SUDEP) is defined as unex- (DLBD), accounting for at least 15%–20% of cases (Mackenzie, 2000);
pected, sudden, non-traumatic, non-drowning death in a person with PD with dementia, frontotemporal dementia in about 10%, corticobasal
epilepsy. While the annual rates range between 0.3 and 6 cases of ganglionic degeneration, progressive supranuclear palsy (PSP), multi-
SUDEP per 1000 adult persons with epilepsy and 1 case of SUDEP per infarct or vascular dementia, Huntington disease, Creutzfeldt-Jakob
4500 children, the etiology cannot be determined at autopsy. A known disease, and FFI account for the rest of the cases. The major sleep
risk factor is recurrent generalized tonic-clonic seizures and the most disturbances in dementing illnesses include insomnia, hypersomnia,
effective SUDEP prevention is seizure control (Whitney and Donner, circadian sleep/wake rhythm disorders, excessive nocturnal motor
2019). Given that SUDEP occurs at night, some have proposed dis- activity, “sundowning,” and respiratory dysrhythmias. Table 101.9
rupted sleep as a potential mechanism facilitating SUDEP and pro- differentiates the key dementias based on the reported sleep disorders
posed exercising proper sleep hygiene; identify and treat insomnia unique to each group (Video 101.9).
and sleep apnea. More data are needed to determine whether patients
with epilepsy are at greater risk of SUDEP when sleep-deprived, and Sleep Disorders in the Tauopathies
whether primary sleep disorders such as sleep apnea, chronic insom- The tauopathies result from misprocessing of tau, a protein associated
nia, and daytime sleepiness may play a role in the pathophysiology with microbules, and include AD, PSP, frontotemporal dementia-Pick
(Somboon et al., 2019). disease, and corticobasal degeneration. Despite intensive motor activ-
Differential diagnosis. Sleep seizures should be differentiated ity and abnormal behavior during REM sleep, patients with RBD do
from other nocturnal events such as NREM and REM parasomnias, not usually complain of EDS. There is a potential for injury to self and
nocturnal panic attacks, psychogenic dissociated states, PLMS, others in patients with RBD; therefore, recognition and treatment are
Video 101.8 Parasomnias and nocturnal frontal lobe epilepsy Video 101.9 Fatal Familial Insomnia A 51-year-old man presented a
(NFLE): Lights and shadows–Controversial points in the differential 5 months history of insomnia and motor behavior during sleep during
diagnosis. (From Bisulli, F., Vignatelli, L., Provini, F., Leta, C., Lugaresi, which he displayed motor gestures mimicking daily-life activities such
E., Tinuper, P., 2011. Parasomnias and nocturnal frontal lobe epilepsy searching for items consistent with oneiric stupor (OS) episode. OS is
[NFLE]: Lights and shadows–Controversial points in the differential an uncommon disorder in which the patient is in a state of unrespon-
diagnosis. Sleep Medicine 12[Suppl 2]. Copyright © 2011 Elsevier B.V.) siveness associated with dream-like mentation, but in the setting of
appropriate motor behaviour in the setting of disorganized sleep struc-
ture. Patients with OS perform these movements which correlate with
theire dream contents which they recall. With disease, progressionm
especailly in the setting of FFI, recall becomes difficult, patients become
more and more confused, as they alternate between wakefulness con-
fused oneiric state. (From Guaraldi P, Calandra-Buonaura G, Terlizzi R,
et al. Oneiric stupor: the peculiar behaviour of agrypnia excitata. Sleep
Med. 2011;12 Suppl 2:S64–67.)
important. Circadian sleep/wake rhythm disturbances are noted in that disruptions to the sleep-wake cycle may be a consequence rather
some conditions, most prominently in AD, and may present as a cycli- than cause of AD pathogenesis (Cedernaes et al., 2017). Recent data
cal agitation syndrome popularly known as the sundowning syndrome. from humans support the hypothesis that AD pathology itself can lead
Another commonly encountered excessive nocturnal motor activity to sleep and circadian disruptions. Past research demonstrated that
that may cause sleep disturbance is PLMS, which may be noted in pathophysiological processes associated with AD, such as Aβ deposi-
many of these dementing illnesses. Sleep-related respiratory dysrhyth- tion in the brain, alter sleep, as well as disrupt circadian rhythms. Since
mias and loud snoring during sleep occur in some of these conditions, Aβ deposition in the brain and cognitive dysfunctions are detectable
particularly in patients with AD, PD, and DLBD. years prior to the clinical onset of AD, this suggests that disruptions
The following factors may be cited as causing sleep disturbances in to the sleep-wake cycle may be a consequence rather than cause of AD
dementing illness: accelerated normal physiological changes of aging, pathogenesis. Alternatively, existing evidence leads us to propose that
which include changes in sleep architecture and stages adding to the there exists a mechanistic interplay between AD pathogenesis and dis-
burden of sleep disturbance in dementia; status of apolipoprotein E ruptions to sleep and interrelated circadian rhythms as summarized in
(ApoE)-eE4 (Bliwise, 2002) genotype; and MAO-A 4-repeat allele Fig. 101.57.
(Craig et al., 2006) genotype. The ApoE-eE4 genotype shows an asso-
ciation with sleep apnea and AD, although contradictory reports have The Alpha Synucleinopathies
also been published. In a recent report, a quantitative sleep disturbance The alpha Synucleinopathies are a group of disorders with abnormal
score was found to be slightly higher in patients with MAO-A 4-repeat deposition of α-synuclein in the cytoplasm of neurons or glial cells,
allele genotypes; in the same report, however, ApoE-eE4 had no influ- as well as in extracellular deposits of amyloid. The main synucleinop-
ence on the development of an altered sleep genotype. Another finding athies causing dementing illnesses include PD and DLBD. The para-
was that environment (e.g., institutionalization) aggravates sleep dis- somnia most commonly associated with some degenerative dementing
turbance, especially in AD patients. Comorbid medical disturbances illnesses is RBD. It has been suggested that in the setting of degen-
(e.g., congestive heart failure, COPD, pain from arthritis, nocturia, erative dementia or parkinsonism, RBD is a manifestation of evolv-
gastroesophageal reflux disease); medications used to treat AD, PD, ing synucleinopathies but is rare in tauopathies (Boeve, 2010; Boeve
and other dementing illnesses; comorbid primary sleep disorders (e.g., et al., 2007; Iranzo et al., 2009, 2010, 2014; Postuma et al., 2009, 2009a,
OSAS, RLS, and PLMS); inadequate sleep hygiene; circadian rhythm 2010a, 2010b, 2010c, 2013; Barone and Henchcliffe, 2018; Mahowald
disruptions; and comorbid psychiatric disorders (e.g., depression) may and Schenck, 2018; Pilotto et al., 2019).
all have adverse effects on sleep. DLBD may be mistaken for AD or PD with dementia. However, the
core diagnostic features of DLBD include fluctuating cognition, recur-
Sleep in the Setting of Alzheimer Dementia rent visual hallucinations, and parkinsonian features (e.g., rigidity,
Sleep dysfunction in AD may occur even in the early stage and scien- postural instability, akinesia, bradykinesia) coupled with other features
tists recently showed that sleep loss may even precede AD symptoms such as repeated falls, neuroleptic sensitivity, and RBD (McKeith et al.,
(Ju et al., 2013), but it is more common and severe in advanced stages. 2005; Mackenzie, 2000).
In addition to sundowning, these patients often sleep early in the eve- In PD, sleep dysfunction is present in 70%–90% of cases, with pro-
ning, waking up frequently and staying awake most of the night. Their gressive impairment with the progression of the disease (Chokroverty,
sleep is fragmented and fractionated throughout a 24-hour period. 2009a; Chokroverty and Provini, 2015). Sleep-onset and maintenance
Sleep apnea has been noted in more than 33% to 53% of patients with insomnia, and sleep fragmentation are common (Peeraully et al., 2012).
AD, more frequently in those with the ApoE-eE4 allele (Bliwise, 2002). Several nocturnal motor abnormalities are noted: RBD, PLMS, sleep-on-
These patients remain somnolent most of the time in the advanced set blinking, REM-onset blepharospasm, and intrusion of REMs into
stages. Sleep dysfunction in DLBD includes RBD (which often pre- NREM sleep. Respiratory dysrhythmias are noted to be more common
cedes the onset of illness), sleep apnea, nocturnal visual hallucinations, in PD than in age-matched controls although there are contradictory
insomnia, and daytime hypersomnolence. reports. Another characteristic feature in PD is daytime hypersomno-
lence and irresistible sleep attacks, which may be due to a combination of
Sleep Disruption, Inflammation and the Risk of Alzheimer the intrinsic disease process and dopaminergic medications.
Dementia In PSP, sleep disturbance is present in almost all cases. Most com-
Recent evidence has linked disturbed sleep, inflammation, and risk of mon sleep disruptions include sleep-onset and maintenance insomnia,
AD dementia precipitated by a cascade of events involving activation of which is worse than in AD or PD. Sleep disturbance increases with the
systemic inflammation (as measured by mediators such as proinflam- severity of motor abnormalities. Important PSG findings include fre-
matory cytokines and C-reactive protein). This cascade results in the quent arousals, reduced REM and stage N2 NREM sleep, and RSWA
formation of primed and dysfunctional, microglial cell which displays (Arnulf et al., 2005; Chokroverty, 2009a; Sixel-Doring et al., 2009).
an amoeboid morphology resulting in reduced and impaired clearance Sleep disturbance in Huntington disease is noted in approximately
of amyloid from the CSF. This step results in an increase in the pro- 20% of cases. Most commonly, sleep disruption with fragmentation is
duction of proinflammatory cytokines, and local inflammation within noted with increasing disease severity. Another characteristic finding is
the CNS (Irwin, 2019; Irwin and Vitiello, 2019). This cascade of events increased sleep spindle density in PSG.
is the final common pathway which precipitates AD dementia progres- Sleep dysfunction in frontotemporal dementia and corticobasal
sion. This is illustrated in Fig. 101. 56.Additional recent data support degeneration resembles that noted in AD, but adequate studies have not
the hypothesis that AD pathology itself can lead to sleep and circadian been conducted in these conditions to characterize sleep disruption.
disruptions. Supporting this idea is an observation that certain patho- Sleep apnea is more common in vascular dementia than in AD and
physiological processes associated with AD, such as Aβ deposition in is very common in MSA and DLBD.
the brain, disrupt sleep, and forever alter circadian rhythms. Given the Fatal familial insomnia is a rare and rapidly progressive autoso-
observation that Aβ deposition in the brain and cognitive dysfunctions mal dominant prion disease with a missense mutation at codon 178
are detectable years prior to the clinical onset of AD, one may conclude of the prion protein gene (PrP) (Montagna, 2011). FFI was originally
COGNITIVE DECLINE
NEUROINFLAMMATION
Resting Primed Activated
microglia microglia microglia
IL-1β
TNF-α
Homeostasis
BB
B
Neuronal
SF
B
afferent
Vagal
BC
death
Diffusion
M1 M2
SYSTEMIC INFLAMMAGING
Sleep Dysfunctional
AGING
disruption adiposity
Fig. 101.56 Disturbed Sleep, Inflammation, and Risk of Alzheimer Disease. The impact of sleep disrup-
tion and dysfunctional aging-related cognitive decline through the common pathway of neuroinflammation.
The aging process and its consequences for sleep and regional fat redistribution contribute to low-grade
inflammation in the periphery. Systemic inflammation primes microglia through neural and humoral pathways
(diffusion across the blood-brain barrier, BBB or blood-cerebrospinal fluid barrier, BCSFB). Primed microglia
are activated to enhance synthesis of proinflammatory compounds that ultimately damage the neuron and
contribute to cognitive decline. M1: classic macrophage activation; M2: alternative macrophage activation.
(From Atienza, M., Ziontz, J., Cantero, J.L., 2018. Low-grade inflammation in the relationship between sleep
disruption, dysfunctional adiposity, and cognitive decline in aging. Sleep Med. Rev. 42, 171–183. ISSN 1087-
0792, https://doi.org/10.1016/j.smrv.2018.08.002.)
described in a family with a progressive neurological illness character- patterns of growth hormone, prolactin, and melatonin are noted. The
ized by insomnia and dysautonomia that terminated in death. Clinical nocturnal secretory peaks of growth hormone are absent. Plasma mel-
manifestations are impaired control of the sleep/wake cycle, includ- atonin levels progressively decrease, and in the most advanced stage of
ing circadian rhythms; autonomic and neuroendocrine dysfunction; the illness, there is a complete abolition of melatonin rhythm. Somatic
and somatic neurological, cognitive, and behavioral manifestations. neurological manifestations are present in all cases, particularly in the
Profound sleep disturbances and, in particular, severe insomnia are later stage of the illness and consist of dysarthria, dysphagia, ataxia, evi-
noted from the very beginning of the illness. PSG shows almost total dence of pyramidal tract dysfunction, myoclonus, tremor, and bizarre
absence of sleep pattern and only short episodes of REM sleep, lasting astasia-abasia (Cortelli et al., 2013). Neuropsychological studies reveal
for a few seconds or minutes, without muscle atonia. This abnormal impairment of attention, vigilance, and memory. The disease progresses
sleep pattern is associated with DEB in the form of complex gestures rapidly and ends in coma and death.
and motions and myoclonus. The terminal stage of the illness is char- The neuropathological hallmark of FFI is severe atrophy of the
acterized by progressive slowing on the EEG, with the patient drifting thalamus, particularly the anterior ventral and dorsomedial tha-
into coma. Autonomic function tests reveal evidence of sympathetic lamic nuclei associated with variable involvement of the inferior
hyperactivity with preserved parasympathetic activity. Neuroendocrine olive, striatum, and cerebellum. There are no spongiform changes,
functions in FFI show a dysfunction of the pituitary-adrenal axis, as man- except in those with the longest duration of symptoms, who show
ifested by striking elevation of serum cortisol but normal corticotropin, mild to moderate spongiform degeneration of the cerebral cortex.
indicating abnormal feedback suppression of corticotropin. Persistently Severe hypometabolism of the thalamus and mild hypometabolism
elevated serum catecholamine levels associated with abnormal secretory of the cingulate cortex are the main findings on PET study in FFI
Feedback loop Damage to +

sleep-wake regulatory
brain cir
Aβ/tau +
Neuronal +
production +
activity Risk for
in brain
Aβ plaques
– and
+ Aβ/tau
Brain orexin + NFTs in brain
clearance
levels
from brain
+
Neuronal + ROS
+
EE production
Oxidative
stress
Neuronal – in neurons
+ Time spent +
Chronically awake antioxidative
disrupted capacity
sleep-wake
cycle Sleep – + higher/increased Neuronal + +
continuity AD risk
– lower/decreased death
+
Endothelial –
BBB
tight junction
dysfunction
expression
Disruption +
Misalignment + of CNS
of central pathways
clocks driven by
central clocks
Fig. 101.57 Overview of proposed mechanisms by which disruptions to the sleep-wake cycle may catalyze
AD pathogenesis in humans. Aβ, amyloid beta; AD, Alzheimer disease; BBB, blood–brain barrier; CNS, cen-
tral nervous system; EE, energy expenditure; NFTs, neurofibrillary tangles.
patients. Based on biochemical, genetic, and transmission studies, it daytime hypersomnolence. PSG shows decreased REM sleep, loss
has been concluded that FFI is a transmissible prion disease resulting of sleep spindles and K complexes, and disruption of REM/NREM
from a mutation at codon 178 of PrP, associated with substitution cycling similar to that noted in FFI (eFig. 101.58, A–C) (Baldelli and
of aspartic acid with asparagine along with the presence of a methi- Provini, 2019). In FFI, prominent pathological findings include neu-
onine codon at position 129 of the mutant allele. All human prion ronal loss in anteroventral and dorsomedial thalamic nuclei, account-
diseases (e.g., Creutzfeldt-Jakob disease and Gerstmann-Sträussler- ing for the sleep disturbances, but in many cases of Creutzfeldt-Jakob
Scheinker disease) should be considered in the differential diagnosis. disease, these characteristic neuropathological findings of FFI are
Approximately 30 unrelated families of patients with FFI have been lacking.
identified so far. FFI has been transmitted to experimental animals
and is thus a transmissible prion disease, representing the third most Sleep Disorders Associated with Neuromuscular Disorders
common hereditary prion disease worldwide. Sporadic instances, Clinicians first became aware of sleep-related respiratory dysrhythmias
however, have also been reported. The study of FFI has rekindled in patients with neuromuscular diseases by observing hypoventilation
investigation of the role of the thalamus in sleep/wake regulation. in poliomyelitis. Sleep disturbances in neuromuscular diseases are gen-
Gemignani et al. (2012), based on a single case cross sectional EEG erally due to respiratory dysrhythmias associated with these diseases
study in FFI, showed that the thalamus is essential for the generation (Bhat et al., 2012b; Chokroverty, 2011a; Chokroverty et al., 2015). In
of slow-wave sleep, and also suggested a role for prions in sleep reg- neuromuscular disorders, sleep disturbances are due to involvement
ulation. FFI has clinical features in common with delirium tremens of respiratory muscles, phrenic and intercostal nerves, or neuromus-
and Morvan chorea, leading to the concept of “agrypnia excitata,” a cular junctions of the respiratory and oropharyngeal muscles. The
clinical condition associated with disruption of a sleep-wake cycle most common complaint is EDS resulting from transient nocturnal
and hyperactivity of the motor, sympathetic, and aminergic systems, hypoxemia and hypoventilation, causing repeated arousals and sleep
and episodes of oneiric stupor related to pathological changes in the fragmentation. In addition to the sleep-related respiratory dysrhyth-
thalamolimbic circuits (Lugaresi et al., 2011). In Creutzfeldt-Jakob mias, some patients—particularly those with painful polyneurop-
disease, prominent sleep disruption is noted even in the early stage athies, muscle pain, muscle cramps, and immobility due to muscle
and is characterized by sleep-onset and maintenance insomnia with weakness—may complain of insomnia. Patients with neuromuscular
FFI
N1/REM
REM
23 1 3 5 7
Time of day
W N1/REM REM
F3-A2
C3-A2
O1-A2
R. EOG
L. EOG
Mylo.
A 1 sec
Healthy control
N1
N2
N3
REM
23 1 3 5 7
Time of day
W N1 N2 N3 REM
F3-A2
C3-A2
O1-A2
R. EOG
L. EOG
Mylo.
B 1 sec
eFig. 101.58 Polysomnographic Findings in the Setting of Fatal Familial Insomnia (FFI). A, Hypnogram
in an age-matched healthy control individual. B, In the FFI patient the hypnogram continuously fluctuates
between wake and sub-wakefulness (N1/REM) with short intrusions of REM sleep; the polysomnographic
excerpts show abolishment of spindle and delta sleep. EEG (F3-A2; C3-A2; O1-A2); R.: right; L.: left; EOG:
electrooculogram; Mylo: mylohyoideus muscle.
Continued
C
eFig. 101.58, cont’d C, Frame sequence montage from a PSG recording of an oneiric stupor episode in a
patient with fatal familial insomnia. The patient performs gestures such as pointing at something and manip-
ulating an inexistent object, quietly mimicking usual daily life activities. (From Baldelli, L., Provini, F., 2019.
Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications.
Auton. Neurosci. 218, 68–86. https://doi.org/10.1016/j.autneu.2019.02.007.)
diseases often complain of breathlessness, particularly in the supine spasticity associated with flexor spasms, neck pain, and central pain
position. syndrome.
Respiratory disturbances are generally noted in the advanced stage Sleep disturbances in poliomyelitis and postpolio syndrome.
of primary muscle disorders or myopathies, but respiratory failure may Respiratory disturbances worsening during sleep may occur in many
appear in an early stage. Sleep complaints and sleep-related respiratory patients during the acute and convalescent stages of poliomyelitis. Some
dysrhythmias are common in Duchenne and limb–girdle muscular are left with the sequelae of sleep-related apnea or hypoventilation,
dystrophies as well as in myopathies associated with acid maltase defi- requiring ventilatory support, especially at night. Another group
ciency (Guilleminault and Shegill, 2002). They may also occur in other of patients develops symptoms decades later that constitute
congenital or acquired myopathies, mitochondrial encephalomyopa- postpolio syndrome, in which sleep disturbances and sleep apnea or
thy, and polymyositis. hypoventilation have also been noted (Bhat et al., 2012a; Chokroverty,
Many patients with myotonic dystrophy have been described with 2011a; Chokroverty and Provini, 2015). Postpolio syndrome is
central, mixed, and upper airway OSAS, alveolar hypoventilation, day- manifested clinically by increasing weakness or wasting of the previously
time fatigue, and hypersomnolence (Bhat et al., 2012a; Chokroverty affected muscles and by involvement of previously unaffected regions of
et al., 2015; Romigi et al., 2011). Nocturnal oxygen desaturation accom- the body, fatigue, aches and pains, and sometimes symptoms secondary
panies alveolar hypoventilation and apneas and worsens during REM to sleep-related hypoventilation (e.g., EDS and tiredness).
sleep. EDS in myotonic dystrophy often occurs in the absence of sleep Sleep dysfunction in amyotrophic lateral sclerosis. ALS, a
apnea. An entity called proximal myotonic myopathy (PROMM) has motor neuron disease, is the most common degenerative disease of the
been described. PROMM, also called DM2, is a hereditary myotonic motor neurons in adults, affecting the spinal cord, brainstem, motor
disorder that is differentiated from myotonic dystrophy by absence of cortex, and corticospinal tracts. It is characterized by progressive
the chromosome 19 CTG trinucleotide repeat that is associated with degeneration of both upper and lower motor neurons, manifesting as
classic myotonic dystrophy. In PROMM there is mutation of the gene a varying combination of lower motor neuron (e.g., muscle weakness,
encoding for zinc finger 9 of chromosome 3q21 causing CCTG repeat. wasting, fasciculation, dysarthria, and dysphagia) and upper motor
Sleep disturbances in these patients consist of difficulty initiating sleep, neuron (e.g., spasticity, hyperreflexia, and extensor plantar responses)
EDS, snoring, and frequent awakenings during sleep and alpha-NREM signs. ALS can be associated with profound sleep disturbances, which
intrusion in overnight PSG, which suggests involvement of the REM- are characterized by EDS as a result of repeated arousals and sleep
and NREM-generating neurons as part of a multisystem membrane fragmentation due to nocturnal hypoventilation, recurrent episodes
disorder (Bhat et al., 2012b; Chokroverty et al., 1997; Chokroverty of sleep apnea, hypopnea, hypoxemia, and hypercapnia (Bhat et al.,
et al., 2015; Romigi et al., 2014). In some patients (unpublished obser- 2012a; Chokroverty, 2011a; Chokroverty et al., 2015). Insomnia may
vations), upper airway OSAs and REM-hypoventilation have also been be present in some patients, which is related to other factors such as
observed (Bhat et al., 2012b; Chokroverty et al., 2015). Most of the decreased mobility, muscle cramps, anxiety, and difficulty swallowing.
findings are derived from case series. There is also a report of increased There is no significant relationship between bulbar involvement and
prevalence of RLS/WED (Lam et al., 2013a). One female patient with severity of SDB or other types of respiratory events. Sleep-related
DM2 had RBD (Chokroverty et al., 2012). breathing disturbances in ALS may result from weakness of the upper
In polyneuropathies, involvement of the nerves supplying the dia- airway, diaphragmatic, and intercostal muscles due to involvement
phragm and the intercostal and accessory muscles of respiration may of the bulbar, phrenic, and intercostal motor neurons. In addition,
cause breathlessness on exertion and other respiratory dysrhythmias. degeneration of central respiratory neurons may occur, causing central
These may worsen during sleep, causing sleep fragmentation and day- and upper airway OSAs. Generally, respiratory failure in ALS occurs late,
time hypersomnolence. In painful polyneuropathies, patients may but occasionally this may be a presenting feature, requiring mechanical
have insomnia. ventilation. Diaphragmatic weakness resulting from degeneration
Neuromuscular junctional disorders (e.g., myasthenia gravis, myas- of phrenic motor neurons is noted frequently in ALS and is mainly
thenic syndrome, botulism, and tic paralysis) are characterized by easy responsible for nocturnal hypoventilation, initially during REM sleep.
fatigability of the muscles, including the bulbar and other respiratory
muscles, as a result of nerve impulses of the neuromuscular junctions Sleep and Headache Syndromes
not being transmitted. Patients with myasthenia gravis may have cen- Sleep-related headaches are a heterogeneous group of unilateral or
tral, obstructive, and mixed apneas and hypopneas accompanied by bilateral headaches occurring during sleep or on awakening from sleep
oxygen desaturation (Chokroverty, 2011a). A sensation of breathless- (AASM, 2014). In day-to-day practice, headaches and sleep complaints
ness on awakening in the middle of the night and early-morning hours are common. Most sleep-related headaches are daytime headaches that
may indicate respiratory dysfunction. Sleep-related hypoventilation may also occur during sleep. The ICSD-III (AASM, 2014) includes clus-
and sleep apnea in neuromuscular junctional disorders may be severe ter headache, chronic paroxysmal hemicrania, migraine, and hypnic
enough to require assisted ventilation (Gonzalez et al., 2002). Impaired headache under the heading of sleep-related primary headaches. PSG
sleep quality and RLS/WED are thought to be more prevalent com- recordings in patients with cluster headaches show a strong relation-
pared with controls in myasthenia gravis patients. ship between REM sleep and attacks of headache. Migraine headaches
may occur during the day and both slow-wave and REM sleep. Cluster
Sleep and Spinal Cord Diseases headaches are thought to be related to REM sleep but may sometimes
Sleep disturbances related to respiratory dysfunction can occur in some be triggered by NREM sleep. Chronic paroxysmal hemicrania, which
patients with high cervical spinal cord lesions. Patients with poliomy- is probably a variant of cluster headache, is most commonly associated
elitis, amyotrophic lateral sclerosis (ALS) affecting the phrenic and with REM sleep. Significant sleep disruption in the form of decreased
intercostal motor neurons in the spinal cord, spinal cord tumors, spi- total and REM sleep time, accompanied by an increased number of
nal trauma, spinal surgery (e.g., cervical cordotomy or anterior spinal awakenings during REM sleep, has been described in patients with
surgery), and nonspecific or demyelinating myelitis may all have sleep chronic paroxysmal hemicrania. PSG recordings have documented
disturbances. The most common symptom is hypersomnia due to sleep apnea in some patients with chronic recurring headache syn-
sleep-related respiratory arrhythmias. Occasionally, patients with spi- dromes. The relationship between early-morning headache and upper
nal cord diseases may complain of insomnia as a result of immobility, airway OSAS has been somewhat controversial, with contradictory
reports. There are occasional reports of the coexistence of OSAS and Mollayeva et al., 2013), but objective sleep studies documenting sleep
cluster headache, with improvement of headache after CPAP titration disturbances in such patients have not been adequately performed (Rao
(Zallek and Chervin, 2000). and Rollings, 2002). After a severe TBI, brainstem function is com-
An uncommon type of headache syndrome called hypnic headache promised, and the patient becomes comatose. Many EEG studies have
syndrome is described in patients older than 50. The headache awakens examined patients with coma after head trauma. However, no studies
the patient from sleep, lasts for at least 15 minutes with a range up to have adequately addressed the sleep/wake abnormalities in these patients
190 minutes, and with a frequency of at least 15 times per month. In after recovery from coma or in patients after minor brain injuries that did
many patients it occurs at a constant time each night. Hypnic headache not result in coma. Many of these patients experience the so-called post-
tends to occur during REM sleep but also has been reported to occur concussion syndrome, which is characterized by a variety of behavioral
in Stage N3. Hypnic headache syndrome is differentiated from chronic disturbances, headache, and sleep/wake abnormalities. A few reports list
cluster headache by generalized distribution, age of onset, and lack of subjective complaints of sleep disturbance but do not include formal
autonomic manifestation. This disorder often responds to lithium, sleep studies. In one report of patients with closed head injury, PSG stud-
indomethacin, or caffeine treatment. ies documented sleep-maintenance insomnia with an increased number
Sleep-related secondary headaches include medical (e.g., hyper- of awakenings and decreased night sleep. The mechanism of these sleep
tension), neurological, psychiatric, and primary sleep disorders (e.g., abnormalities is unknown. Post-traumatic hypersomnia is listed under
OSAS). hypersomnia due to medical condition in the ICSD-III (AASM, 2014).
TBIs may cause central and upper airway OSA (prevalence may range
Stroke and Sleep/Wake Disturbance from 25%–35% (Mollayeva et al., 2013) by inflicting functional or struc-
Sleep disturbances and sleep complaints have been described in tural alterations on the brainstem respiratory control system. Many of
patients with cerebral hemispheric, paramedian thalamic, and brain- these patients may, however, have had sleep apnea syndrome before sus-
stem infarctions (Bassetti and Hermann, 2011; Chokroverty et al., taining a TBI. Circadian rhythm sleep disturbances have been described
2015; Davis et al., 2013; Dyken et al., 2011; Johnson and Johnson, in patients with TBI (Ayalon et al., 2007). There are reports of DSPS after
2010; Mansukhani et al., 2011). Sleep apnea, snoring, and stroke are TBIs (Quinto et al., 2000; Smits and Nagtegaal, 2000).
intimately related; sleep apnea may predispose to stroke, and stroke
may predispose to sleep apnea. There is an increased frequency of sleep Sleep and Multiple Sclerosis
apnea in both infratentorial and supratentorial strokes (Bassetti and Sleep-related breathing abnormalities and other sleep difficulties
Hermann, 2011; Bassetti and Valko, 2006; Davis et al., 2013; Johnson including insomnia, EDS, and depression have been described in
and Johnson, 2010; Mansukhani et al., 2011). Based on findings of an patients with MS. Sleep disturbances in MS are thought to result from
AHI of 10 or greater, it has been estimated that approximately 50%– immobility, spasticity, urinary bladder sphincter disturbances, second-
70% of all stroke patients have sleep apnea. The SBDs improve after ary narcolepsy, RBD, circadian rhythm disturbance, RLS-PLMS, pain,
the acute phase of stroke, but up to 60% of patients may still exhibit and sleep-related respiratory dysrhythmias due to affected respiratory
AHI of 10 or greater 3 months after the acute event. Many confound- muscles or impaired central control of breathing (Chokroverty et al.,
ing variables such as hypertension, cardiac disease, age, BMI, smoking, 2015). Fig. 101.59 summarizes the etiology of sleep problems in MS,
and alcohol intake, which are common risk factors for sleep apnea and based on direct and indirect causes.
stroke, must be considered before a clear relationship can be estab-
lished among these conditions. Reports by Yaggi and colleagues (2005) Sleep Disorders in Multisystem Atrophy
and Valham et al (2008) demonstrated an increased prevalence of In a consensus statement by the American Autonomic Society and the
stroke in patients with OSAS following a longitudinal follow-up study. American Academy of Neurology (Gilman et al., 1999, 2008), the term
Patients valuated for stroke risk using the Berlin questionnaire deter- multisystem atrophy was suggested to replace the term Shy-Drager syn-
mined that up to 60% were at high risk for OSA. They also found that drome (see Chapters 96 and 108). MSA defines a sporadic adult-onset
those with a previous diagnosis of OSA were at increased risk of death progressive disorder of multiple systems characterized by autonomic
within the first month after stroke. In an earlier meta-analysis of 29 dysfunction, parkinsonism, and ataxia in various combinations (eBox
articles, Johnson and Johnson (2010) found that up to 72% of stroke 101.24). Striatonigral degeneration is the name used when the predom-
patients (AHI ≥5) and up to 63% with AHI of ≥10 had SDB (primarily inant feature is parkinsonism, whereas olivopontocerebellar atrophy is
OSA). The meta-analysis also found that OSA was more common in used when the cerebellar features are the predominant manifestations.
those with recurrent and cryptogenic (unknown etiology) strokes, and The term Shy-Drager syndrome is still used when the autonomic fea-
the type and location of stroke were irrelevant factors. It is important ture is predominant. Sleep dysfunction is common in MSA and con-
to make a diagnosis of sleep apnea in stroke patients because of the sists of insomnia with sleep fragmentation, RBD, and sleep-related
possible adverse effects on the long-term outcome and because cur- respiratory dysrhythmias (Chokroverty et al., 2015). RBD is common
rently available data appear to suggest improvement of long-term sur- (present in 80%–95% of MSA patients) and may precede the illness,
vival in those who are compliant with CPAP treatment (Davis et al., present concomitantly, or present after the onset of MSA (Boeve et al.,
2013), although adherence (compliance) to CPAP treatment remains 2007; Iranzo et al., 2006; Plazzi et al., 1997). PET and SPECT find-
a problem. The Sleep SMART (Sleep for Stroke Management and ings indicate that RBD in MSA is related to nigrostriatal dopaminer-
Recovery Trial) represnts the first large scale trial designed to evalaute gic deficit (Gilman et al., 2003). The most severe sleep disturbance in
whether positive pressure therpay (PAP) for obstructive sleep apnea patients with MSA results from respiratory dysrhythmias associated
after stroke/transient ischemic attack improves/reduces stoke outcome with repeated arousals and hypoxemia. Sleep-related respiratory dys-
by pospective evaluation for improved functional recovery, rates of rhythmias in MSA may include obstructive, central, or mixed apneas,
recurrent vascular events or death (Brown et al., 2020). hypopneas, and Cheyne-Stokes breathing or a variant of Cheyne-
Stokes breathing. Other breathing disorders during sleep in MSA are
Traumatic Brain Injury and Sleep Disturbances nocturnal inspiratory stridor, apneustic breathing, inspiratory gasping,
TBIs include concussion, contusion, laceration, hemorrhage, and cere- or dysrhythmic breathing. Hypersomnia often results from nocturnal
bral edema. Insomnia, hypersomnia, and circadian rhythm sleep dys- sleep disruption. Sudden nocturnal death in patients with MSA, pre-
function may occur after TBI (Castriotta, 2015; Mathias et al., 2012; sumably from cardiorespiratory arrest, has been reported. The current
eBOX 101.24 Salient Clinical Manifestations of Multiple System Atrophy

Autonomic Features Bradykinesia or akinesia
Cardiovascular Postural instability
Orthostatic hypotension
Postprandial hypotension Cerebellar Dysfunction
Postural syncope Ataxic gait
Postural dizziness, faintness, or blurring of vision Scanning speech
Orthostatic intolerance Dysmetria
Dysdiadochokinesia
Genitourinary Intention tremor
Urinary bladder dysfunction (incontinence, hesitancy, frequency, nocturia)
Impotence in men Upper Motor Neuron Signs
Extensor plantar responses
Sudomotor Hyperreflexia
Hyperhidrosis or anhidrosis Spasticity
Gastrointestinal Lower Motor Neuron Signs

Gastroparesis Muscle wasting
Intermittent diarrhea or constipation (intestinal or colonic dysmotility) Fasciculations
Abnormal swallowing (esophageal dysmotility)
Respiratory
Ocular Sleep apnea-hypopnea
Horner syndrome Other respiratory dysrhythmias
Unequal pupils
Rapid Eye Movement Sleep Behavior Disorder
Nonautonomic Manifestations Normal Sensation
Parkinsonism
Rigidity
SLEEP PROBLEMS IN MULTIPLE SCLEROSIS
Direct Indirect
CNS Hypersomnia MS Treatment

hypersomnia
and narcolepsy
Insomnia Spasticity
Immobility
REM sleep
behavior
disorder (RBD) Sleep apnea
Pain
Nocturia
Circadian
Restless legs
rhythm
syndrome
disorders Depression
(RLS)
Periodic leg
movement
disorder
Fig. 101.59 Direct and Indirect Causes of Sleep Disturbances in Patients with Multiple Sclerosis. Solid-line arrows demonstrate a causative
effect; double dotted-line arrows highlight bidirectional effects discussed in text. (From Braley, T., Avidan, A., 2011. Sleep in multiple sclerosis. In:
Giesser, B., [Ed.] Primer on Multiple Sclerosis. Cambridge.)
diagnostic criteria including those derived from the second consensus head banging, head rolling, and body rocking. Rhythmic movement
statement (Gilman et al., 2008) consider dementia as a nonsupporting disorder is a benign condition, and the patient outgrows the episodes.
feature, but there is compelling emerging evidence of cognitive impair-
ment (mainly frontal executive dysfunction) in both subtypes of MSA Sleep-Related Leg Cramps
patients (Stankovic et al., 2014). This finding may lead to a future con- These are intensely painful sensations accompanied by muscle tight-
sensus statement to revise the diagnostic criteria. ness that occur during sleep. The spasms usually last for a few seconds
Both direct and indirect mechanisms are responsible for the but sometimes persist for several minutes. Cramps during sleep are
pathogenesis of sleep disruption in MSA. These may include one or generally associated with awakening. Many normal individuals have
more of the following: degeneration of the sleep/wake-generating nocturnal leg cramps; the cause remains unknown. Local massage or
neurons in the brainstem and hypothalamus; degeneration of the movement of the limbs usually relieves the cramps. Pharmacological
respiratory neurons in the brainstem or direct involvement of pro- therapy, however, has not been shown to provide long-term significant
jections from the hypothalamus and central nucleus of the amygdala benefit and current practice guidelines have not been conducted.
to the respiratory neurons in the NTS and nucleus ambiguus; inter-
ference with vagal inputs from the peripheral respiratory receptors Bruxism
to the central respiratory neurons; sympathetic denervation of the Bruxism often presents between age 10 and 20, but it may persist
nasal mucosa, promoting upper airway obstructing apnea; and loss throughout life, often leading to secondary problems such as tem-
of cholinergic neurons in the medullary arcuate nucleus region, con- poromandibular (TMJ) joint syndrome. Both diurnal and nocturnal
tributing to central alveolar hypoventilation during sleep. SPECT bruxism may be associated with various movement and degenerative
findings by Gilman and colleagues (2003) suggested decreased pon- disorders such as oromandibular dystonia and Huntington disease
tine cholinergic projections to the thalamus as contributing to OSA (Tan et al., 2000). It is also commonly noted in children with mental
in MSA. retardation or cerebral palsy. Nocturnal bruxism is noted most prom-
inently during stages N1 and N2 sleep and REM sleep. The episode
Sleep-Related Movement Disorders is characterized by stereotypical tooth grinding and is often precipi-
This category of sleep-related movement disorders in the ICSD-III tated by anxiety, stress, and dental disease. Occasionally, familial cases
(these movements consist of relatively simple stereotyped movements have been described. Local injections of botulinum toxin into masseter
disturbing sleep) includes seven specific disorders: RLS, PLMS, rhyth- muscles may be used to prevent dental and TMJ complications (Tan
mic movement disorder, bruxism, sleep-related leg cramps, benign and Jankovic, 2000) and may improve total sleep time as well as the
sleep myoclonus of infancy, and propriospinal myoclonus at sleep frequency and duration of bruxing episodes (Ondo et al., 2018; Video
onset (Chokroverty et al., 2013). RLS and PMLS have been described 101.10).
in this chapter.
Benign Sleep Myoclonus of Infancy
Rhythmic Movement Disorder Benign sleep myoclonus of infancy occurs during the first few weeks of
Rhythmic movement disorder is noted mostly before age 18 months life and is generally seen in NREM sleep but sometimes during REM
and is a benign condition, which disappears later in childhood. It is sleep. Episodes often occur in clusters involving arms, legs, and some-
a sleep-wake transition disorder with three characteristic movements: times the trunk. The movements consist of jerky flexion, extension,
Video 101.10 Bruxism A patient with bruxism. Note the characteris-

tic EEG and EMG pattern as well as the audible tooth grinding. (From
Berry, R.B., Wagner, M.H., 2015. Sleep Medicine Pearls, third ed. ©
2015 Elsevier. All Rights Reserved.)
abduction, and adduction. The condition is benign, needing no a history of sleep terrors in adolescents. Therefore, a previous clinical
treatment. picture compatible with sleep terrors in early life, should prompt the
clinician to review and assess for the probability of migraines later in
Propriospinal Myoclonus at Sleep Onset life (Fialho et al., 2013).
Propriospinal myoclonus occurs between wakefulness and the moment
of sleep onset (predormitum) and is characterized by transient sudden Confusional Arousals
muscle jerks predominantly involving the axial muscles. Patients com- Confusional arousals occur mostly before age 5. As in sleepwalking
plain of sleep-onset insomnia. Propriospinal myoclonus may be a spe- and sleep terrors, there is a high incidence of familial cases, and the
cial type of spinal myoclonus originating from a myoclonic generator episodes arise out of slow-wave sleep but occasionally may occur
in the midthoracic region with propagation up and down the spinal out of stage N2 NREM sleep. Patients may have some automatic
cord at a very slow speed (3–16 m/sec). and inappropriate behavior, including abnormal sexual behav-
ior (“sexsomnia” or sleep sex) when this occurs in adults. Most
Parasomnias spells are benign, but sometimes violent and homicidal episodes in
Parasomnias can be defined as abnormal movements or behaviors that adults have been described. Precipitating factors are the same as in
occur in sleep or during arousals from sleep; they may be intermittent sleepwalking and sleep terrors and in adults may also include SDB.
or episodic, and sleep architecture may not be disturbed. The ICSD- Rarely, occurrences of sleep violence homicide have been reported,
III classifies parasomnias into three broad categories (see eBox 101.6): and sometimes abnormal sexual behavior (sexsomnia) occurs. As in
disorders of arousal (from NREM sleep), which include confusional sleep-related violence noted in other arousal disorders, precipitating
arousals, sleepwalking, sleep terrors, and sleep-related eating disor- factors are also related to conditions that deepen slow-wave sleep
der (SRED); parasomnias usually associated with REM sleep, which (Videos 101.11 and 101.12).
include RBD, recurrent isolated sleep paralysis, and nightmare disor-
der; other parasomnias including sleep enuresis, exploding head syn- Sleep-Related Eating Disorders
drome, sleep-related hallucinations, and parasomnia due to drugs or SRED is an important disorder of arousal common in women between
substances, medical conditions, or unspecified. the ages of 20 and 30 and consists of recurrent episodes of involuntary
This classification thus lists 15 items, and some of these entities eating and drinking during partial arousals from sleep. Patients with
are rare. Some parasomnias, particularly somnambulism, night ter- SRED display strange eating behavior (e.g., consumption of inedible
ror, confusional arousals, sleep enuresis, RBD, and nightmares may or toxic substances such as frozen pizza, raw bacon, and cat food).
be mistaken for nocturnal seizures, particularly of the complex partial Episodes cause sleep disruption with weight gain; occasionally injury
seizures type. The intersection of parasomnias, psychiatric diseases, has been reported. The condition can be either idiopathic or comor-
and nocturnal seizures (as can be appreciated in Fig. 101.60) presents bid with other sleep disorders (e.g., sleepwalking, RLS-PLMS, OSAS,
a clinical challenge and a diagnostic enigma. Characteristic clinical fea- irregular sleep/wake circadian rhythm disorders, and use of medica-
tures combined with EEG and PSG recordings are essential to differ- tions such as triazolam, zolpidem, quetiapine, and other psychotro-
entiate these conditions (Thorpy and Plazzi, 2010). Fig. 101.61 depicts pic agents) (Nzwalo et al., 2013; Santin et al., 2014; Winkelman et al.,
a diagrammatic representation of the common disorders of arousals 2011). More recent data highlight an important relationship between
(NREM parasomnias), based on clinical semiology as a function of amnestic SRED in the setting of RLS misclassified and incorrectly
time (Derry et al., 2009). treated with hypnotic agents. Hypnotics, specifically benzodiazepine
modulators, could suppress memory and executive function, and
Somnambulism (Sleepwalking) therefore disinhibit amnestic SRED, suggesting that the latter could
Sleepwalking is common in children between the ages of 5 and 12 (eBox represent a nonmotor manifestation of RLS (Howell and Schenck,
101.25). Sometimes it persists into adulthood or (rarely) begins in 2012). Clinically, it is indeed mandatory to investigate eating behav-
adults. Sleepwalking starts with the abrupt onset of motor activity aris- ior in patients presenting with RLS symptoms as abnormal nocturnal
ing out of slow-wave sleep during the first one-third of sleep. Episodes eating could be a major risk factor for increased BMI (Antelmi et al.,
generally last less than 10 minutes. There is a high incidence of pos- 2014) and poor glucose control in RLS patients with diabetes.
itive family history. Injuries and violent activity have been reported The most common PSG findings are multiple confusional arousals
during sleepwalking episodes, but generally individuals can negotiate with or without eating, arising predominantly from slow-wave sleep but
their way around the room. Sleep violence, associated with amnesia also from other stages of NREM sleep and occasionally from REM sleep.
to the event, leading to injury and homicide have been reported, and
are probably precipitated by conditions that deepen slow-wave sleep Rapid Eye Movement Sleep Behavior Disorder
such as sleep deprivation, fatigue, concurrent illness, and sedatives RBD is a critically important REM sleep parasomnia seen in older per-
(Mahowald et al., 2005; Shneerson, 2009; Siclari et al., 2010). Contrary sons (eBox 101.27). A characteristic feature of RBD is intermittent loss
to prior suggestions, alcohol probably does not play a role in triggering of REM sleep-related muscle hypotonia or atonia and the appearance of
somnambulism (Pressman et al., 2013). various abnormal quasi dream enactment motor activities during sleep
(Fig. 101.63). The patient experiences violent DEB during REM sleep,
Sleep Terrors (Pavor Nocturnus) often causing self-injury (Fig. 101.64; see Fig. 101. 63) or injury to the
Sleep terrors also occur during slow-wave sleep (eBox 101.26 and Fig. bed partner (Iranzo et al., 2009, 2010; Olson et al., 2000; Schenck and
101.62). Peak onset is between 5 and 7 years of age. As with sleepwalk- Mahowald, 2003; Schenck et al., 2009). Some patients have been known
ing, there is a high incidence of familial cases of sleep terror. Episodes to construct specific restraining contraptions to prevent themselves from
of sleep terrors are characterized by intense autonomic and motor enacting their violent dream and sustaining injury, as is illustrated from
symptoms including a loud, piercing scream. Patients appear highly the author’s sleep clinic in Fig. 101.65 (Videos 101.13 and 101.14).
confused and fearful. Many also have a history of sleepwalking epi- RBD may be idiopathic or secondary; however, most cases are now
sodes. Precipitating factors are similar to those described with sleep- thought to be secondary and associated with neurodegenerative dis-
walking. A recent study found that migraine is strongly associated with eases. It is seen with increasing incidence in patients with PD, MSA,
eBOX 101.25 Features of Sleepwalking eBOX 101.27 Features of Rapid Eye

(Somnambulism) Movement Sleep Behavior Disorder
Onset: common between ages 5 and 12 yr. Onset: middle-aged or elderly men.
High incidence of positive family history Unique feature: Presents with complex, vigorous, and at times violent
Abrupt onset of motor activity arising out of slow-wave sleep during first one- dream-enacting behavior during sleep, causing injury to self or bed partner.
third of the night Often misdiagnosed as a psychiatric disorder or nocturnal seizure (partial com-
Duration: less than 10 min plex seizure).
Injuries and violent activity occasionally reported Etiology: In younger adults (age <30), the majority are probably idiopathic or
Precipitating factors: sleep deprivation, fatigue, concurrent illness, sedatives cryptogenic and are related to alcohol or drugs (sedative-hypnotics, tricy-
Treatment: precaution, benzodiazepines, imipramine clic antidepressants, anticholinergics). In the older patient population (age
>50), the majority are likely secondary associated with neurodegenerative
disease (predominantly synucleinopathies) and other structural central ner-
vous system lesion or
eBOX 101.26 Features of Sleep Terrors Polysomnography: rapid eye movement sleep without muscle atonia (RWSA).
Onset: peak is between ages 5 and 7 yr Experimental model: bilateral perilocus coeruleus lesions.
High incidence of familial occurrences Treatment: 90% response to clonazepam, but management with melatonin
Abrupt arousal from slow-wave sleep during first one-third of the night, with a (regular release 3–12 or sustained/continuous release 5–15 mg QHS) may
loud unique feature: piercing scream, sympathetic hyperactivity, in a child be equally/more effective with fewer side effects.
who is amnestic to these spells
Intense autonomic and motor components
Sleepwalking also seen in many patients
Precipitating factors: stress, sleep deprivation, fever Video 101.13 REM Sleep Behavior Disorder 1 A patient undergoing
a CPAP titration manifests jerking motion of his body and arms during
Treatment: psychotherapy, benzodiazepines, tricyclic antidepressants
REM sleep. (From Berry, R.B., Wagner, M.H., 2015. Sleep Medicine
Pearls, third ed. © 2015 Elsevier. All Rights Reserved.)
Video 101.14 REM Sleep Behavior Disorder 2 A patient with the REM
Video 101.11 NREM Parasomnia (Confusional Arousal) The patients
sleep behavior disorder sleeps quietly until he starts waving his right
presented with nighttime events characterized by paroxysms of sud-
arm and “swats” at something on his right side. This is the position
den awakening followed by exploratory behavior, smiling, or laughing.
usually occupied by his wife. (From Berry, R.B., Wagner, M.H., 2015.
The spells occurred during NREM sleep during which he opened his
Sleep Medicine Pearls, third ed. © 2015 Elsevier. All Rights Reserved.)
eyes, sat up in bed, and looked around. The EEG during the episode
demonstrated onset of a hypersynchronous delta activity that persisted
for the entire period of arousal. Both the semiology of the event and
the corresponding EEG was suggestive of confusional arousals. (From
Pincherle, A., Proserpio, P., Didato, G., Freri, E., Dyljgeri, S., Granata, T.,
et al., 2012. Epilepsy and NREM-parasomnia: a complex and reciprocal
relationship. Sleep Medicine. 13[4], 442–444. © Elsevier. https://doi.
org/10.1016/S1389-9457(1200144-X).)
Video 101.12 NREM Parasomnia (Confusional Arousal) The patient

had nocturnal spells occurring during slow-wave sleep during which
she appeared incoherent and confused. The electroencephalogram
(EEG) preceding the episodes depicted periodical occurrence of a
hypersynchronous delta activity, often seen with disorders of arousal
as in this case of confusional arousals. (From Pincherle, A. Proserpio,
P., Didato, G., Freri, E., Dyljgeri, S., Granata, T., et al., 2012. Epilepsy
and NREM-parasomnia: A complex and reciprocal relationship. Sleep
Medicine. 13[4], 442–444. © Elsevier. https://doi.org/10.1016/S1389-
9457(1200144-X).)
NOCTURNAL SPELLS: OVERLAPPING STATES
• RBD • Confusional
• Hypnagogic arousals
hallucinations Sleep • Sleepwalking
• Sleep paralysis phenomena • Sleep terrors
Wake
REM Non-REM
Psychogenic
NFLE Seizures
spells
• Dissociative
disorders
• PTSD
Fig. 101.60 Overlapping States of Being as Described by Mahowald and Schenck. Parasomnias are
explainable on the basic notion that sleep and wakefulness are not mutually exclusive states but may dis-
sociate and oscillate rapidly. The abnormal admixture of the three states of being—nonrapid eye movement
(NREM) sleep, REM sleep, and wakefulness—may overlap, giving rise to parasomnias. REM parasomnias
are due to the abnormal intrusion of wakefulness into REM sleep, and NREM parasomnias such as sleep-
walking are due to abnormal intrusions of wakefulness into NREM sleep. Other nocturnal spells that may be
confused with parasomnias include nocturnal frontal lobe epilepsy (NFLE) and psychogenic spells such as
post-traumatic stress disorder (PTSD) and dissociative disorders. RBD, REM sleep behavior disorder.
Behavior Confusional Arousals Somnambulism
Distressed
ed
Nonagitated Motor If displac
Arousal
Time Time
Sleep Terrors Hybrid Attacks
Intense autonomic discharge

Distressed
Nonagitated Motor
Arousal
Time Time
Fig. 101.61 Diagrammatic representation of the common disorders of arousals (nonREM parasomnias),
based on clinical semiology, represented as hierarchical combinations of the 3 fundamental behavior states
on the y axis (Arousal nonagitated motor distressed state) and as a function of time (1–10 min) on
the x axis. Panel 1 represents a typical confusional arousal spell. The parasomnia consists of normal arousal
behaviors but of abnormal duration only. Panel 2 depicts a classic somnambulistic event comprised of normal
arousal behaviors at onset, proceeding to nonagitated motor behavior. Panel 3 illustrates typical sleep terrors,
beginning with a distressed, predominantly negative emotional behavior of sudden onset. Motor and normal
arousal behaviors are usually also seen during these events, either at onset or offset. Panel 4 is a mixed
type, an admixture of two arousal disorders, comprising waxing and waning of the multiple behavior types.
All events usually start in stage N3 NREM sleep and terminate either in wakefulness or lighter NREM sleep.
The episodes are typically brief (solid lines) but can sometimes be prolonged (hatched lines). (From Derry,
C.P., Harvey, A.S., Walker, M.C., Duncan, J.S., Berkovic, S.F., 2009. NREM arousal parasomnias and their
distinction from nocturnal frontal lobe epilepsy: A video EEG analysis. Sleep 32 [12], 1637–1644.)
CHARACTERISTIC PATTERN OF SLEEP TERROR

Events typically last 3–5 min
Slow-wave
sleep
Amnesia for the event
Attempts
to wake Sudden arousal
increase
confusion
Sits up and
Mumbled screams
speech
Panic
No response
to parents
Tremendous autonomic
Confusion/disorientation discharges
Fig. 101.62 Sleep terrors are characterized by a sudden arousal associated with a scream, agitation, panic,
and heightened autonomic activity. Inconsolability is almost universal. The child is incoherent and has altered
perception of the environment, appearing confused. This behavior may potentially be dangerous and could
result in injury.
corticobasal degeneration, DLBD, olivopontocerebellar atrophy, and Experimentally, similar behavior has been noted after bilateral per-
PSP. Many patients with narcolepsy, a probable autoimmune disease ilocus coeruleus lesions in cats and a current putative neuroanatomical
causing depletion, may also present with RBD. Some authors (Boeve, explanation implicated the glutamatergic pontine SLD as the key factor
2010; Boeve et al., 2001, 2007) proposed that RBD may be an α-sy- for RBD (Krenzer et al., 2013). A possible pathophysiological scheme
nucleinopathy disorder, because α-synuclein inclusions have been to help the reader appreciate RBD is provided in Fig. 101.68.
observed in many of the associated neurodegenerative diseases (e.g., RSWA is the most important phenotype based on PSG findings.
PD, MSA, and DLBD). RBD may precede many of these degenerative However, when formal polysomnography is not available or cannot be
diseases (Classen et al., 2010). One recent study from Spain demon- obtained, one can employ a number of well validated questionnaires
strates a “dose response” relationship between the onset of “prodro- to help establish a probable RBD diagnosis to facilitate time-sensitive
mal” form of RBD to isolated RBD and later on to the development assessment, enhance the diagnostic accuracy, and allow for monitor-
of a neurodegenerative syndrome (Fig. 101.66). The time interval ing of disease progress of RBD (Lam et al., 2013b). At our center, we
between the emergence of IRBD diagnosis to neurodegenerative dis- employ the Mayo Sleep Questionnaire (MSQ), which asks bed part-
order phenoconversion was 33.1% at 5 years, 75.7% at 10 years, and ners of patients with the suspected condition if they have ever seen the
90.9% at 14 years, with a median conversion time of 7.5 years (Iranzo patient appear to “act out his/her dreams” while sleeping (i.e., punch-
et al., 2014), as depicted in Fig. 101.67. Data from other cohorts reveal a ing or flailing arms in the air, shouting, or screaming) (Boeve et al.,
similar trend, with a 5-year risk of neurodegenerative disease of 17.7%, 2013). The MSQ yielded a sensitivity of 100% and specificity (SP) of
10-year risk of 40.6%, and a 12-year risk of 52.4% (Postuma et al., 95% for the diagnosis of RBD.
2009). A follow-up by the group which initially discovered RBD as a The author points out a crucial message that RBD provides an
sleep diagnosis recently revealed that often following a prolonged dor- important window with important clinical and research implica-
mant interval, the majority of patients initially diagnosed with iRBD tions in the converging disciplines of neurology, sleep medicine, and
eventually developed a parkinsonian disorder or dementia, where the neuroscience, highlighting the impotence of conducting future pro-
specificity of iRBD converting to parkinsonism/dementia is striking spective research analysis evaluating putative neuroprotective agents
(Schenck et al., 2013a). to slow down and delay the progression to parkinsonism (Schenck
Studies have demonstrated several potential markers of neurode- et al., 2013a). The International Rapid Eye Movement Sleep Behavior
generative diseases in idiopathic RBD (Iranzo et al., 2010; Postuma Disorder Study Group (IRBD-SG) has recently published that while
et al., 2009a, 2009b, 2010a, 2010b, 2010c; Stockner et al., 2009). These iRBD patients are ideal candidates for neuroprotective studies, to
markers may be present along with RBD in the “prodromal” phase of date there are no agents with proven evidence of either disease-mod-
the disorder and include a heterogeneous set of biomarkers includ- ification or neuroprotective properties in PD (Schenck et al., 2013b).
ing impaired cognition, visuospatial dysfunction, impaired color Nevertheless, the IRBD-SG provides an important platform for
vision, olfactory deficits, autonomic dysfunction (particularly ortho- international collaboration to develop studies on RBD review-
static hypotension), EEG slowing, midbrain hyperechogenicity, and ing the role of environmental risk factors for iRBD, and candidate
decreased dopamine transporter imaging. RBD may sometimes be drug active treatment studies for both symptomatic and neuroprotective
induced (e.g., sedative-hypnotics, tricyclic antidepressants, anticholin- therapy (Schenck et al., 2013b). One recent imitative is the develop-
ergics) or associated with alcoholism and structural brainstem lesions. ment of the North American Prodromal Synucleinopathy (NAPS)
RBD has been linked to dopamine cell dysfunction, based on PET scan Consortium which facilitates collaborative efforts across geographically
findings of reduced striatal presynaptic dopamine transporter and diverse institutions to help shed more light on characterizing RBD phe-
SPECT scan findings of reduced postsynaptic dopamine D2 receptors. notypes with the shared purpose of planning for a clinical trials which
Stage R (REM) Sleep REM Without Atonia
LOC-A1
ROC-A1
T3-Cz
Cz-T4
C3-ET
T3-O1
50 Pv
CHIN-EMG
ECG
LA-EMG
RA-EMG
L-LEG-EMG
R-LEG-EMG
INTRC
NA
OA
TM
Sao2
3 SEC
B C
Fig. 101.63 The Rapid Eye Movement Sleep Behavior Disorder Leading to a Subdural Hemorrhage in a 73-Year-Old Man with a Decade
History of Aggressive Dream Enactment Behavior. A, The nocturnal polysomnograph depicts an unusually high level of electromyographic (EMG)
augmentation during rapid eye movement sleep consistent with REM Sleep Without Atonia (RSWA). ET, Ears tied; O, occipital; INTRC, intercostal
EMG; LA, left arm; L-LEG, left leg; LOC, Left outer canthus; NA, nasal airflow; OA, oral airflow; RA, right arm; R-LEG, right leg; ROC, right outer
canthus; T, temporal; C, central; TM, thoracic movement. B, A magnetic resonance imaging scan of the brain and brainstem showed a right sub-
dural hematoma following an injury sustained during a dream enactment. C, Physical examination demonstrating skin abrasion and right infraorbital
hematoma. (A, From Dyken, M.E., Yamada, T., Lin-Dyken, D.C., 2001. Polysomnographic assessment of spells in sleep: nocturnal seizures versus
parasomnias. Semin. Neurol. 21 [4], 377–390; B, C, From Dyken, M.E., Lin-Dyken, D.C., Seaba, P., et al., 1995. Violent sleep-related behavior leading
to subdural hemorrhage. Arch Neurol. 52, 318–321.)
Fig. 101.64 Photograph of a 74-year-old patient with REM sleep behavior disorder (RBD) who experienced
severe facial and dental injuries following a dream enactment episode when she “dove out of her bed”
and landed on the corner of a piece of furniture. This example exemplifies the need to carefully assess the
bedroom environment of patients with this REM parasomnia and intervene by removing sharp objects and
furniture (Level A evidence) and when appropriate intervene with pharmacological treatment using clonaze-
pam or melatonin (Level B evidence). (From Schenck, C.H., Lee, S.A., Bornemann, M.A., Mahowald, M.W.,
2009. Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: Review of
the literature and forensic implications. J. Forensic Sci. 54 [6], 1475–1484.)
Fig. 101.65 Set of handcuffs and mattress belt constructed by a 65-year-old man with a history of dream
enactment episodes to prevent himself from moving and hurting himself and his wife. The nocturnal epi-
sodes became extremely dangerous in the last few months before presentation at a sleep disorder clinic.
(From Avidan, A.Y., 2009. Parasomnias and movement disorders of sleep. Semin. Neurol. 29, 372–392.)
Tool Normal Prodromal RBD Isolated RBD Overt α-synucleinopathy
Video
polysomnography
Meets video criteria
Meets video criteria for RBD in the context
Single minor movements ≥2 RBE for RBD of α-synucleinopathy
EMG
Increased tonic and phasic >32% of 3s REM
EMG activity >32% of 3s REM mini-epochs having
Single EMG twitches No cut-off defined (or above mini-epochs having any chin or phasic FDS
often associated cut-off but without any chin or phasic activity in the context
with REM sleep behaviours) FDS activity of α-synucleinopathy
Nature Reviews | Neurology

Fig. 101.66 The New Concept of Prodromal Rapid Eye Movement Sleep Behavior Disorder. Neurophysiolog-
ical and behavioral findings on polysomnography and signature EMG (electromyography) findings of augmented
tone probably represent the earliest sign of an emergent α-synucleinopathy which progress along a continuum
over time. From initially normal findings, patients enter a prodromal stage of rapid eye movement (REM) sleep
behavior disorder (RBD) that progresses into isolated RBD, and eventually into RBD with overt α-synucleinopathy.
FDS, Flexor digitorum superficialis; RBEs, REM sleep behavioral events. (From Högl, B., Stefani, A., Videnović, A.,
2018. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat. Rev. Neurol. 14, 40–55.)
Kaplan-Meier curve for RBD conversion rates
1.00
0.75
Survival probability
0.50
0.25
Log-rank
p < 0.0001
0.00
0 5 10 15
Time
Disease type
PD MSA DLB MCI Dementia AD Other
Fig. 101.67 Rates of neurological-disease-free-survival according to the time of iRBD diagnosis in a sample
of 174 patients from Spain utilizing Kaplan-Meier analysis. There is a “dose response” relationship between
the years since documenting RBD episodes to phenoconversion to a neurodegenerative disease in the fol-
lowing relationship: 5 years -> 33%, 10 years -> 76%, 14 years -> 91%. Emerging diagnoses were dementia
with Lewy bodies (DLB), Parkinson disease (PD), multiple system atrophy (MSA), and mild cognitive impair-
ment (MCI). (From Iranzo, A., Fernández-Arcos, A., Tolosa, E., et al., 2014. Neurodegenerative disorder risk
in idiopathic REM sleep behavior disorder: study in 174 Patients. PLoS ONE 9 [2], e89741.)
PATHOPHYSIOLOGY OF REM SLEEP BEHAVIOR DISORDER
Pedunculopontine centers
Perilocus coeruleus
Stimulation
Inhibition
Lateral tegmentoreticular tract
RBD Medullary centers

Lack of pontine-mediated Magnocellularis neurons
medullar inhibition of
spinal motor neurons
Spinal cord
Ventrolateral reticulospinal tract
Lack of medullary-mediated
spinal motor neuron inhibition Spinal motor neuron
Skeletal
muscle
Lack of REM atonia REM-associated atonia

Fig. 101.68 The normally generalized muscle atonia during rapid eye movement (REM) sleep results from
pontine-mediated peri-locus coeruleus inhibition of motor activity. This pontine activity exerts an excitatory
influence on medullary centers (magnocellularis neurons) via the lateral tegmentoreticular tract. These neu-
ronal groups in turn hyperpolarize the spinal motor neuron postsynaptic membranes via the ventrolateral
reticulospinal tract. In REM sleep behavior disorder (RBD), the brainstem mechanisms generating the muscle
atonia normally seen in REM sleep may be disrupted. The pathophysiology of RBD in humans is based on the
cat model. In the cat model, bilateral pontine lesions result in a persistent absence of REM atonia associated
with prominent motor activity during REM sleep, similar to that observed in RBD in humans. The patho-
physiology of the idiopathic form of RBD in humans is still not very well understood but may be related to
reduction of striatal presynaptic dopamine transporters. (Modified with permission from Avidan, A.Y., 2005.
Sleep disorders in the older patient, In: Lee-Choing, T. [Guest Ed.], Primary Care: Clinics in Office Practice,
vol. 32, Sleep Medicine. Elsevier, St. Louis, pp. 563–586.)
would be ready to enroll patients for treatments trials in the hope of occur in a very small percentage (<1%) of individuals. Nightmares can
delaying/preventing neurodegenerative diseases before the condition also occur as side effects of certain medications such as antiparkinso-
is irreversible (https://www.naps-rbd.org/ https://clinicaltrials.gov/ct2/ nian drugs (pergolide, levodopa), anticholinergics, and antihyperten-
show/NCT03623672 Vvidenovic A, Ju Y-eS, Arnulf i, et al. J Neurol sive drugs, particularly beta-blockers. Nightmares are common after
Neurosurg Psychiatry 2020;91:740–749.). sudden withdrawal of REM sleep-suppressant drugs (e.g., tricyclic
antidepressants, SSRIs). Benzodiazepines (e.g., diazepam, clonaze-
Nightmares (Dream Anxiety Attacks) pam) often suppress nightmares, but withdrawal from these drugs
Nightmares are fearful, vivid, often frightening dreams, mostly visual may precipitate nightmares. Nightmares have also been reported after
but sometimes auditory, and seen during REM sleep. Nightmares may alcohol ingestion or sudden withdrawal from barbiturates. Nightmares
accompany sleep talking and body movements. These most commonly may sometimes be the initial manifestation of schizophreniform psy-
occur during the middle to late part of sleep at night. Nightmares are chosis, along with severe sleep disturbance. Many people with a cer-
mostly a normal phenomenon. Up to 50% of children, perhaps even tain personality type have nightmares throughout life. Nightmares
more, have nightmares beginning at age 3–5 years. The incidence of generally do not require any treatment except reassurance. In patients
nightmares continues to decrease as the child grows older, and elderly with recurring and fearful nightmares, however, combined behavioral
individuals have very few or no nightmares. Very frightening and recur- or psychotherapy and REM sleep-suppressant medications may be
ring nightmares (e.g., one or more per week) are not common and may helpful.
Isolated Symptoms, Apparently Normal Variants, and sleep at an appropriate time as a result of inadequate enforcement of
Unresolved Issues bedtime by the caregiver. As the child grows older, behavioral insom-
nia generally resolves.
This category (see eBox 101.6), listed under a separate sleep disorder in
Obstructive sleep apnea in children. OSAS occurs in children,
ICSD-II, has been eliminated as a separate category in ICSD-III and incor-
but there are certain differences from OSAS in adults (AASM, 2014).
porated into the seven major categories of sleep which are most relevant
Children may present with EDS, but common symptoms include
to these entities. These isolated symptoms and normal variants include
hyperactivity and behavioral problems during the daytime, impaired
long sleeper, short sleeper, snoring, sleep talking, sleep starts, benign sleep
school performance, intellectual changes, increased motor activity,
myoclonus of infancy, hypnagogic foot tremor, alternating leg muscle
disturbed sleep at night, and nocturnal snoring for many months
activation during sleep, and excessive fragmentary myoclonus (EFM).
or years (eBox 101.28). Some young children may have obstructive
Sleep Talking (Somniloquy) hypoventilation consisting of prolonged periods of partial upper airway
obstruction associated with oxygen desaturation and hypercapnia.
Sleep talking is apparently very common, occurring in as many as 50% of
Obstructive hypoventilation with continuous snoring as well as
children. Sleep talking that significantly disturbs others is rare. In adults,
paradoxical breathing are commonly present in children. Another
sleep talking seems to be more common in males than in females, and it
important feature is that the upper airway obstruction is noted
has a familial tendency. Clinically, sleep talking consists of utterances of
predominantly in REM sleep. All apneic episodes may not be followed
speech or sounds that occur during the sleep episode without awareness
by cortical arousals, but they do have autonomic activation following the
of the event. The episodes are generally brief, infrequent, and devoid of
apneic episodes. Sleep architecture in children with OSA is often normal
signs of emotional stress. The course is usually self-limited and benign.
with an adequate amount of slow-wave sleep. Some children may have
Catathrenia (Expiratory Groaning) UARS with a similar presentation as in adults. An important cause in
children is enlargement of tonsils and adenoids. If OSAS is suspected,
This is characterized by recurrent episodes of expiratory groaning
an overnight PSG study is indicated for documenting OSA. In contrast
(high-pitched, loud humming, or roaring sounds) and occurs in
to adults, removal of the tonsils and adenoids in children promotes
clusters, predominantly during REM sleep, but it may also occur
symptomatic improvement. Some occurrences of sudden infant death
during NREM sleep. PSG findings resemble central apnea with
syndrome have been linked to sleeping in the prone position, and every
protracted expiratory bradypnea without oxygen desaturation.
attempt must be made to keep the infant in the supine position.
Simultaneous audio recordings will bring out the characteristic
Primary sleep enuresis (listed under other parasomnia in the ICSD-III)
groaning. The clinical relevance and pathophysiology of this condi-
is a condition of recurrent involuntary bedwetting after age 5 years occur-
tion remain unknown.
ring at least twice a week and present for at least 3 months in a patient who
has never been consistently dry during sleep for 6 consecutive months
Sleep Starts (AASM, 2014). If the child or adult began to have bed wetting at least
Additional text available at http://expertconsult.inkling.com. twice a week for at least 3 months after remaining dry for 6 consecutive
months, then it is considered secondary sleep enuresis. Enuretic episodes
Pediatric Sleep Disorders occur during all stages of sleep, most commonly during the first one-
Despite a high incidence of sleep disturbance in children, the field of third of the night. SBD is reported in 8%–47% of children with enuresis.
pediatric sleep disorders remains neglected. Several recent surveys found Treatment includes behavioral modification and tricyclic antidepressants
that approximately 25% of children aged 1–5 years have some kind of (e.g., imipramine) and desmopressin, either as a nasal spray or tablets.
sleep problem. Mentally handicapped children and those with ADHD ADHD includes symptoms of inattention and hyperactivity/impulsivity.
and Tourette syndrome have higher rates of sleep disorders than normal There is an increased prevalence of RLS, PLMS, and sleep disordered
children (Hanna et al., 2013). The common sleep problems in children breathing (DB) in children with ADHD. It is important to diagnose
include a variety of parasomnias such as sleepwalking, nightmares, sleep associated conditions such as SDB because treatment of the condition
talking, sleep enuresis, bruxism, sleep terrors, and rhythmic movement may improve the patient’s symptoms of inattention and hyperactivity.
disorder; sleeplessness due to a specific childhood-onset disorder or
food allergy; EDS (e.g., narcolepsy or OSA); and DSPS or ASPS. ICSD-
III (AASM, 2014) does not separately list pediatric sleep disorders but
LABORATORY ASSESSMENT OF SLEEP DISORDERS
these are scattered throughout other categories. Some specific examples Laboratory investigation for sleep disorders should be considered an
include OSA, pediatric; congenital central alveolar hypoventilation syn- extension of the history and physical examination. First and foremost,
drome; primary CSA of infancy; primary CSA of prematurity; irregular in the diagnosis of a sleep disorder is a detailed history, including sleep
sleep wake rhythm disorders in childhood autism spectrum disorder, and and other conditions, as outlined under Approach to a Patient with
ADHD. ADHD should be conceptualizing as a 24-hour disorder with sig- Sleep Complaints. This should be followed by a careful physical exam-
nificant relevance to sleep which requires the clinician to evaluate sleep/ ination to uncover any underlying medical, neurological, or other
wake schedule patterns and sleep symptoms such as sleepiness, snoring, causes of sleep dysfunction. Laboratory tests should include a diag-
leg discomfort as potential opportunities for interventions in individuals nostic workup for the primary condition causing secondary sleep dis-
with ADHD (Becker, 2020). turbance and a workup for the sleep disturbance itself. The two most
Behavioral insomnia of childhood includes difficulty falling asleep, important laboratory tests for diagnosis of sleep disturbance are PSG
staying asleep, or both, related to specific behavior such as inappro- and the MSLT. Various other tests are also important for assessment of
priate sleep-onset associations or inadequate limit setting. Sleep-onset a patient with sleep dysfunction (Box 101.29).
association includes impairment of sleep onset because of the absence
of a certain object or set of circumstances (e.g., using a bottle, suck- Polysomnographic Study
ing on a pacifier, being rocked, watching television, or listening to An overnight PSG study is the single most important laboratory
the radio). Sleep is normal when the particular association is present. test for the diagnosis and treatment of patients with sleep disorders,
Limit-setting type is characterized by child’s stalling or refusing to go to particularly those associated with EDS. An all-night PSG study is
Sleep Starts of SDB, repeated arousals with oxygen desaturation at night, sleep
Hypnic jerks, or “sleep starts,” occur at sleep onset in many normal fragmentation, sleep-stage shifts, reduced slow-wave sleep, shortened
individuals and are physiological phenomena without any pathological sleep-onset latency in MSLTs, and sometimes REM sleep abnormali-
significance (Chokroverty et al., 2013; Chokroverty and Gupta, 2010). ties. When a patient presents to a sleep specialist with a sleep distur-
The episodes are associated with sudden brief myoclonic movement of bance, either with a complaint of insomnia or hypersomnia, a detailed
the limbs or the whole body lasting for a few seconds. Sometimes these medical history, other histories, and a thorough physical examination
are accompanied by sensory phenomena, such as a sensation of falling. to uncover the cause of sleep disturbance are essential.
These may be triggered by stress, fatigue, or sleep deprivation. Sleep In an important epidemiological study by Gislason and Almqvist
starts may occur in up to 70% of the general population. involving a random sample of 3201 Swedish men aged 30 to 69 years,
the major sleep complaints were difficulty initiating or maintain-
Hypnagogic Foot Tremor ing sleep and too little sleep, followed by EDS (Chokroverty, 2015b).
Hypnagogic foot tremor is characterized by a rhythmic movement of Sleep-maintenance problems occurred more often with increasing age.
feet or toes occurring at the transition between wake and sleep or during The following conditions were associated with sleep complaints: sys-
stages 1 and 2 NREM sleep. This is a relatively common finding, and the temic hypertension, bronchitis and bronchial asthma, musculoskeletal
clinical significance remains unknown. PSG findings consist typically of disorders, obesity, and diabetes mellitus. The authors suggested that
trains of 1–2 Hz (range, 0.3–4 Hz) EMG potentials or movement in one the reported increased mortality among patients with sleep complaints
or both feet, with the burst duration longer than 250–1000 microsec- might be related to the intercurrent somatic diseases.
onds; the minimum number needed to make a train is four bursts.
Cardiovascular Disease and Sleep (see also earlier section on
Alternating Leg Muscle Activation sleep apnea syndrome)
Alternating leg muscle activation consists of brief activation of the Sleep disturbance is common in patients with ischemic heart dis-
tibialis anterior muscle in one leg alternating with similar activation ease. Pain may awaken the patient often, thereby reducing sleep effi-
in the other leg during sleep or arousals from sleep. This is a PSG ciency. Nocturnal angina is known to occur during both REM and
finding, with a frequency of 0.5–3Hz with an individual activation NREM sleep. Epidemiologically, there is a clear relationship between
duration between 100 and 500 ms; a minimum of four alternat- increased cardiovascular morbidity and mortality and sleep distur-
ing activations with less than 2 seconds between the activations is bances associated with SDB. Shahar and colleagues (2001) reported
required for diagnosis, and each sequence may last up to 30 seconds. on the cross-sectional data from the Sleep Heart Health Study cohort
The clinical significance of this entity is not known. showing modest to moderate effects of SDB on various manifestations
of cardiovascular disease (e.g., myocardial ischemia, heart failure, or
Excessive Fragmentary Myoclonus stroke) within a range of AHI values that are considered normal or
EFM is characterized by small muscle jerks without visible movements mildly elevated. Patients with coronary artery disease and OSA may
of the fingers, toes, or corners of the mouth or small muscle twitches have an increased cardiac risk due to nocturnal myocardial ischemia
resembling fasciculations that do not cause gross movement across triggered by apnea-associated oxygen desaturation. An important
the joint space. EFM may resemble physiological fragmentary myoc- finding in several reports is circadian susceptibility to MI (attacks are
lonus of REM sleep, but this is seen in all stages and states (NREM and most likely between midnight and 6:00 am).
REM) of sleep. The clinical significance of EFM remains uncertain; it is Heart failure is the leading cause of disability in individuals older
seen in a variety of sleep disorders. EFM is predominantly a PSG find- than 65 years of age, and the prevalence increases with age. Heart fail-
ing consisting of brief myoclonic bursts (75–150 ms) of more than 5 ure may be systolic with reduced ejection fraction or diastolic with
potentials per minute, sustained for at least 20 minutes during NREM preserved ejection fraction. Both obstructive and central apneas,
sleep. including Cheyne-Stokes breathing, have been observed in such
patients, although the incidence and prevalence of sleep apnea in dia-
Sleep in Other Medical Disorders stolic heart failure are not definitely known (Arias et al., 2005; Fung
A number of medical disorders other than neurological illnesses may et al., 2002; Javaheri and Somers, 2011). Approximately 1.5%–2% of
cause severe disturbances of sleep and breathing that have import- the US population has heart failure, and about 40%–80% of patients
ant practical implications for diagnosis, prognosis, and treatment with systolic heart failure have sleep apnea. From 30% to 60% of
(Chokroverty, 2015c). Sleep disturbances may have adverse effects on patients with systolic heart failure have predominantly central apnea,
the course of a medical illness. A vicious cycle may result from the and 5%–32% have predominantly obstructive apnea (Javaheri and
effect of sleep disturbance on the medical illness and the effect of the Somers, 2011; Randerath and Javaheri, 2015). It is known that atrial
medical illness on sleep architecture. Sleep architecture, sleep conti- fibrillation and hypertension are commonly associated with diastolic
nuity, and sleep organization may be affected by a variety of medical heart failure. Diabetes mellitus, coronary artery disease, and hyperlip-
illnesses. Patients may present with either insomnia or hypersom- idemia are commonly associated with systolic heart failure. There is a
nolence, but most medical disorders present with insomnia. Some high prevalence of CSA in systolic heart failure (reduced ejection frac-
patients may have a mixture of insomnia and hypersomnolence (e.g., tion) patients (Randerath and Javaheri, 2015) who are generally not
those with COPD or nocturnal asthma). The general features of insom- obese and lack subjective daytime sleepiness, and they often have an
nia and medical disorders causing insomnia, as well as hypersomno- unexplained sleep maintenance insomnia. There is approximately 25%
lence and medical conditions presenting with hypersomnolence have mortality at 1 year and 65% mortality at 5 years in patients with dia-
been briefly described in this chapter. PSG findings in those presenting stolic heart failure. Survival at 1–5 years in both systolic and diastolic
with insomnia include prolonged sleep latency, reduction of REM and groups is about equal (Aurigemma, 2006). Bitter et al. (2009) found
slow-wave sleep, more than 10 awakenings per night, frequent stage a high prevalence of CSA in diastolic heart failure (normal ejection
shifts, early-morning awakening, increased waking after sleep onset, fraction) after evaluating 244 patients using an AHI of ≥15/hour and
and increased percentage of wakefulness and stage 1 NREM sleep. observed sleep apnea in about 50% of the patients (half had OSA and
PSG findings in those presenting with hypersomnolence may consist half had CSA).
There are reports of improvement of quality of life and reduction of nocturnal cough resulting from accumulated bronchial secretions, and
mortality in patients with systolic heart failure associated with obstruc- associated hypoxemia and hypercapnia. Severe nocturnal hypoxemia
tive and central apneas, including Cheyne-Stokes breathing, using in many patients with COPD may be accompanied by sleep-related
CPAP treatment (Kaneko et al., 2003; Somers et al., 2008). Although apnea, hypopnea, or periodic breathing, as well as impairment of gas
a large Canadian study contradicted this (Bradley et al., 2005), a later exchange. In some patients (≈11%) COPD may coexist with OSAS—a
analysis of the data agreed with benefit of CPAP. Despite strong evi- condition called overlap syndrome (Chaouat et al., 1995), which
dence, the data remain controversial; large-scale randomized con- causes profound gas exchange abnormalities leading to a higher risk
trolled trials are needed to confirm cardiovascular benefit after CPAP of pulmonary hypertension and heart failure than in those with only
treatment of OSA patients. Sleep apnea (both OSA and CSA/CSB) is OSAS. Repeated or prolonged oxygen desaturation at night may cause
highly prevalent in heart failure patients and it is important to screen cardiac arrhythmias and may lead to pulmonary hypertension and
every heart failure patient for sleep apnea. cor pulmonale. Administration of supplemental oxygen at 2 L/min by
Myocardial infarction and sleep. Factors contributing to nasal cannula during sleep is found to improve both oxygen saturation
myocardial ischemia, infarct, or arrhythmia include increased at night and sleep architecture by decreasing sleep latency and
sympathetic surge during REM sleep, increased platelet aggregability, increasing all stages of sleep, including REM and slow-wave sleep. It
hypotension associated with slow-wave sleep, and altered balance should, however, be remembered that in some patients, 100% oxygen
between fibrinolytic and thrombic factors, oxygen desaturation, and administration may worsen breathing events (Chokroverty et al., 1969;
increased ventricular diastolic pressure and volume associated with Motta and Guilleminault, 1978). Most treatments include smoking
supine posture (Randerath and Javaheri, 2015; Somers et al., 2008). cessation, bronchodilators or inhaled steroids, and pulmonary
The risk of congestive heart failure is also increased among patients rehabilitation (Sutherland and Cherniack, 2004).
with the onset of MI at night. Patients with diabetes, advancing age, and Sleep disturbances in bronchial asthma. A variety of sleep
impaired ventricular function are at an increased risk for developing disturbances have been noted in patients with asthma, including early-
nocturnal MI. Nondippers—those hypertensive patients whose blood morning awakenings, difficulty maintaining sleep, and EDS. Sleep
pressure during sleep does not decline or declines less than 10% from disturbances in general consist of a combination of insomnia and
daytime to nighttime readings—have significant risk for developing hypersomnia. PSG studies may reveal disruption of sleep architecture
cardiac arrhythmia, stroke, and death from cardiovascular disease as well as sleep apnea in some patients. Nocturnal exacerbation of
(Ben-Dov et al., 2007; Javaheri and Somers, 2011). In patients with symptoms during sleep is a common finding in asthmatic patients.
ischemic heart disease, 24-hour Holter monitoring may reveal several There is also evidence of progressive bronchoconstriction and
different electrocardiographic (ECG) changes during sleep, including hypoxemia during sleep in patients with asthma. Several pathogenic
ST-segment depression and T-wave inversion. Nocturnal cardiac mechanisms, including circadian factors, have been suggested for sleep
ischemia associated with ST-segment depression and elevation has been disturbances and nocturnal exacerbation of asthma.
noted during sleep in some middle-aged men and postmenopausal
women. Miscellaneous Disorders and Sleep
Sleep and cardiac arrhythmias. Although human studies Gastrointestinal diseases and sleep. Sleep disturbances in peptic
reveal contradictory results about the effect of sleep on ventricular ulcer patients characteristically result from episodes of nocturnal
arrhythmia, the majority show an antiarrhythmic effect of sleep on epigastric pain. These symptoms cause arousals and repeated
ventricular premature beats (Chokroverty, 2015c). awakenings, thereby fragmenting and disturbing sleep considerably.
Sleep and sudden cardiac death. An analysis of the time of sudden With duodenal ulcers, there is increased nocturnal acid secretion,
cardiac death in 2023 individuals by Muller and associates revealed which can be abolished by vagotomy, thus improving healing of ulcers.
high incidence from 7:00 am to 11:00 am. Nonfatal MI and myocardial Furthermore, patients with duodenal ulcers do not have inhibition
ischemic episodes are also more likely to occur in the morning. It is of gastric acid secretion during the first 2 hours after sleep onset.
known that sympathetic activity increases in the morning, increasing In light of evidence about the role of Helicobacter pylori infection
myocardial electrical instability; thus, sudden cardiac death may result and nonsteroidal anti-inflammatory drugs in the pathogenesis of
from a primary fatal arrhythmia. Another cause of sudden death in gastroduodenal ulcers, the theory of hypersecretion of acid in peptic
young adults in the Western literature is Brugada syndrome, described ulcer patients has been displaced.
in 1992 (Antzelevitch et al., 2007). Patients with this syndrome Gastroesophageal reflux disease, which is preferable to the term
present with life-threatening ventricular tachyarrhythmias without reflux esophagitis, characteristically causes “heartburn,” or retroster-
any structural cardiac lesions, and the ECG shows characteristic nal burning pain. This pain causes difficulty in initiating sleep,
abnormalities of atypical right bundle branch block and ST-segment frequent awakenings, and fragmentation of sleep. Facilities for all-
elevation over the right precordial leads. The Brugada syndrome has night PSG study and 24-hour esophageal pH monitoring have con-
a genetic basis; the ideal treatment is implantation of a cardioverter- tributed to an understanding of the association between sleep and
defibrillator. Sudden unexplained nocturnal death syndrome peptic ulcer diseases and esophageal reflux. Sleep adversely affects
(SUNDS) is another disorder similar to Brugada syndrome but is patients with gastroesophageal reflux disease by increasing the epi-
found in Southeast Asia. sodes of reflux and prolonging acid clearance time (Orr, 2007, 2011,
2015). Furthermore, repeated spontaneous reflux episodes adversely
Respiratory Disease and Sleep affect sleep by causing arousals, frequent awakenings, and sleep
Sleep and chronic obstructive pulmonary disease. Disturbances fragmentation.
in sleep architecture in patients with COPD have been reported by Sleep and endocrine diseases. In patients with myxedema,
several authors and may be summarized as follows: a reduction of upper airway OSA and CSA that disappear after thyroxine replacement
sleep efficiency, delayed sleep onset, increased wake time after sleep therapy have been described. Mechanisms of SDB in this condition
onset, frequent stage shifts, and frequent arousals. Factors that may include deposition of mucopolysaccharides in the upper airway as
be responsible for sleep disturbance in COPD include the use of drugs well as impaired central respiratory drive, as evidenced by decreased
that have a sleep-reducing effect (e.g., methylxanthine), increased hypercapnic and hypoxic ventilatory responses.
Patients with diabetes mellitus, particularly that associated with sleep disturbances such as insomnia, hypersomnia, and sleep-related
autonomic neuropathy, may have upper airway OSA and CSA. These respiratory dysrhythmia (Drouot et al., 2012; Gabor et al., 2001; Hardin,
sleep-related respiratory dysrhythmias may cause fragmentation of 2009; Kamdar et al., 2013; Weinhouse, 2011). The ICU environment
sleep, resulting in EDS. itself is deleterious to normal sleep and conducive to sleep deprivation,
CSA has been described in many patients with acromegaly and has with attendant complications such as ICU psychosis. Noise, bright
been generally associated with increased levels of growth hormone. light, and constant activity by ICU personnel for monitoring and
The relationship between growth hormone level and sleep apnea, how- drug administration play a significant role in disturbing the sleep of
ever, has remained somewhat controversial. Octreotide, a long-acting ICU patients. A variety of drugs in the ICU may aggravate sleep and
somatostatin analog, is an effective noninvasive treatment for sleep sleep-related respiratory disturbances. ICU syndrome is a characteristic
apnea in acromegaly. mental state defined as a reversible confusional state developing 3–7
Sleep disturbances in chronic renal failure. Sleep disturbances days after ICU admission; sleep deprivation has been cited as the
are common in patients with chronic renal failure with or without major cause of ICU syndrome. ICU psychosis is more common in
dialysis, particularly in those with end-stage renal disease. Sleep surgical than in medical ICUs. PSG findings to document disruption
complaints include insomnia, EDS, and day/night reversal or disturbed of sleep structure in the ICU consist of marked diminution of slow-
nocturnal sleep. PSG findings include reduced sleep efficiency, wave sleep and REM sleep, frequent awakenings, sleep fragmentation,
increased sleep fragmentation, frequent awakenings with difficulty and reduced total sleep time. ICU patients often have EDS because
maintaining sleep, decreased slow-wave sleep, and disorganization of disturbed night sleep. It is important to be aware of various ICU
of the sleep cycle. Many patients with chronic renal failure have sleep factors contributing to the problem of sleep disturbances so that
apnea syndrome, mainly upper airway OSAS, and may have PLMS. A correct diagnosis and management of secondary complications can be
PSG study to establish the diagnosis of OSA should be performed in implemented promptly.
any patient with a history of EDS and disturbed night sleep, because Acquired immunodeficiency syndrome. Acquired immuno
CPAP titration has been found to be an effective form of treatment deficiency syndrome (AIDS) is a multisystem disorder caused
in OSA patients undergoing hemodialysis. Another important finding by infection with human immunodeficiency virus (HIV). Sleep
in patients with chronic renal failure is the presence of a secondary disturbances (insomnia, hypersomnia, and circadian dysrhythmia) have
form of RLS. Uremic RLS and idiopathic RLS resemble each other and been reported in many patients with AIDS (Phillips, 1999), but adequate
cannot be distinguished clinically. There have been reports of cure of systematic PSG studies to document sleep disruption have not been
this form of RLS after successful kidney transplantation. undertaken (Chokroverty, 2015c; Gamaldo et al., 2013). The causes are
Fibromyalgia syndrome. Fibromyalgia syndrome is characterized multifactorial. HIV infection can also cause SDB.
by diffuse muscle aches and pains not related to diseases of the joints, African sleeping sickness (trypanosomiasis). African sleeping
bones, or connective tissues; specific diagnostic criteria for this sickness is caused by Trypanosoma gambiense or Trypanosoma
syndrome have been established. Sleep disturbance is very common rhodesiense and is transmitted to humans by the bite of tsetse flies.
in fibromyalgia. The characteristic PSG finding is intermittent alpha CNS involvement is initially characterized by personality changes
activity during NREM sleep, giving rise to the characteristic alpha-delta followed by delusions, hallucinations, and reversal of the sleep/wake
or alpha-NREM sleep pattern in the recording. Another important rhythm. The patient remains somnolent in the daytime and progresses
association is the presence of PLMS on PSG examination. Alpha- gradually into the stages of stupor and coma. PSG studies document
NREM sleep pattern is not specific for this condition and has been disruption of the circadian sleep/wake rhythm, which is proportional
noted in patients with other rheumatic disorders and even in normal to the severity of the illness. Circadian disruption of plasma cortisol,
individuals as well as some psychiatric patients. The most common prolactin, and sleep/wake rhythms is seen in the patients with the
complaints in patients with fibromyalgia include nonrestorative sleep most advanced disease. These findings of circadian disruption suggest
associated with nonspecific PSG abnormalities of sleep fragmentation, selective changes in the SCN. The diagnosis of trypanosomiasis is based
increased awakenings, decreased sleep efficiency, and alpha-NREM on history as well as confirmation that the organism is in blood, bone
sleep. marrow, CSF, lymph node aspirates, or a scraping from the chancre.
Chronic fatigue syndrome. Chronic fatigue syndrome is an ill- The treatment of choice for patients in the meningoencephalitic stage
defined, medically unexplained heterogeneous condition with multiple is arsenical melarsoprol.
causes (Evengard and Klimas, 2002). The condition is characterized by Sleep disturbances in psychiatric illness. Sleep disturbances
insidious onset of disabling fatigue present for at least 6 months without are common in psychiatric illnesses and may be observed at some
any causes despite intense laboratory investigations. Arthralgias, point in the course of the illness in up to 50%–80% of patients (Becker,
myalgias, sore throat, headache, and sleep disturbances are included 2006); insomnia is present more often than hypersomnia. Specific
as minor criteria. Orthostatic hypotension and orthostatic tachycardia examples of psychiatric conditions that are associated with insomnia
syndrome on a tilt-table study may be present in some of these patients include depression (including bipolar disorder), anxiety disorders,
(Gerrity et al., 2002). Sleep complaints include disturbed night schizophrenia, and post-traumatic stress disorder. Hypersomnia is
sleep and EDS, but adequate PSG studies have not been undertaken generally present in patients with seasonal affective disorder and may
to characterize the precise sleep disturbance. Guilleminault et al. also be present in some patients with depression. Many patients with
(2006b), however, reported an abnormal EEG CAP and an increase eating disorders, some of whom have associated major depression,
in respiratory effort and nasal air flow limitation (suggesting subtle may also have significant sleep complaints. Finally, antidepressant
undiagnosed OSA) accompanied by unrefreshing sleep and chronic and neuroleptic drugs used to treat psychiatric illnesses may cause
fatigue. sleep disruption. Assessment of sleep disturbances in psychiatric
Sleep of intensive care unit patients. Patients in an intensive patients should follow the general guidelines discussed in this chapter.
care unit (ICU) are generally admitted with acute medical, surgical, Primary treatment should target the psychiatric illness causing sleep
or neurological illnesses. All these conditions can be associated with disruption.
BOX 101.28 Typical Features of

Obstructive Sleep Apnea in Children
Prevalence: 1%–4% of children 2–8 years old
Adenoid face
Mouth breathing
Chest deformity (e.g., pectus excavatum [i.e., inward retraction])
Snoring
Witnessed apneas
Supraclavicular and intercostal retraction
Sweating
Bed wetting or its recurrence (enuresis)
Awakening (late or forced)
Abnormal posture in bed (i.e., hyperextended neck, half-sitting in bed)
Daytime sleepiness
Abnormal behavior (e.g., hyperactivity)
Poor school performance
BOX 101.29 Diagnostic Tests for Assessing Sleep Disorder

• Diagnostic workup for the primary or comorbid condition causing sleep distur- Histocompatibility leukocyte antigen for suspected narcolepsy (HLA DQB1*0602)
bance Cerebrospinal fluid hypocretin-1 levels in suspected narcolepsy (1 narcolepsy
• Laboratory tests for the diagnosis and monitoring of sleep disorders: had measured CSF concentrations below 110 ng/mL in this assay [mean
Overnight polysomnography (PSG) value of <50 pg/mL]) CSF amyloid-β42 and tau protein.
Specialized PSG (i.e., with electroencephalography (EEG)/EMG montage to Serum iron, ferritin levels and transferrin for patients with RLS
evaluate for nocturnal seizures, RBD, other parasomnias and movement Electromyography and nerve conduction studies to exclude comorbid or
disorders of sleep. secondary RLS
Multiple sleep latency tests (MSLT) Cardiological investigations including electrocardiogram (EKG), Holter EKG,
Maintenance of wakefulness test (MWT) and echocardiogram
Actigraphy Endocrine tests
Video-PSG with multiple muscle montage Autonomic function tests in patients with suspected autonomic and
• Laboratory tests for suspected seizure disorders sleep-related breathing disorders
Standard EEG • Home Sleep Apnea Tests (HSAT)
Video-EEG monitoring for suspected seizure disorders Indications
Video-PSG with special seizure montage May be alternatives for the initial evaluation of OSA in patients with a high
• Imaging studies: pretest probability for the conditions
Upper airway imaging for obstructive sleep apnea syndrome Contraindications to portable sleep study:
Neuroimaging studies (e.g., computed tomography, magnetic resonance 1. Pediatric setting/patient is 18 years old or younger
imaging [MRI], MR-angiography, diffusion tensor MRI, and MR tractogra- 2. Moderate or severe chronic obstructive pulmonary disease (COPD)—
phy) and cerebral angiography in cases of suspected neurological illness FEV1/FVC less than or equal to 0.7 and FEV1 less than 80% of
causing sleep disorder predicted
Positron emission tomography and single-photon emission computed tomog- 3. Moderate or severe congestive heart failure (CHF)—NYHA class III or IV
raphy in special situations 4. Cognitive impairment (inability to follow simple instructions)
Positron emission tomography (PET) with Fludeoxyglucose (FDG)/amyloid 5. Neuromuscular impairment
imaging 6. Suspicion of a sleep disorder other than OSA (e.g., central sleep apnea,
Cardiac MIBG scintigraphy and midbrain transcranial sonography in idiopathic narcolepsy, restless legs syndrome, circadian rhythm disorder, parasom-
RBD to uncover preclinical markers for neurodegeneration nias, periodic limb movement disorder)
Fiberoptic endoscopy and cephalometric radiographs of the cranial base and 7. Previous technically suboptimal home sleep study (2 nights of study
facial bones to locate site of the upper airway collapse, and to assess attempted)
posterior airway space in OSA patients 8. Previous 2-night home sleep study which did not diagnose OSA in a
• Miscellaneous tests: patient with ongoing clinical suspicion of OSA
Standard blood and urine analysis 9. Patient is oxygen dependent for any reason
Pulmonary function tests including arterial blood gases (ABGs) in cases 10. History of cerebrovascular accident (CVA) within the preceding 30 days
of suspected bronchopulmonary and neuromuscular disorders causing 11. History of ventricular fibrillation or sustained ventricular tachycardia
sleep-disordered breathing
EMG, Electromyography; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; MIB, metaiodobenzylguanidine; NYHA, New York
Heart Association; OSA, obstructive sleep apnea; RBD, REM sleep behavior disorder; RLS, restless legs syndrome.
required rather than a single-day nap study. A daytime single-nap such as microarousal episodes. The Rechtschaffen and Kales (1968)
study generally misses REM sleep, and the most severe apneic epi- technique of sleep scoring, despite limitations, remained the standard
sodes are noted during REM sleep. Maximum oxygen desaturation for sleep staging until the recent publication of the AASM Manual for
also occurs at this stage, so a daytime study cannot assess severity of the Scoring of Sleep and Associated Events (Iber et al., 2007). Ideally, sleep
symptoms. For CPAP titration, an all-night sleep study is essential. scoring should be performed manually; computerized scoring is unre-
To determine the optimal level of pressure during CPAP titration, liable. This manual also lists criteria for sleep and other event scoring
both REM and NREM sleep are required. In this section, the PSG in children older than 2 months of age. For newborn infants, the tech-
study is described under three headings: technical considerations, nique recommended by Anders et al. (1971) may be used. The follow-
indications for a PSG study, and characteristic PSG findings in var- ing terms are essential for sleep staging and scoring (Iber et al., 2007):
ious sleep disorders. • Total sleep period: time from sleep onset to final awakening.
• Total sleep time: total time spent between sleep onset and final
Technical Considerations awakening, excluding time spent awake during sleep time.
A PSG study includes simultaneous recording of various physiological • Sleep latency: time from lights-out to sleep onset.
characteristics, which allows assessment of sleep stages and wakeful- • REM sleep latency: time from sleep onset to the first REM sleep onset.
ness, respiration, cardiocirculatory functions, and body movements. • Sleep efficiency: ratio of total sleep time to total time in bed,
Sleep staging is based on EEG, electro-oculogram, and EMG of some expressed as a percentage.
skeletal muscles, especially chin muscles. Multiple EEG channels of • Sleep stages: NREM sleep stages and REM sleep, expressed as a per-
recordings are preferable to one or two channels for documentation of centage of total sleep time. NREM sleep is now divided into stage
focal and diffuse neurological lesions, accurate localization of epilepti- N1, stage N2, and stage N3 (slow-wave sleep); REM sleep is now
form discharges in patients with seizure disorders, and more accurate labeled as stage R.
determination of various sleep stages, awakenings, and transient events • Wake after sleep onset: time spent awake during total sleep period.
5. For the diagnosis of PLMD in adults, an index of 15 or more is sug-

BOX 101.30 Indications for Overnight
gested. Details on the technical aspects of PSG recording are beyond
Polysomnography the scope of this chapter.
• A polysomnography (PSG) study is routinely indicated:
• For the diagnosis of sleep-related breathing disorders Indications for Polysomnography
• For continuous positive airway pressure (CPAP) titration in patients with Box 101.30 lists the indications for overnight PSG proposed by the
sleep-related breathing disorders AASM (Kushida et al., 2005). These include diagnosis of SBD, posi-
• Before undergoing uvulopalatopharyngoplasty (UPPP) tive airway pressure titration in patients with SBD, follow-up treat-
• For assessment, the efficacy of mandibular advancement devices (MAD) ment to assess effectiveness in OSAS patients, preoperative procedure
for treatment of obstructive sleep apnea syndrome (OSAS) in patients undergoing upper airway surgery for OSAS, evaluation of
• To evaluate for parasomnias in patients with atypical features, semi- suspected narcolepsy, evaluation of atypical or violent parasomnias
ology, unusual or atypical or if the behaviors are violent or otherwise including RBD, and diagnosis of PLMD and nocturnal seizures.
potentially injurious to the patient or others
• To support the diagnosis of rapid eye movement sleep behavior disorder Polysomnographic Findings in Sleep Disorders
(RBD). Characteristic PSG findings in OSAS include recurrent episodes of
• An overnight PSG, preferably video-PSG with multiple channels of elec- apnea and hypopnea, which are mostly obstructive or mixed, and few
troencephalography (EEG), is indicated in patients suspected of having episodes of central apnea accompanied by oxygen desaturation and fol-
sleep-related epilepsy lowed by arousals with resumption of breathing (Chokroverty, 2010;
• A PSG study may be indicated for patients whose insomnia has not Chokroverty et al., 2015). An AHI score of 5 or below is considered
responded satisfactorily to a comprehensive behavioral or pharmacolog- normal. An AHI score of 5–15 may be considered evidence of mild
ical treatment program for the management of insomnia. However, if a OSAS, 16–29 as evidence of moderate OSAS, and 30 or more as evi-
sleep-related breathing disorder or associated periodic limb movements in dence of severe OSAS. Similarly, 85%–89% oxygen saturation may be
sleep (PLMS) is strongly suspected in a patient with insomnia, a PSG study found in mild OSAS, whereas in moderate OSAS, 80%–84% is typical,
is indicated. and in severe OSAS, 79% and below is the usual finding. An arousal
• A follow-up PSG is indicated: index of up to 10 is considered normal; 10–15 can be considered bor-
• When the clinical response is inadequate or when symptoms reappear derline. An arousal index above 15 is definitely abnormal. There are
despite a good initial treatment with CPAP some sleep architectural changes in OSAS (reduction of slow-wave and
• After substantial weight loss or weight gain, which may have occurred REM sleep); most of the sleep is spent in stage N2 sleep. Other findings
in patients previously treated successfully with CPAP. include short latency, increased time spent awake after sleep onset, and
• Overnight PSG followed by multiple sleep latency tests (MSLT) the next day excessive snoring. In patients with CSA syndrome, the apneas are all
is routinely indicated in patients with suspected narcolepsy. central. PSG findings in patients with Cheyne-Stokes breathing con-
• An overnight PSG is required in persons with suspected PLMS or PLM disor- sist of a characteristic crescendo-decrescendo pattern of breathing fol-
der but is not routinely performed to diagnose restless legs syndrome (RLS). lowed by apnea or hypopneas.
Video Polysomnographic Study

• Sleep cycles: number of sleep cycles, including REM cycles, during A video PSG study is important for documenting abnormal move-
total sleep period. ments and behavior during sleep at night in patients with parasom-
• Stage shifts: a change from one stage to another during NREM nias including RBD, nocturnal seizures (Fig. 101.69, A and B), and
sleep. other unusual movements occurring during sleep. Parasomnias are
• State shifts: a change from NREM to REM sleep or to wakefulness. generally diagnosed on the basis of the clinical history, but some-
• Arousal index: number of arousals per hour of sleep. times a video PSG study is required to document the condition. For
The PSG study should also include airflow, respiratory effort, con- suspected nocturnal epilepsy, a video PSG study using additional
tinuous recording of oxygen saturation by finger oximetry, an ECG electrodes to include multiple-channel EEG and multiple mon-
and muscle activity, particularly mental or submental and bilateral tages covering both parasagittal and temporal regions bilaterally
EMG recordings of the tibialis anterior muscles (Chokroverty et al., is required for optimal detection of epileptiform activities. Ideally,
2011). It is advantageous to record snoring and body positions. if sleep epilepsy is suspected, the video PSG recording should be
Thermistors or thermocouples are generally used to qualitatively interpreted using EEG analysis at the standard EEG speed of 30
record oronasal airflow, but these are not reliable for accurate deter- mm/sec to identify epileptiform discharges. Multiple EMG chan-
mination of hypopnea. Most laboratories now record nasal pressure nels to record from additional muscles (e.g., forearm flexor and
using a nasal cannula-pressure transducer, which is more sensitive extensor muscles, masseter and other muscles) are recommended
than a thermocouple or thermistor for detecting airflow limitation in patients with suspected RBD.
(Ayappa et al., 2000). Respiratory efforts can be recorded by use of
strain gauges or inductance plethysmography. Inductance plethys- Multiple Sleep Latency Test
mography and a piezoelectric strain gauge are the preferred meth- The MSLT is an important test to effectively document EDS.
ods; they can be used in a qualitative or semiquantitative fashion to Narcolepsy is the single most important indication for performing
monitor chest and abdominal movements. Intraesophageal balloon MSLT. The presence of two sleep-onset REMs on four or five nap
recording, an invasive method, accurately determines intrathoracic studies (a SOREMP in the preceding overnight sleep may substi-
pressure swings and is essential for documentation of UARS. EMG tute for one MSLT SOREMP) and sleep-onset latency of less than 8
recordings of the intercostal muscles using surface electrodes may minutes strongly suggest a diagnosis of narcolepsy (AASM, 2014).
also be helpful in determining respiratory effort. SDB events are Abnormalities of REM sleep regulatory mechanisms (e.g., OSAS,
recorded as an AHI or RDI score. PLMS are recorded from tibialis insufficient sleep syndrome, use of REM suppressant medications) or
EMG recordings. The PLMS index is expressed as the number of circadian rhythm sleep disturbance may also lead to REM sleep abnor-
PLMS per hour of sleep. The upper limit of the normal PLMS index is malities during MSLT.
Overnight PSG findings in patients with narcolepsy include short plus symptoms of sleep disturbance. A high PLMS index with arousal
sleep latency, excessive disruption of sleep with frequent arousals, is more significant than the index without arousal.
reduced total sleep time, excessive body movements, reduced slow- PSG findings in myopathies including Duchenne and other muscular
wave sleep, and SOREMs (seen in 40%–50% of patients). Some nar- dystrophies as well as myotonic dystrophy, may include sleep fragmenta-
coleptic patients may have associated sleep apneas, particularly central tion and disorganization; increased number of awakenings; reduced total
apneas. In approximately 9%–59% of patients, PLMS have been noted, sleep time; central, mixed, and upper airway obstructive apnea or hypo-
and in up to 36% of narcoleptic patients, RBD has been described pnea associated with oxygen desaturation; and nonapneic oxygen desat-
(Chokroverty, 2015). uration worsening during REM sleep. Similar findings may be noted in
PSG findings in MSA show a reduction of slow-wave, REM, and polyneuropathies or neuromuscular junctional disorders. In addition, in
total sleep time; increased sleep latency; increased number of awaken- painful polyneuropathies and neuromuscular conditions associated with
ings during sleep; absence of muscle atonia in REM sleep in those with muscular pain and cramps, a PSG study may show sleep-onset insomnia
RBD; and a variety of respiratory dysrhythmias. Similar but less intense and reduced sleep efficiency, and alpha-NREM sleep.
findings have been reported in patients with olivopontocerebellar atro- PSG findings in ALS may consist of central, mixed, or upper air-
phy (Chokroverty et al., 2015). way obstructive apnea and hypopnea and hypoventilation, particularly
In AD, the essential features of sleep architectural alterations are during REM sleep accompanied by oxygen desaturation and sleep
reduced total sleep time, decreased REM and slow-wave sleep, reduc- fragmentation.
tion of sleep spindles and K complexes, increased nighttime awak-
enings, and sleep fragmentation. There is a high incidence of sleep Maintenance of Wakefulness Test
apnea in those with AD compared to age-matched control subjects The maintenance of wakefulness test (MWT) is a variant of MSLT
(Chokroverty et al., 2015). In PD, a PSG study shows a variety of sleep measuring the subject’s ability to stay awake. It also consists of four
architectural changes: decreased sleep efficiency, increased awaken- to five trials of remaining awake recurring every 2 hours. Each trial
ings, sleep fragmentation, decreased REM and slow-wave sleep, reduc- is terminated if no sleep occurs after 40 minutes or immediately after
tion of sleep spindles, disruption of NREM-REM sleep cycling, PLMS, the first three consecutive epochs of stage 1 NREM sleep or the first
absence of muscle atonia, and presence of increasing EMG activities in epoch of any other stage of sleep (Littner et al., 2005). If the mean sleep
those presenting with RBD (Chokroverty et al., 2015). The characteris- latency is less than 8 minutes, it is then considered an abnormal test;
tic PSG findings in RBD consist of absence of muscle atonia and pres- values greater than this but less than 40 minutes are of uncertain signif-
ence of increased transient EMG bursts in the upper and lower limbs icance. There are no universally accepted normative data available. The
and cranially innervated muscles (during REM sleep). It is important MWT is less sensitive than the MSLT as a diagnostic test for narcolepsy
to record EMGs from both upper and lower limbs, because in some but is more sensitive in assessing the effect of treatment (e.g., CPAP
patients with RBD, EMG activities are present in the upper limbs but titration in OSAS and stimulant therapy in narcolepsy). The MWT
not in the lower limbs. 40-minute protocol is also indicated to assess an individual’s ability
In RLS, PSG findings document sleep disturbance and PLMS, to remain awake when his/her inability to remain awake constitutes a
which is found in at least 80% of patients. Diagnosis of PLMD is based public, occupational or personal safety issue.
on a PLMS index (number of PLMS per hour of sleep) of 15 and over,
F7–T3
T3–T5
T5–O1
F3–C3
C3–P3
P3–O1
F4–C4
C4–P4
P4–O2
F8–T4
T4–T6
T6–O2 100 3 seconds
µv
Chin EMG
A
F7–T3
T3–T5
T5–O1
F3–C3
C3–P3
P3–O1
F4–C4
C4–P4
P4–O2
F8–T4
T4–T6 100 1 second

µv
T6–O2
Chin EMG
B
Fig. 101.69 Portion of polysomnographic recording showing the onset of a partial seizure using (A) 10 mm/sec and (B) 30 mm/sec paper speed.
Twelve channels of electroencephalogram ([EEG] International Ten-Twenty electrode placement) and chin electromyogram are shown. Underlying
activity represents rhythmic ictal discharges beginning at F3-C3 (left frontocentral) and spreading rapidly to the right hemisphere, and it is accompa-
nied by clinical seizure. The underlying activity superficially resembles muscle artifacts at 10 mm/sec paper speed (A), but it is obvious at 30 mm/sec
paper speed (B) that this activity is the beginning of the rhythmic epileptiform discharges in the EEG. (Reproduced with permission from Aldrich, M.,
Jahnke, B., 1991. Diagnostic value of video-EEG polysomnography. Neurol. 41, 1060.)
Actigraphy documentation of seizures. If the results of the EEG recording, includ-

Actigraphy is another laboratory test for assessing sleep disorders. It ing long-term monitoring, and neuroimaging are discordant in local-
uses an actigraph (also known as an actometer) worn on the nondomi- izing the focus, or in making a diagnosis of seizure in a patient strongly
nant wrist or ankle to record acceleration or deceleration of body move- suspected to have it, the patient should be referred to a specialized epi-
ments (Fig. 101.70, A), which indirectly indicates sleep or wakefulness. lepsy center for intracranial recordings.
The actigraph can be worn for days or weeks, and this test comple-
ments a sleep log or diary in diagnosing circadian rhythm sleep disor- Neuroimaging Studies
ders and other primary sleep disorders such as insomnia and idiopathic Neuroimaging studies include anatomical and functional (physiolog-
hypersomnia (see Fig. 101.60, B) or assessing a patient’s treatment such ical) studies. These studies are essential when a neurological illness is
is in the case of a patient with AD with irregular sleep-wake disorder suspected of causing a sleep disturbance.
(see Fig. 101.70, C) and those with prolonged daytime sleepiness. In addition to computed tomography (CT) and magnetic resonance
imaging (MRI), which are important for detecting structural lesions of the
Special Electroencephalographic Studies in CNS (e.g., tumors, infarction, vascular malformations), cerebral angiogra-
Nocturnal Seizure phy—including digital subtraction arteriography and magnetic resonance
In addition to standard EEG recording, 24-hour ambulatory EEG angiography (MRA)—may be necessary in investigations for strokes.
recording and long-term video EEG monitoring may be needed for MRI is also helpful in patients with demyelinating and degenerative
weekend
(A) Normal sleep
weekend
weekend
(B) Insomnia
weekend
weekend
(C) Idiopathic hypersomnia
weekend
weekend
(D) DSPD
weekend
weekend
(E) ASPD
weekend
weekend
(F) N24HSWD
(Non-24-hour sleep)
weekend
weekend
(G) ISWR
weekend
9 15 19 23 7 13
Time of day
A B Current opinion in genetics and development
Fig. 101.70 The Application of Actigraphy in Sleep Medicine. (A) The Actigraph. Actigraphs are miniature computerized wristwatch-like devices that
measure limb activity, based on which sleep and wake periods can be indirectly calculated. Actigraphs help to determine whether sleep is insufficient
and to confirm sleepiness. (B) Actigraphy in Representative Sleep-Wake Disorders: Normal Sleep (A): Normal sleep in health patients with normal sleep
duration (7 hrs) and sleep regularity; Insomnia (B): Reduced ability to imitate and maintain sleep, despite sufficient opportunity for sleep; Idiopathic
Hypersomnia (C): uninterrupted sleep of long duration (≥11 hour/day); DSPD (Delayed Sleep phase disorder) (D): Stable delay of the habitual sleep
period; ASPD (Advanced Sleep phase disorder) (E): Stable advance of the habitual sleep period; N24HSWD (Non-24 Hour Sleep Wake Disorder)
(F): Chronic but stable delay of daily sleep and wake schedule by 1-2 hours; ISWR (Irregular Sleep-Wake Rhythm) (G): Absence of a clearly visible sleep-
wake circadian rhythm.
Continued
12:00 18:00 00:00 06:00 12:00
Mi
Do
Fr
Sd
So
Mo
Di
Mi
Do
Fr
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So
Mo
Di
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Do
Fr
Sa
So
Mo
Di
Mi
Do
Fr
Sa
So
Mo
Di
Mi
C
12:00 18:00 00:00 06:00 12:00

Mi
Do
Fr
Sa
So
Mo
Di
Mi
Do
Fr
Sa
So
Mo
Di
Mi
Do
Fr
Sa
So
Mo
Di
Mi
Do
Fr
Sa
So
Mo
Di
Mi
Do
Fr
Sa
So
Mo
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Mi D
Fig. 101.70 Cont’d (C) Actigraphy in the setting of Irregular sleep-wake rhythm prior to light therapy (C), depicting an irregular sleep onset and wakeup
time and establishing of a more regular rhythm following (D) light therapy (from the sun). The sleep period is indicated by white areas, and waking
period is indicated by black bars, while physiological body shifts and movements during sleep are indicated by a few black bars in the white areas.
(A, From Rowlands, A.V., Stiles, V.H., 2012. Accelerometer counts and raw acceleration output in relation to mechanical loading. J. Biomechan. 45 [3],
2; 448–454; B From Wulff, K., et al., 2009. Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Curr. Opin. Gen. Dev. 19
[3], 237–246; C, D, From Steinig, J., Klösch, G., Sauter, C., Zeitlhofer, J., Happe, S., 2007. Sleep Med. 8 [2], 184–185, Copyright © 2006 Elsevier B.V.).
neurological disorders that may be responsible for disturbed sleep and

BOX 101.31 Sleep Hygiene Measures
sleep-related breathing dysrhythmias. Other imaging studies which may
be helpful include diffusion tensor MR imaging, MR tractography, and Maintain a regular sleep-wake schedule, especially on weekends.
functional MRI (these are currently used mostly for research purposes). Avoid caffeinated beverages after lunch.
A PET study dynamically measures cerebral blood flow, oxygen Avoid tobacco compounds, especially in the evening.
uptake, and glucose utilization and is helpful in the diagnosis of dement- Avoid alcohol in the evening and bedtime.
ing, degenerative (e.g., PD and MSA), and seizure disorders. SPECT, Restrict time in bed awake
which dynamically measures regional cerebral blood flow, may be useful Adjust bedroom environment to be conducive to sleep (cooler temperature,
for patients with cerebrovascular disease, AD, or seizure disorders. PET dark, noise free)
and SPECT can also be performed to investigate dopamine D2-receptor Do not engage in any work planning the next day’s activities at bedtime.
changes in RLS-PLMS as well as narcolepsy and RBD, which may Exercise regularly for about 20–30 min in the afternoon.
also show reduced striatal presynaptic dopamine transporter uptake. Foods high in tryptophan and melatonin precursors may have a soporific effect
Functional MRI can be useful to study the generators and areas of acti- (i.e., tart cherry juice).
vation in RLS-PLMS. Doppler ultrasonography is an important test for Avoid exposure to blue light especially from computer, light emitting devices/
investigation of stroke due to extracranial vascular disease. Myelography tablets, TV, and other light emitting devices in the evening.
other than CT and MRI is important for diagnosis of spinal cord dis- Go to bed only when sleepy.
eases. Finally, meta-iodobenzylguanidine (MIBG) cardiac scintigra- Get out of bed if unable to fall asleep within 20 min and go to another room
phy may also show reduced cardiac uptake, and midbrain transcranial and either read something with low intensity light or listen to some light
sonography may show hyperechogenicity in RBD. relaxing music. Return to bed only when sleepy. Repeat this step as many
In selected patients, fiberoptic endoscopy may be performed to times as necessary throughout the night.
locate the site of collapse of the upper airway, and cephalometric Do not watch television, read, eat, worry, or stay awake while in bed.
radiographs of the cranial base and facial bones may be obtained to Remember the 3S for bedroom activities: sleep, sex, sickness.
assess posterior airway space or maxillomandibular deficiency. These Set an alarm clock to wake up at a fixed time each morning, including weekends.
are important when surgical treatment is planned. For research inves- Strategic naps during the day may consist of 15–20 minute “power naps” between
tigations, cross-sectional areas of the upper airway during wakefulness 1 and 3 pm, but longer naps that are outside of this time window are ill advised.
may be measured by CT and MRI (Korson and Guilleminault, 2015).
Pulmonary Function Tests

PRINCIPLES OF MANAGEMENT OF SLEEP DISORDERS
The principle of treatment of sleep disorders is first to find the cause
Other Laboratory Tests for sleep disturbance and vigorously treat the primary or comorbid
Appropriate laboratory tests should always be performed to exclude any condition causing it. If a satisfactory treatment is not available for the
suspected medical disorders that may be the cause of patients’ insom- primary condition or does not resolve the problem, then treatment
nia or hypersomnia. These tests may include blood analysis and urinal- should be directed at a specific sleep disturbance. It is beyond the scope
ysis, ECG, Holter ECG, echocardiogram, chest radiography, and other of this chapter to discuss the management of various neurological and
investigations to rule out gastrointestinal, pulmonary, cardiovascular, medical disorders causing sleep disturbance, and the reader is referred
endocrine, and renal disorders. In rare patients, when autonomic fail- to the standard texts. Some general sleep hygiene measures (Box
ure causes a sleep disturbance or SBD, autonomic function tests may 101.31) should apply to all sleep disorder patients. The treatment of
be required for the diagnosis of the primary condition. In patients with most commonly encountered sleep disorders is briefly discussed here.
narcolepsy, HLA typing may be performed because most of the patients
with narcolepsy show positivity for HLA DR2DQ1 and DQB1*0602 Treatment of Narcolepsy and Cataplexy
antigens (Mignot, 1998). Another important test is measurement of CSF Treatment of narcolepsy and cataplexy includes nonpharmacological
hypocretin 1 levels, which are found to be low (<110 pg/mL) in patients and pharmacological measures. Nonpharmacological measures include
with narcolepsy type 1 who are HLA DQB1*0602 positive (Mignot et al., scheduled short daytime naps, sleep hygiene measures, and periodic
2002). In patients with narcolepsy type 2 and in some other neurologi- attendance at narcolepsy support groups. For management of EDS,
cal conditions, CSF hypocretin may be low normal. In selected patients administration of a wake promoting agent such as armodafinil and
suspected of having a psychiatric cause of EDS, neuropsychiatric testing modafinil, and a stimulant such as methylphenidate, dextroamphet-
(e.g., the Minnesota Multiphasic Personality Inventory) may be helpful. amine, or methamphetamine is the treatment of choice. New treatment
In patients with RLS, EMG and nerve conduction studies are options include the selective histamine H3 receptor inverse agonist,
important to exclude polyneuropathies or lumbosacral radiculop- Pitolisant, which was recently approved to treat excessive sleepiness in
athies and other lower motor neuron disorders that may be associ- patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative
ated with RLS or cause symptoms resembling idiopathic RLS. Other with dopaminergic and noradrenergic activity is also a fairly new ther-
important laboratory tests in patients with RLS include those neces- apeutic option to treat EDS in NT1 and NT2. Modafinil, armodafinil
sary to exclude diabetes mellitus, uremia, anemia, and other associated (the R-isomer of racemic modafinil), sodium oxybates [sodium salt of
conditions. It is particularly important to obtain levels of serum iron gamma-hydroxybutyrate (GHB)] and solriamfetol. (Thorpy, 2020).
(including serum ferritin and transferrin), serum folate, fasting blood Methylphenidate may also be used based on data indicating a signifi-
glucose, blood urea, and creatinine. In a subgroup of patients with cant improvement of EDS and sleep attacks can be obtained. Treatment
RLS, serum iron and ferritin levels are found to be low; it is import- of cataplexy or other auxiliary symptoms of narcolepsy depends on the
ant to measure these because correction of these abnormalities may severity and/or frequency of the episodes. For cataplexy, treatments with
improve the condition. The role of nerve biopsy remains controversial. tricyclic antidepressants (e.g., protriptyline, imipramine, clomipramine)
In the vast majority of patients, a nerve biopsy is not necessary, but and SSRIs such as fluoxetine are used with success. In some patients,
it may be obtained for research purposes and when there is a strong viloxazine, a combined SSRI and norepinephrine reuptake inhibitor, has
suspicion of polyneuropathy. been useful when other drugs have failed. Pitolisant, Sodium oxybate and
Pulmonary function tests exclude the presence of intrinsic bronchopul- disorders causing dysfunction of the metabolic respiratory control-
monary disease, which may affect SBD. Pulmonary function tests may lers, as well as in patients with obesity-hypoventilation (Pickwickian)
include assessment of ventilatory functions (forced expiratory volume syndrome.
in 1 second [FEV1], forced vital capacity [FVC], the FEV1:FVC ratio,
peak expiratory flow rate, and forced expiratory flow rate), measure- Electrodiagnosis of Respiratory Muscles
ment of lung volumes (total lung capacity, residual volume, and func- EMG recordings of the upper airway and diaphragmatic and intercos-
tional residual capacity), gas distribution and gas transfer, and arterial tal muscles may detect changes in these muscles in various neurolog-
blood gases (Po2 and Pco2). Respiratory muscle function of individuals ical diseases. A laryngeal EMG recording may detect laryngeal paresis
with neuromuscular disorders should be specifically assessed, and it is in patients with MSA with laryngeal stridor. A phrenic nerve and inter-
important to measure the maximal static inspiratory and expiratory costal nerve conduction study may detect phrenic and intercostal
pressures. Finally, chemical control of breathing (hypercapnic and neuropathy, which may cause diaphragmatic and intercostal muscle
hypoxic ventilatory responses) may be needed to assess respiratory changes in some patients with neurological disorders.
functions and control systems in patients with various neurological
BOX 101.32 Drug Treatment of BOX 101.33 Treatment of Upper Airway

Narcolepsy—Types I and II Obstructive Sleep Apnea Syndrome
Drugs Used for Management of Excessive Sleepiness in the General Measures
Setting of Narcolepsy Avoid alcohol and sedative-hypnotics, especially in the evening
Modafinil (Provigil)* 200 mg/day, up to a maximum of 400 mg/day Reduce body weight if overweight
Armodafinil (Nuvigil): *,† start with 75 mg/day and increase if needed to 150 Avoid sleep deprivation
mg/day (maximum 250 mg/day) Participate in regular exercise program
**Sodium oxybate (Xyrem): 3–9 g in two divided doses, first dose at bedtime Avoid supine sleeping position
and second dose up to 2–4 h later (*) Treat nasal congestion/allergies
**Calcium, magnesium, potassium, and sodium oxybates (Xywav): 3–9 g in two
divided doses, first dose at bedtime and second dose up to 2–4 h later.‡ Mechanical Devices
Methylphenidate (Ritalin): 5 mg in the morning and another day at noon, with a Continuous positive airway pressure (CPAP) titration
maximum dose of 50 mg/day and rarely 100 mg/day; may need to combine Bilevel positive airway pressure titration
regular and extended release medication Auto-CPAP
Dextroamphetamine (Dexedrine): 5 mg bid, up to 50 mg/day Mandibular advancement devices (MAD, also known as oral appliances),
Methamphetamine (Methedrine): 5 mg bid, up to 50 mg/day including various mandibular advancement devices
Solriamfetol (Sunosi): 75–150 mg/day in the morning Tongue-retaining device
Pitolisant (Wakix): 9–36 mg/day in the morning
(*) Only formal approval for treatment of pediatric patients aged 7–17 years Surgical Techniques
with narcolepsy Weight loss surgery (bariatric surgery/gastric bypass surgery)
Uvulopalatopharyngoplasty (UPPP)
Drugs Used to Treat Cataplexy and Other Auxiliary Symptoms Radiofrequency UPP (somnoplasty)
Sodium oxybate (Xyrem): 3–9 g in two divided doses, first dose at bedtime and Nasal surgery
second dose up to 2–4 h later (*) Maxillomandibular advancement
Venlafaxine (Effexor): Initiate at 37.5 mg/day bid with usual dose (75–100 mg bid) Anterior hyoid advancement
Fluoxetine (Prozac): 20 mg/day, up to a maximum of 80 mg/day Tonsillectomy and adenoidectomy (pediatric obstructive sleep apnea )
Sertraline (Zoloft): 50 mg/day. Usual dose (50–150 mg), Maximum dose: 200 mg Tracheostomy (under rare circumstances)
Protriptyline (Vivactil): 5–10 mg/day TID/BID, Maximum dose: 30 mg/day Neurostimulators
Clomipramine (Anafranil): 5 0 mg/day 75–125 mg/day, Maximum dose: 250 mg/day Upper airway stimulation system
Hypoglossal nerve stimulator
* Half-life approximately 15 h, reduces efficacy of steroidal oral contra-
ceptives, can cause serious rashes and allergic reactions.
† Armodafinil is the longer-acting isomer of modafinil (R-(-)-modafinil).
** Indicated in the management of cataplexy or excessive daytime procedures (Box 101.33). The general measures include avoidance of
sleepiness (EDS) in patients with narcolepsy ages seven and older. alcohol, particularly in the evening, and of sedatives and hypnotics,
‡ Adults may be initiated dosage at 4.5 g per night orally, divided into
because these agents aggravate SBD. Lifestyle modification of critical
two doses at night and titrated to effect in increments of up to 1.5 g per importance include measures weight loss through diet, exercise and
night per week with the recommended dosage range at 6 g to 9 g per bariatric surgery for people with high BMI, avoidance of sleep depri-
night orally. For patients 7 years and older, the recommended starting vation, and avoidance of supine sleeping position.
pediatric dosage, titration regimen, and maximum total nightly dosage
are based on patient weight. Prescribers are encouraged to review the Pharmacological Treatment
product information profile https://www.xywavhcp.com and https://pp.
jazzpharma.com/pi/xywav.en.USPI.pdf for specific recommendations. Pharmacological therapy remains unsatisfactory (Morgenthaler et al.,
2006); in very mild cases, partial relief has been obtained with pro-
calcium, magnesium, potassium, and sodium oxybate, are indicated for triptyline and medroxyprogesterone, but these drugs are generally
the treatment of cataplexy as well as daytime sleepiness (Thorpy, 2020; not used today. There have been isolated reports of the use of SSRIs
Wakix (pitolisant) [prescribing information], 2020; Xyrem (sodium oxy- in mild cases and topical nasal corticosteroids for OSAS in children,
bate) [prescribing information], 2021.). Sodium oxybates acts as a hyp- with minimal benefit. In a subset of OSAS patients on adequate CPAP
notic and consolidates REM and slow-wave sleep. Because of its short titration complaining of residual daytime sleepiness, armodafinil
half life, sodium oxybates have to be given in two divided nightly doses at or modafinil, a novel wake-promoting agent, has been useful as an
bedtime and 2.5–4 hours later. Pitolisant is a histamine 3 receptor antag- adjunct treatment.
onist/inverse agonist which activates histamine release in the brain and
decreases excessive daytime sleepiness and cataplexy rates. Solriamfetol, Positive Airway Pressure (PAP) Therapy
is a dopamine and norepinephrine reuptake inhibitor with activity medi- The devices useful for OSAS (Kushida et al., 2006a) include nasal CPAP
ated through its inhibition of dopamine/norepinephrine reuptake. In with or without expiratory pressure relief, bilevel positive airway pres-
refractory cases of narcolepsy-cataplexy, a combination of drugs may sure (BPAP), and auto-CPAP and auto-BPAP titration. The treatment
have to be given. Box 101.32 lists the medications for treatment of nar- of choice for moderate to severe OSAS patients is CPAP titration,
colepsy-cataplexy. The treatment of idiopathic hypersomnia is similar to which is effective in more than 70% of cases. CPAP acts as a pneu-
the stimulant treatment of narcolepsy, but the therapeutic response is less matic splint, opening the upper airway passages and thereby eliminat-
satisfactory supporting that it is a different disease entity than narcolepsy. ing obstructive apneas, hypoxemias, snoring, and sleep fragmentation.
The optimal pressure for CPAP must be determined during an over-
Treatment of Obstructive Sleep Apnea Syndrome night PSG recording. Some patients may require BPAP titration, which
The treatment of upper airway OSAS consists of general mea- delivers a higher pressure during inspiration and a lower pressure
sures, pharmacological therapy, mechanical devices, and surgical during expiration. A regular follow-up visit, particularly shortly after
recommending CPAP treatment, is essential for good adherence. The during sleep by stimulating the genioglossus muscle. Activation of
unit must be used regularly during nightly sleep. The goal of treatment this muscle via stimulation of the hypoglossal nerve is a creative new
is to improve quality of life and prevent life-threatening complications approach for treatment of OSA (Strollo, 2014).
such as cardiac arrhythmias, congestive heart failure, pulmonary and Severe respiratory compromise or severe apnea associated with
essential hypertension, strokes, and cognitive impairment. Recently, dangerous cardiac arrhythmias creating a life-threatening situation
auto-CPAP machines that automatically titrate pressure according to may require emergency tracheostomy.
detected abnormal breathing events have been introduced. The role of
these devices remains to be determined. Despite using a 2-cm reduc- Treatment of Cheyne-Stokes Breathing
tion in mean pressure compared to fixed-pressure CPAP, there is so far and Central Sleep Apnea
no benefit in increasing adherence with auto-CPAP. In patients with CSA, including Cheyne-Stokes breathing associated with heart fail-
neuromuscular disorders, intermittent positive-pressure ventilation ure, requires aggressive treatment of heart failure (e.g., beta-block-
through a nasal mask may be needed to treat sleep hypoventilation or ers, digoxin, diuretics) and, if needed, heart transplant. Measures
apnea. to improve ventilation include CPAP or BiPAP titration, oxygen
administration, and gas modulation with inhaled carbon dioxide
Alternative to PAP Therapy through the nasal mask as well as administration of theophylline
Non-PAP therapy is beneficial in carefully selected patients who are and acetazolamide. Acetazolamide has been found to be useful in
not compliant with PAP or in patients with mild to moderate disease Cheyne-Stokes breathing associated with high altitude. CPAP titra-
who refuse CPAP therapy. Mandibular advancement devices (dental tion was thought to improve the mortality in patients with heart fail-
devices) appliances (Kushida et al., 2006b) can reduce snoring and ure, but a recent large-scale Canadian study (Bradley et al., 2005)
help patients control mild to moderate sleep apnea but predicting showed no improvement in mortality, although there was improve-
which patients will respond to a particular treatment is not always ment in ejection fraction and other measures; a later reanalysis of
predictable. Upper airway surgery for sleep apnea (such as uvulopal- the data supported the usefulness of CPAP in heart failure. Another
atopharyngoplasty, UPPP) has been proposed and utilized for years. treatment that has been found to be useful in patients with Cheyne-
Unfortunately, as of 2021, uniform consensus regarding the role of Stokes breathing and CSA is adaptive servo ventilation (Randerath
surgery in people with sleep apnea is lacking. This is most likely due and Javaheri, 2015; Philippe et al., 2006; Randerath et al., 2009). The
to the various sleep apnea phenotypes, varying degrees of severity role of this treatment measure in terms of long-term benefit remains
and anatomical collapse, and the lack of consistent screening and to be determined (Randerath, 2012).
objectively verifiable indicators to predict success (Epstein et al.,
2009). In children with OSAS, tonsillectomy and adenoidectomy Treatment of Insomnia
have been successful if not curative in most cases (Overland et al., The first step in the treatment of insomnia is an assessment of the
2021). Upper airway stimulation improves upper airway patency type of insomnia (see eBoxes 101.6 and 101.10 and Box 101.9) and
TABLE 101.8 Classification of Central Disorders of Hypersomnolence

ICSD-III Alternate Names Cataplexy Hypocretin Sleep Studies HLA Titers
Narcolepsy type 1 Hypocretin deficiency Yes Hcrt-1 ≤110 pg/mL or 1/3 of Mean MSLT SL ≤8 min with ≥2 HLA DQB1*0602 positiv-
syndrome, narcolepsy- normal mean values SOREMPs (1 may be on prior PSG) ity= 100% (except in
cataplexy, narcolepsy with narcolepsy type 1 due
cataplexy to medical condition)
Narcolepsy type 2 Narcolepsy without No Hcrt-1 >110 pg/ml or 1/3 of Mean MSLT SL ≤8 min with ≥2 HLA DQB1*0602 posi-
cataplexy normal mean values SOREMPs (1 may be on prior PSG) tivity= 25% (except in
In the absence of cataplexy, if narcolepsy type 1 due
measured at ≤110 pg/mL or to medical condition)
1/3 of normal mean values,
reclassify as narcolepsy type 1
Idiopathic hyper- Idiopathic CNS hypersom- No Hcrt-1 >110 pg/mL or 1/3 of MSLT shows (1 of 2):
somnia nolence normal mean values <2 SOREMPs on MSLT or no
SOREMPs on prior PSG where
REM latency ≤ 15 minutes
AND.
The presence of one of the following:
(a) MSLT shows mean sleep
latency of ≤ 8 minutes.
(b) Total 24-h sleep time ≥660 min
on 24-h monitoring by PSG (after
correction of sleep deprivation)
or wrist actigraphy averaged over
7 days with unrestricted sleep
CNS, Central nervous system; HLA, human leukocyte antigen; ICSD, International Classification of Sleep Disorders; MSLT, multiple sleep latency
test; PSG, polysomnographic; SOREMP, sleep-onset rapid eye movement (REM) period.
Adapted from American Academy of Sleep Medicine. 2014. International Classification of Sleep Disorders, third ed. American Academy of Sleep
Medicine, Darien, IL.
TABLE 101.8A Currently Approved Hypnotic for the Management for Insomnia (Approval as
of February, 2021)
Class of
Hypnotic and Most Common Side Pregnancy
Name Doses (mg) Half-life (h) Indications Effects DEA Class Category
Benzodiazepine Immediate Release
Flurazepam 15, 30 48–120 “Treatment of insomnia characterized Dizziness, drowsiness, IV X
(Dalmane) by difficulty in falling asleep, lightheadedness, staggering,
frequent nocturnal awakenings, loss of coordination, falling
and/or early morning awakening”
Temazepam 7.5, 15, 22.5, 30 8–20 “Short-term treatment of insomnia” Drowsiness, dizziness, IV X
(Restoril) lightheadedness, difficulty
with coordination
Triazolam (Halcion) 0.125, 0.25 2–4 “Short-term treatment of insomnia” Drowsiness, headache, IV X
dizziness, lightheadedness,
“pins and needles” feelings
on your skin, difficulty with
coordination
Quazepam (Doral) 7.5, 15 48–120 “Treatment of insomnia characterized Drowsiness, headache IV X
by difficulty in falling asleep,
frequent nocturnal awakenings,
and/or early morning awakenings”
Estazolam (Prosom) 1, 2 8–24 “Short-term management of insomnia Somnolence, hypokinesia, IV X
characterized by difficulty in dizziness, abnormal
falling asleep, frequent nocturnal coordination
awakenings, and/or early morning
awakenings, administered at
bedtime improved sleep induction
and sleep maintenance”
Nonbenzodiazepine Immediate Release

Zolpidem (Ambien) 5, 10 1.5–2.4 “Short-term treatment of insomnia Drowsiness, dizziness, IV C
characterized by difficulties with diarrhea, drugged feelings
sleep initiation”
Zaleplon (Sonata) 5, 10 1 “Short-term treatment of insomnia, Drowsiness, lightheadedness, IV C
shown to decrease the time to dizziness, “pins and needles”
sleep onset” feeling on your skin, difficulty
with coordination
Eszopiclone 1, 2, 3 5–7 “Treatment of insomnia… Unpleasant taste in mouth, dry IV C
(Lunesta) administered at bedtime decreased mouth, drowsiness, dizzi-
sleep latency and improved sleep ness, headache, symptoms of
maintenance” the common cold
Nonbenzodiazepine Extended Release

Zolpidem ER 6.25, 12.5 2.8–2.9 “Treatment of insomnia characterized Headache, sleepiness, IV C
(Ambien CR) by difficulties with sleep onset and/ dizziness
or sleep maintenance (as measured
by wake time after sleep onset)”
Nonbenzodiazepine Alternate Delivery

Zolpidem 5, 10 ∼2.5 “Short-term treatment of insomnia Drowsiness, dizziness, IV C
Oral spray characterized by difficulties with diarrhea, drugged feelings
(Zolpimist) sleep initiation”
Zolpidem 5, 10 ∼2.5 “Short-term treatment of insomnia Drowsiness, dizziness, IV C
Sublingual (Edluar) characterized by difficulties with diarrhea, drugged feelings
sleep initiation”
Zolpidem 1.75, 3.5 ∼2.5 “As needed for the treatment of Headache, nausea, fatigue IV C
Sublingual insomnia when a middle-of-the-
(Intermezzo) night awakening is followed by
difficulty returning to sleep”
TABLE 101.8A Currently Approved Hypnotic for the Management for Insomnia (Approval as
of December 2019)—cont’d
Class of
Hypnotic and Most Common Side Pregnancy
Name Doses (mg) Half-life (h) Indications Effects DEA Class Category
Selective Melatonin Receptor Agonist

Ramelteon (Roz- 8 1–2.6 “Treatment of insomnia characterized Drowsiness, tiredness, None C
erem) by difficulty with sleep onset” dizziness
Selective Histamine H1 Receptor Antagonist

Doxepin (Silenor) 3, 6 15.3 “Treatment of insomnia characterized Somnolence/sedation, nausea, None C
by difficulties with sleep mainte- upper respiratory tract
nance” infection
Hypocretin (Orexin) Receptor Antagonist

Suvorexant (Bel- 5, 10, 15, 20 12 “Treatment of insomnia, characterized Somnolence, depression, rare IV C
somra) by difficulties with sleep onset and/ but possible risk of REM
or sleep maintenance” intrusion phenomena.
Lemborexant 5, 10 17–24 h Treatment of insomnia, characterized Somnolence, headache, and IV C
by difficulties with sleep onset and/ sleep paralysis
or sleep maintenance”
TABLE 101.8B Currently Approved Hypnotic for the Management for Insomnia: (Approval as
of December 2019)
Sleep with Limited Required
Agent Initiates Sleep Maintains Sleep Opportunity inactivity (hr) Dose (mg)
Eszopiclone √ √ 8+ 1, 2, 3
Zaleplon √ √ 4 5, 10
Zolpidem √ 7–8 5, 10
Extended release √ √ 7–8 6.25, 12.5
Sublingual zolpidem (Intermezzo) √* √ 4 1.75, 3.5
Oral spray zolpidem (Zolpimist) √ 4 5, 10
Sublingual zolpidem for sleep initiation (Edluar) √ 4 5, 10
Ultra-low-dose doxepin (Silenor) √ 7–8 3, 6
Ramelteon (Rozerem) √ — 8
Suvorexant (Belsomra) √ √ 7–8 5, 10, 15 and 20
Lemborexant √ √ 7–8 5, 10
*Provided that 4 additional hours of sleep/time in bed are available. Currently available hypnotics agents: Drug selection is based on the timing of
the insomnia (i.e., sleep initiation, sleep maintenance): age, gender, history of drug abuse behavior and comorbidities. Benzodiazepine modulators,
H1 receptor antagonists, and melatonin agonists. The reader is advised to review US Food and Drug Administration bulletins about these agents,
especially regarding dose adjustments in unique cohorts (i.e., susceptible individuals such as women and older adults) paying close attention to the
development of adverse effects. Physicians’ desk reference 2014.
treatment of comorbid conditions associated with it (see eBoxes 101.11 effects, the older drugs are used infrequently now. The most frequently
and 101.12). Treatment should be broadly divided into two classes: used newer benzodiazepine receptor agonists include zolpidem (reg-
pharmacological and nonpharmacological. ular and controlled-release), zaleplon, and eszopiclone. Melatonin
receptor agonists (e.g., ramelteon) may also be used for sleep-onset
Pharmacological Treatment insomnia. Patients who do not respond to these medications may be
Hypnotic medication used judiciously is the mainstay of treatment for given benzodiazepines, especially intermediate-acting (e.g., temaze-
acute, transient, or short-term insomnia. This treatment should last pam). Ultra-low-dose doxepin, a histamine H1 receptor antagonist,
for a few nights to a maximum of 4 weeks. The most commonly used has also received FDA approval for the treatment of chronic sleep ini-
hypnotics are the benzodiazepine receptor agonists, which act on the tiation and maintenance insomnia.
GABAA receptor complex. In the past, benzodiazepines were mostly For chronic insomnia, nonpharmacological measures combined
used, but because of their side effects and the availability of newer non- with judicious use of hypnotics are the best treatment. Intermittent
benzodiazepine receptor agonists with shorter half-lives and fewer side use of hypnotics is particularly useful for patients with chronic primary
TABLE 101.9 Neurodegenerative Conditions and their Associated Sleep Disorder

Amyloidopathy Synucleinopathy Tauopathy TDP-43-opathy
Alzheimer disease Parkinson disease Frontotemporal dementias ALS
Lewy body dementia Progressive supranuclear palsy Frontotemporal dementia (FTLD-U)
Multiple system atrophy Corticobasal degeneration
Insomnia Insomnia None characteristic (all possible, but ALS: SDB
Circadian rhythm changes Excessive somnolence tend to be less prominent)
Somnolence later REM sleep behavior disorder
ALS, Amyotrophic lateral sclerosis; REM, rapid eye movement.
TABLE 101.10 Cognitive and Behavioral Therapy for Insomnia

Sleep Restriction Excessive time spent in bed; fragmented Therapist instructs patient to curtail the time in bed to the actual sleep time. The time in
sleep bed is subsequently adjusted based on sleep efficiency. Time in bed can be increased
by 15–20 min/wk if sleep efficiency is >85% and decreased if sleep efficiency is <80%.
Daytime sleepiness is a potential side effect of this behavioral therapy, which may
impact adherence
Stimulus Control Therapy Excessive time spent in bed; fragmented Therapist instructs patient to curtail the time in bed to the actual sleep time. The time in
sleep bed is subsequently adjusted based on sleep efficiency. Time in bed can be increased by
15–20 min/week if sleep efficiency is >85% and decreased if sleep efficiency is <80%.
Daytime sleepiness is a potential side effect of this behavioral therapy, which may
impact adherence. Improve sleep continuity by limiting time spent in bed awake.
Relaxation Techniques High physiologic, cognitive, or emotional The goal of relaxation therapy is to reduce arousal at bedtime or on nighttime awakening
hyperarousal by reducing somatic tension using progressive muscle relaxation or intrusive thoughts
such as imagery training, meditation.
Sleep Hygiene Behaviors that undermine good quality sleep Encourage habits that promote sleep, provide rationale for subsequent instructions.
target inadequate sleep hygiene (e.g., Sleep hygiene education includes guidelines about health practices (e.g., diet, exercise,
irregular bed and wake time, caffeine and substance abuse) and environmental factors (e.g., light, noise, temperature) that may
alcohol before bedtime, excessive naps, promote or interfere with sleep
watching TV in bed). Excessive time awake
in bed, irregular sleep–wake schedules,
hyperarousal and activities incompatible
with sleep
Cognitive Therapy Unrealistic sleep expectations, misconcep- The goal of cognitive therapy is to modify dysfunctional sleep cognitions (such as changing
tions about sleep, anxiety associated with faulty beliefs and attitudes about sleep). Reduce arousal and decrease anxiety (progres-
sleep anticipation, and poor cognitive sive muscular relaxation, transcendental meditation, yoga, biofeedback). Facilitate the
coping skills development of more rational thoughts about sleep and the consequences of sleep loss.
CBTi is a structured program that helps patients with insomnia identify and replace thoughts and behaviors known to cause or exacerbate insomnia
with habits that promote sound sleep. The program is most effective when supervised and coached by a sleep psychologist. The table summarizes
the specific technique, the abnormal insomnia behavior that the technique targets, and the overall goal.
Adapted from Bootzin, R.R., Perlis, M.L., 1992. Nonpharmacologic treatments of insomnia. J Clin Psychiatry 53(suppl), 37–41 [Evidence Level C];
Hauri, P.J., 1998. Insomnia. Clin Chest Med 19, 157–168 [Evidence Level C].
and psychophysiological insomnia or when the patient does not the insomnia is associated with psychosis. Many patients with chronic
respond adequately to nonpharmacological measures. The efficacy of insomnia use over-the-counter medications (e.g., diphenhydramine,
non-nightly use (e.g., 3–5 nights/week) has been proven in some clin- melatonin, valerian). These medications have some hypnotic proper-
ical trials, but further studies are needed to confirm the usefulness of ties, but there are many side effects and the long-term effects are not
this approach (Hajak, 2006). Hypnotic medications in general should known; therefore, their use should be discouraged. Orexin/hypocre-
be discouraged for chronic insomnia. Hypnotic use is contraindicated tin antagonists, suvorexant, and lemborexsant are available to manage
in pregnancy and should also be avoided or used judiciously in patients both sleep onset and maintenance insomnia and may have utility in
with alcoholism or renal, hepatic, or pulmonary disease. Hypnotics managing insomnia in the setting of Alzheimer dementia. Table 101.8
should be avoided in patients with sleep apnea syndrome. Sedative lists the pharmacological agents used to treat insomnia.
antidepressants (e.g., trazodone, amitriptyline, doxepin, mirtazap-
ine) have been used in patients with insomnia comorbid with depres- Nonpharmacological Treatment
sion, but double-blind placebo-controlled studies to understand the Nonpharmacological measures should be the mainstay of treatment
effectiveness of these drugs have not been undertaken. The newer for chronic insomnia and consists of sleep hygiene measures, stimulus
antipsychotics that have hypnotic properties (e.g., olanzapine, que- control, sleep restriction, relaxation, and cognitive therapies. A com-
tiapine, risperidone) should not be used in chronic insomnia unless bination of all these measures constitutes cognitive behavioral therapy
(Table 101.10). Sleep hygiene measures are simply some common-

BOX 101.34 Nonpharmacological
sense steps to address both homeostatic and circadian factors (see Box
Treatment of Restless Legs Syndrome 101.31). Stimulus control therapy is directed at discouraging learned
General sleep hygiene measures (see Box 101.31) associations between bedroom and wakefulness and re-establishing the
Avoid the following: bedroom as the major stimulus for sleep. These techniques have been
Caffeine and caffeinated beverages reported to improve insomnia complaints in approximately 50% of
• Smoking (tobacco compounds) individuals after 1 year.
• Alcohol Relaxation therapy includes progressive muscle relaxation; biofeed-
• Antidepressants (e.g., tricyclic antidepressants, selective serotonin back may be added to reduce somatic arousal. Sleep restriction therapy
reuptake inhibitors, venlafaxine), exception is bupropion is based on the principle that restricting total sleep time in bed may
• Antihistamines (especially over-the-counter sleep aids that may contain improve sleep efficiency. Total sleep time is then gradually increased to
these compounds) improve the level of daytime function and overall sleep quality. Some
• Dopamine antagonists (e.g., most antipsychotics, antiemetics, some 25% of patients with insomnia benefit from such a regimen. The best
calcium channel blockers) nonpharmacological approach has not been established, but cognitive
• Sleep deprivation behavioral therapy is associated with the most sustained improvement
Encourage the following: in sleep (Morin and Benca, 2015; Morin et al., 1999). Recent data sup-
• Mild to moderate exercise port the use of a novel forehead temperature-regulating device that
• Vibratory stimulation pads promotes improvement in insomnia supported by PSG measures of
• Physical activity (e.g., leg stretching) and massaging legs before bedtime the patients’ ability to fall asleep by delivering frontal cerebral thermal
• Hot bath 2–3 h before bedtime or cold compresses (in some patients) therapy. The therapy utilizes frontal cerebral hypothermia therapy at
• Remain mentally engaged 14–16°C, equivalent to 57–61°F) with a benign safety profile, and may
TABLE 101.11 Pharmacological Treatment of Restless Leg Syndrome

Generic/Brand Dose Risks
Iron
Ferrous sulfate 325 mg BID/TID GI side effects: constipation. Role in treatment under current inves-
Recommended for Ferritin < 75 μg tigation
Dopamine Agonists
Pramipexole* 0.125–0.5 mg, 1.5–2 hr before bedtime. Augmentation, rebound, impulse control behaviors, sleepiness,
Ropinirole* 0.25–2 mg 1.5–2 h before bedtime (+) nausea reported in some cases, headaches, dizziness. Hypoten-
Rotigotine patch* 1–3 mg applied QD sion, hallucinations. Application site allergic reaction (specific to
rotigotine)
Dopamine Precursor Agents

Levodopa/Carbidopa (Sinemet) 25/100 mg: 1/2 tab-3 tabs 30 min before bedtime Nausea, sleepiness, augmentation of daytime symptoms, insomnia,
sleepiness, gastrointestinal disturbances. Not recommended to be
used chronically due to significant risks of augmentation. May be
useful when used intermittently, in an “on demand” pattern
Alpha-2-Delta Ligands
Gabapentin (Neurontin) 300–2700 mg/day initially in the evening, later Excessive daytime sleepiness, nausea, headache, dizziness
divided if needed for daytime symptoms
Gabapentin Enacarbil* 300–600 mg Q5PM
Pregabalin 50–300 mg in the evening
Benzodiazepines
Clonazepam 0.125–0.5 mg at bedtime Nausea, sedation, dizziness; caution in sleep apnea patients because
of depressing effects on breathing and upper airway muscles
Central Alpha-2 Adrenergic Agonist

Clonidine (Catapres) 0.1 mg BID Dry mouth, drowsiness, constipation, sedation, weakness, depres-
May be helpful in patients with hypertension sion (1%), hypotension
Opioids
Darvocet (Darvocet-N) 300 mg/day Nausea, vomiting, restlessness, constipation. Addiction, tolerance
Darvon (Propoxyphene) 65–135 mg at bedtime may be possible
Codeine, methadone; also oxycodone 30 mg/day
*FDA-indicated as of February, 2021
BOX 101.35 First-Line Medication and Treatment Consideration in Newly Diagnosed Restless
Legs Syndrome
α2δ ligands as suggested as first-line therapy given the lack of augmentation, which
is problematic in the setting of dopamine agonists. Gabapentin Enacarbil may be Attributes to Consider Treatment Choice
preferred as long-term studies have not been performed with gabapentin in restless Impaired renal function Select a drug that is not renally
legs syndrome (RLS) and absorption is variable, thereby complicating dosing. excreted or reduce dose of renally
If dopamine agonists are used the treatment should keep dopaminergic load as excreted drugs (pramipexol, α2δ
low as possible with regular screening for augmentation. ligand)
The clinician should also weigh in the following factors in selecting the appro- Increased risk of falls Dopamine-receptor agonist (DA)
priate medication: Painful restless legs α2δ ligand
RLS with comorbid pain syndrome α2δ ligand
Attributes to Consider Treatment Choice History of impulse control disorder α2δ ligand
Time of day (daytime symptoms) Select a long-acting agent, or Twice-a- History of alcohol or substance abuse DA agonist or α2δ ligand
day dosing of a short-acting agent Very severe symptoms of RLS DA
Sleep disturbance disproportionate to α2δ ligand Obesity, metabolic syndrome DA
other symptoms of RLS e.g., severe Availability or cost of drug DA or α2δ ligand
insomnia Comorbid depression CA
Comorbid insomnia α2δ ligand Comorbid generalized anxiety disorder α2δ ligand
Pregnancy risk Avoid both DAs and α2δ ligands Higher potential for drug interactions Select drug that is not hepatically
Consider the use of iron metabolized (pramipexol, gabapentin
enacarbil)
Symptomatic periodic limb Dopamine-receptor agonist
movements in sleep
Adapted from Garcia-Borreguero, D., Silber, M.H., Winkelman, J.W., Hogl, B., Bainbridge, J., Buchfuhrer, M., et al., 2016. Guidelines for the first-
line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force
of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep. Med. 21, 1–11. https://doi.org/10.1016/j.sleep.2016.01.017: Garcia-Borreguero, D.,
Kohnen, R., Silber, M.H., et al., 2013. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and
clinical consensus best practice guidance: a report from the international restless legs syndrome study group. Sleep Med. 14(7), 675–684; Silber,
M.H., Becker, P.M., Earley, C., Foundation Medical Advisory Board of the Willis-Ekbom Disease, 2013. Willis-Ekbom disease foundation revised
consensus statement on the management of restless legs syndrome. Mayo Clin. Proc. 88(9), 977–986; Silber, M.H., Krahn, L.E., Morgenthaler,
T.I., 2010. Sleep Medicine Clinical Practice, second ed. Informa Healthcare, London.
be suggested to complement existing therapies for the treatment of Due to the risk of augmentation, the most appropriate initial treat-
chronic insomnia (Roth et al., 2018). ment in most cases is an alpha 2 delta agent or perhaps a dopamine
agonist provided that dopamine load is kept low and augmentation is
Treatment of Restless Legs Syndrome-Periodic screened for regularly (Garcia-Borreguero et al., 2016). In mild cases,
Limb Movements in Sleep one may start with nonpharmacological measures with or without
Both pharmacological and nonpharmacological measures are used to additional gabapentin or pregabalin. In patients who are intractable, a
treat RLS (Hening et al., 2009; Wijemanne and Jankovic, 2015). In a combination of two or three drugs may have to be used. The principle
mild case, nonpharmacological measures (Box 101.34) may be the of treatment is to start at the lowest possible dose and then increase
only treatment needed, and these should also be used in combination by one tablet every 5–7 days until maximum benefit is reached or side
with medications in moderate to severe cases. Nonpharmacological effects are noted. Medication is generally given 1.5–2 hours before bed-
treatments include sleep hygiene measures (see Box 101.31), avoid- time. Depending on the timing of symptoms, the medication may have
ance of sleep deprivation, and avoidance of agents that trigger or to be given in two divided doses—for example, early in the evening
aggravate RLS (e.g., caffeine, alcohol, smoking, antihistamines, neu- and later at bedtime. In some severe cases, when daytime symptoms
roleptics, tricyclic antidepressants, SSRIs and other antidepressants, are present, a daytime dose may be added; however, symptoms should
certain antinausea medications). A hot bath or leg massage at bed- be differentiated from augmentation, which is a drug-related exacerba-
time and mild to moderate exercise may also be helpful, particularly tion of symptoms noted mostly with carbidopa-levodopa but also seen
in mild cases. with other dopamine agonists (Chokroverty, 2011b). In many idio-
Pharmacological treatment (Table 101.11) includes four groups pathic RLS patients, serum iron or ferritin levels may be low; appropri-
of drugs (Garcia-Borreguero et al., 2013): dopaminergic agents (e.g., ate treatment with ferrous sulfate combined with ascorbic acid, which
carbidopa-levodopa and dopamine agonists such as pramipexole, promotes iron absorption, is recommended. Box 101.35 lists specific
ropinirole, and rotigotine parch), benzodiazepines (e.g., clonazepam, recommendations in mild or intermittent, moderate, and severe cases.
temazepam), anticonvulsants (e.g., gabapentin, gabapentin enacarbil, In most cases RLS can be treated medically, but when the symptoms
pregabalin), and opiates (e.g., codeine, propoxyphene, oxycodone, are severe and disabling despite optimal medical therapy deep brain
hydrocodone, methadone). Rotigotine, a nonergoline dopaminergic stimulation targeting the globus pallidus may be considered as a very
agent delivered through a transdermal patch—ensuring continuous last resort (Ondo et al., 2012).
delivery over 24 hours, sustaining a near-constant blood level—has Nonpharmacological therapy for RLS has been reviewed and may
been FDA approved in addition to pramipexole, ropinirole, and gab- include exercise later in the day, repetitive transcranial magnetic stim-
apentin enacarbil for treatment of moderate to severe primary RLS. ulation, compression devices, and counterstrain manipulation, which
TABLE 101.12 Pharmacological and were significantly more effective for RLS severity than control con-
ditions. However, other modes including vibration pads, yoga, cryo-
Nonpharmacological Treatment of Disorders
therapy, compression devices, and acupuncture may have some role in
of Arousal improving sleep-related outcomes but may be more limited in RLS per
Parasomnia Treatment se. (Harrison et al., 2019) (Video 101.15).
Somnambulism (sleep Safeguard the sleep environment and protect
Treatment of Circadian Rhythm Sleep Disorder
walking) the patient
Avoid precipitants:
The most effective treatment for DSPS is exposure to bright light
Sleep deprivation
(5000–10,000 lux). The patient sits in front of the light for about
Lithium
30 minutes in the morning; in addition, the room light must be
Nonbenzodiazepine receptor agonists.
reduced in the evening to achieve the desired result. Melatonin at
Anticipatory awakenings
bedtime has also been used in combination with bright light ther-
Benzodiazepines
apy in these patients. Chronotherapy (intentional delay of sleep
Clonazepam (0.5–1 mg)
onset by 2–3 hours on successive days until the desired bedtime has
Diazepam (10 mg)
been achieved) is helpful in many patients with DSPS, at least in the
Triazolam (0.25 mg)
beginning. In ASPS, bright light therapy may be given in the eve-
Imipramine (50–300 mg)
ning, and light must be restricted in the morning. Melatonin has also
Confusional arousal Reassurance of benign nature
been found to be useful in some subjects with jet lag and shift-work
Avoid precipitants:
sleep disorders, as well as in patients with circadian rhythm disorder,
Sleep deprivation
free-running type (non-24-hour circadian rhythm disorder). Jet lag
Alcohol
and shift-work sleep disorder may also be treated with zolpidem or
CNS depressants
the melatonin receptor agonist, ramelteon. Armodafinil (sustained
Escitalopram (10 mg)—for sexsomnia
action) or modafinil has been approved for shift-work sleep disorder
Sleep terrors Reassurance of benign nature
to treat excessive sleepiness.
Cognitive Behavior Therapy
Treatment of Parasomnias
Paroxetine (20–40 mg)
Clonazepam (0.5–1 mg)
Most parasomnias require no special treatment. Preventive measures
Sleep-related eating disorder Topiramate
to protect patients from injuring themselves or others should be insti-
Pramipexole (when comorbid with RLS
tuted in patients with partial arousal disorders and REM behavior dis-
[WED])
order. If attacks of sleepwalking or sleep terrors are frequent or violent,
treatment with a tricyclic antidepressant or small doses of benzodiaze-
CNS, Central nervous system; RLS, restless legs syndrome. pine (e.g., clonazepam) may be used for a short period (Table 101.12).
TABLE 101.13 Pharmacological Treatment of REM Sleep Behavior Disorder

Drug* Dose Level of Recommendation Special Considerations
Melatonin 3–12 mg before bedtime (regular Suggested† Effective in patients with alpha-synucleinopathies, memory
formulation) or 5-15 mg (sustained problems, and sleep-disordered breathing.
release) Side effects include headaches, sleepiness, and delusions/
hallucinations.
Clonazepam 0.25–2.0 mg before bedtime (usual Suggested† Use with caution in patients with dementia, gait disorders,
recommended dose is 0.5–2.0 mg) or concomitant OSA.
Side effects include sedation, impotence, motor incoordina-
tion, confusion, and memory dysfunction.
Zopiclone 3.5–7.5 mg before bedtime May be considered†† Side effects include rash and nausea.
Yi-Gan San 2.5 mg tid May be considered†† Studied mainly on patients that could not take clonaze-
pam. No side effects were reported when used for the
treatment of RBD.
Sodium oxybate Unknown May be considered††
Donepezil 10–15 mg May be considered††
Rivastigmine 4.5–6 mg bid. May be considered†† Studied mainly on patients with dementia of Lewy body.
Temazepam 10 mg May be considered††
Alprazolam 1–3 mg May be considered††
Desipramine 50 mg qhs May be considered††
Carbamazepine 500–1500 mg qd May be considered††
*Not FDA approved for the treatment of RBD.
†Supported by sparse high-grade evidence data, or a substantial amount of low-grade data and/or clinical consensus.
††Supported by low-grade data.
Adapted from Aurora, R.N., Zak, R.S., Maganti, R.K., et al.,2010. Committee Standards of Practice, and Medicine American Academy of Sleep,
2010. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 6(1), 85–95.
Video 101.15 Willis-Ekbom Disease Foundation Revised Consensus The restlessness is often present the entire night. (Kryger MH, Avidan,
Statement on the Management of Restless Legs Syndrome. (From AY, Berry, R. Atlas of clinical sleep medicine. Second edition. ed.
Silber, M.H., Becker, P.M., Earley, C., et al., 2013. Mayo Clinic Proceed- Philadelphia, PA: Elsevier/Saunders; 2013)
ings, 2013-09-01, 88[9], 977–986, Copyright © 2013 Mayo Foundation Video 101.19 Pediatric Sleep Surgery. (From Cory, R.M., 2019. Atlas
for Medical Education and Research.) of the Oral and Maxillofacial Surgery Clinics of North America. 27[1],
Video 101.16 Explaining the Results It is extremely important that 67–75. © 2018.)
the patient understand the results of the sleep test. An effective way Video 101.20 Seventy-year-old male patient with a 15-year history
of accomplishing that is to show the patient the actual study and the of Parkinson disease, severe depression, and longstanding RBD
synchronized digital video. This is often a “teachable moment” that can displaying marked episodes of laughter during REM sleep. The fol-
have a great effect on the patient but also is likely to improve CPAP lowing morning, he reported a dream of a funny conversation with
compliance and motivate the patient to deal with comorbidities.(From his former boss. Episodes of laughter contrasted with his severe
Kryger, Kryger MH, Avidan, AY, Berry, R. Atlas of clinical sleep medi- hypomimia and depressive mood during daytime. (From Siclari,
cine. Second edition. ed. Philadelphia, PA: Elsevier/Saunders; 2013) F., Wienecke, M., Poryazova, R., Bassetti, C.L., Baumann, C.R., 2011.
Video 101.17 A 58-Year-Old Man With Position-Dependent Noctur- Laughing as a manifestation of rapid eye movement sleep behavior dis-
nal Dyspnea Nocturnal video polysomnography showing the patient order. Parkinsonism Relat. Disord. 17[5], 382–385. Copyright © 2011
with central sleep apnea/Cheyne-Stokes respiration causing moderate Elsevier Ltd.)
oxygen desaturations in the left lateral position and central sleep apnea/ Video 101.21 Ictal Bruxism Treated with Temporal Lobectomy
Cheyne-Stokes respiration with central apneas followed by a greater (From Marc, G., Cecile, V.E., Antonio, D., Javier, A., Xavier, S., Núria, B.,
degree of desaturation in the right lateral position during the second et al., 2015. Ictal bruxism treated with temporal lobectomy. Sleep Med.
part of the video. (From Schertel, A., Horvath, C.M., Hefti, J.P., Aubert, 16[11], 1429–1431.Copyright © 2015 Elsevier B.V.)
J.D., Brill, A.K., 2017. Chest, 152[2], e51–e55. Copyright © 2017 Amer- Video 101.22 Familial Idiopathic Rapid Eye Movement Sleep Behav-
ican College of Chest Physicians.) ior Disorder (From Aurélie, P.J., Annie, L., Isabelle, A., 2016. Familial
Video 101.18 A 12-Year-Old Boy with Sleep Apnea and Restless idiopathic rapid eye movement sleep behavior disorder. Sleep Med. 30,
Sleep This 12-year-old boy came to medical attention with restless 29–30, Copyright © Elsevier 2016.)
sleep, a common presentation of sleep apnea in children of all ages.
benefit sleep in some patients. Antihistamines such as diphenhydr-

BOX 101.36 Treatment of Sleep
amine may promote sleep in addition to the modest antiparkinsonian
Disturbance in Alzheimer Disease and effect. A small dose of carbidopa-levodopa, with a second dose later
Related Dementias at night when the patient awakens, may sometimes help those with
General Measures insomnia. Nocturnal dyskinesias related to levodopa causing insom-
Reduce or eliminate medications that may contribute to sleep disturbance or nia may respond to a reduction in the dose of dopamine agonists or
sleep apnea the addition of a small dose of a benzodiazepine. In patients with psy-
Treat associated depression or anxiety chosis and severe nocturnal hallucinations, clozapine or newer drugs
Eliminate alcohol or caffeine in the evening such as olanzapine may be used with considerable benefit. During
Institute regular sleep/wake schedule and sleep hygiene clozapine treatment, the usual precautions of monitoring blood cell
Avoid excessive daytime naps count and testing liver function should be taken. Patients with PD
Encourage regular exercise (e.g., walking) associated with RBD should be treated with a small dose of clonaze-
Attend to environmental factors pam or melatonin. Patients with PD with OSAS associated with oxy-
Timed exposure to bright light in the evening and in the morning may be helpful gen desaturation and repeated arousals should be treated with CPAP
titration. In some patients with insomnia, judicious short-term use
of hypnotics may be recommended. Some patients with PD showing
the phenotype of narcolepsy with EDS not associated with OSAS may
Most cases of RBD respond dramatically to a small dose of clonaz- be treated with a small dose (100 mg in the morning) of modafinil or
epam (e.g., 0.5–2 mg at night). For patients who do not respond to armodafinil (150 mg in the morning). This is, however, an off-label
clonazepam, melatonin or pramipexole may be tried. In resistant cases, indication.
a combination of clonazepam and melatonin may be useful. A recent
practice guideline published by the AASM has provided some consen-
sus in approaching RBD therapy, listing the data for both clonazepam
CONCLUSION
and melatonin as primary agents for this disorder with level B evidence In conclusion, an explosive growth in sleep medicine and increasing
of therapy and safety measures (removal of sharp objects from the bed- awareness about the importance of sleep in everyday life has pro-
room area as level A evidence) (Aurora et al., 2010) (Table 101.13). pelled the topic of sleep to the forefront of neuroscience. It is more
important than ever for all physicians, particularly neurologists and
Treatment of Sleep Dysfunction Associated with Neuro- general practitioners, to take sleep medicine seriously and gain a basic
logical Disorders understanding and adequate knowledge of this discipline as it applies
Treatment of neurological disorders associated with insomnia, SBD, cir- to clinical practice. This chapter has attempted to give an overview
cadian rhythm sleep disorders, and parasomnias should follow the pre- of the science of sleep to stimulate physicians to be familiar with
viously outlined principles of treatment. For the treatment of patients sleep medicine. Sleep deprivation at night related to either lifestyle
with AD and related dementias associated with sleep disturbance, cer- habits or sleep disorders is associated with increasing morbidity and
tain general measures, as outlined in Box 101.36, should be instituted. mortality, and it is time for the medical profession to recognize and
For nocturnal agitation and sundowning, the patient should be treated not neglect this silent epidemic. Many sleep disorders remain undi-
with antipsychotics including the newer agents (haloperidol, 0.5–1.5 agnosed and underdiagnosed, but effective treatment is available to
mg; thioridazine, 10–100 mg; risperidone, 1–1.5 mg; olanzapine, 5–10 prevent short- and long-term adverse consequences. This chapter has
mg; quetiapine, 12.5–100 mg). Depression is often an important fea- outlined approaches to a patient with sleep complaints and methods
ture in patients with AD, so a sedative-antidepressant may be helpful. to diagnose and treat these disorders. Sleep/wake generating neurons
Frequency of urination in such patients may result from infection or are located within the CNS, and patients with neurological illnesses
enlarged prostate and may disturb sleep at night. Appropriate measures are particularly susceptible to sleep/wake dysfunction. Because sleep
should therefore be taken in such conditions. In some patients, timed may adversely affect neurological disorders, it is especially incum-
exposure to bright light in the evening may improve nighttime sleep. bent upon neurologists to have a basic understanding of sleep and its
Sleep has not been consistently improved in patients with PD fol- disorders, which may encroach upon almost every aspect of neurol-
lowing antiparkinsonian medications. In those patients with reacti- ogy in clinical practice.
vation of parkinsonian symptoms during sleep at night, adjustment
in the timing and choice of medication may be helpful. Dopamine The complete reference list is available online at https://expertconsult.
agonists or longer-acting preparations of levodopa at bedtime may inkling.com/.
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102
Headache and Other Craniofacial Pain
Ivan Garza, Carrie E. Robertson, Jonathan H. Smith, Mark A. Whealy
OUTLINE
Pain Transmission and Modulation as Related to Headache, 1745 Headaches and the Cervical Spine, 1755
Classification, 1745 Medication Overuse Headache, 1756
Secondary Headaches, 1746 Primary Headaches, 1757
Headache Attributed to Nonvascular, Noninfectious Intracranial Migraine, 1757
Disorders, 1746 Chronic Daily Headache, 1769
Headaches Due To Elevated Intracranial Pressure, 1747 Cluster Headache, 1770
Headache Attributed to Low Cerebrospinal Fluid Pressure, 1749 Other Trigeminal Autonomic Cephalalgias, 1774
Headache Attributed to Trauma or Injury to the Head and/or Other Primary Headaches, 1775
Neck, 1750 Other Headaches and Facial Pains, 1777
Headache Attributed to Infection, 1750 Neck-Tongue Syndrome, 1777
Headache Attributed to Cranial or Cervical Vascular Disorders, Painful Trigeminal Neuropathy, 1778
1751 Persistent Idiopathic Facial Pain, 1778
Headache Associated With Disorders of Homeostasis, 1754 Cranial and Facial Neuralgias, 1778
Headache Caused by Disorders of the Cranium, Neck, Eyes, Headache in Children and Adolescents, 1781
Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Migraine and Migraine Variants, 1782
Structures, 1755

PAIN TRANSMISSION AND MODULATION AS innervation of this compartment is by the second and third cervical
nerve roots, which also supply the back of the head. However, poste-
RELATED TO HEADACHE rior lesions or cervical spine pathological conditions may also produce
Headache arises from activation of pain-sensitive intracranial struc- frontal headache, because the caudal portion of the trigeminal nucleus
tures. In the 1930s, Ray and Wolff identified which intracranial com- extends down as far as the dorsal horn at the C3 level. Impulses arriv-
ponents were pain sensitive and mapped the pattern of pain referral ing from C2 to C3 converge on neurons within the trigeminal nucleus
based on studies in which various intracranial structures were stim- and may refer pain to the somatic distribution of CN V.
ulated during intracranial surgery performed during local anesthesia. Afferent pain impulses into the trigeminal nucleus are modulated
Intracranial pain-sensitive structures include the arteries of the circle by descending facilitatory and inhibitory input from brainstem struc-
of Willis and the first few centimeters of their medium-sized branches, tures, including the periaqueductal gray matter, rostral ventromedial
meningeal (dural) arteries, large veins and dural venous sinuses, and medulla, locus ceruleus, and dorsal raphe nuclei. Opioids diminish
portions of the dura near blood vessels. More recent data from patients pain perception by activating the inhibitory systems, whereas fear,
during awake craniotomies also suggest that, contrary to prior belief, anxiety, and overuse of analgesics may activate the facilitatory systems,
the pia mater and small cerebral vessels are pain-sensitive (Fontaine thereby aggravating pain.
et al., 2018). Pain-sensitive structures external to the skull cavity
include the external carotid artery and its branches, scalp and neck
CLASSIFICATION
muscles, skin and cutaneous nerves, cervical nerves and nerve roots,
mucosa of sinuses, and teeth. Cranial nerves (CN) V, VII, IX, and X, In 1988, the Headache Classification Committee of the International
in addition to cervical spine nerve/nerve roots, carry pain from these Headache Society introduced a detailed classification of headaches.
structures. This has been subsequently revised, most recently in 2018, into what
Trauma, inflammation, traction, compression, malignant infil- is now the International Classification of Headache Disorders 3rd edi-
tration, and other disturbances of pain-sensitive structures lead to tion (ICHD-3) (Headache Classification Committee of the International
headache. Superficial structures tend to refer pain locally, whereas Headache Society [IHS], 2018). Its four main parts include: (1) primary
deeper-seated lesions may refer pain imprecisely. A purulent maxil- headaches, (2) secondary headaches, (3) painful cranial neuropathies,
lary sinus, for example, causes pain over the involved sinus, whereas other facial pain, and other headaches, and (4) appendix (Box 102.1).
within the cranial vault, nociceptive signals reach the central nervous Secondary headaches are those in which head pain is a symptom of an
system (CNS) largely by way of the first division of the trigeminal nerve underlying disease affecting pain-sensitive structures, while in primary
(CN V), so an occipital lobe tumor may refer pain to the frontal head headache disorders head pain occurs in the absence of such disease.
region. Infratentorial lesions tend to refer pain posteriorly because The purpose of the appendix in the ICHD-3 is to present research
1745
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in all electronic versions of this book.
publication.
with headache presence at onset (Russo et al., 2018). Progressive head-

BOX 102.1 Classification of Headache
aches (i.e., those with increases in intensity, frequency, and duration
Disorders of pain) can be due to worsening of cerebral edema, the presence of
Part One: The Primary Headaches midline shift, and hydrocephalus. Factors that increase the risk of brain
1. Migraine tumor–related headaches include a personal history of a primary head-
2. Tension-type headache ache disorder and younger age at diagnosis (Valentinis et al., 2010).
3. Trigeminal autonomic cephalalgias Although headache is typically not an isolated symptom at the time
4. Other primary headache disorders of brain tumor diagnosis, not uncommonly it can be the first and most
severe symptom that the patient experiences (Valentinis et al., 2010).
Part Two: The Secondary Headaches In a prospective study of 211 patients with brain tumors, headache
5. Headache attributed to trauma or injury to the head and/or neck was the most frequent initial manifestation of the tumors (22% of
6. Headache attributed to cranial and/or cervical vascular disorder the patients) and headache was the sole presenting symptom in 19%
7. Headache attributed to nonvascular intracranial disorder (Valentinis et al., 2010). In a series of 527 adults with glioma, 12.5%
8. Headache attributed to a substance or its withdrawal indicated headache as a presenting symptom of their disease (Russo
9. Headache attributed to infection et al., 2018).
10. Headache attributed to disorder of homeostasis There is wide variation in the characteristics of headaches attributed
11. Headache or facial pain attributed to disorder of the cranium, neck, eyes, to intracranial tumors. Most commonly, such headaches are consid-
ears, nose, sinuses, teeth, mouth, or other facial or cervical structure ered “nonclassifiable,” meaning that their phenotype does not meet
12. Headache attributed to psychiatric disorder the phenotypic characteristics of a primary headache disorder such as
migraine or tension-type headache (Valentinis et al., 2010). A head-
Part Three: Painful Cranial Neuropathies, Other Facial Pain, ache phenotype that is “nonclassifiable” is followed in frequency by
and Other Headaches headaches that resemble tension-type headache and then migraine
13. Painful lesions of the cranial nerves and other facial pain (Valentinis et al., 2010). Specifically in gliomas, however, tension-type
14. Other headache disorders headache was the most common phenotype (47% of cases) in a recent
series (Russo et al., 2018). Most brain tumor headaches are felt bilater-
Part Four: Appendix
ally and are described as causing a pressure sensation. There is substan-
From Headache Classification Committee of the International tial variability in the frequency, duration, and specific location of pain.
Headache Society (IHS). 2018. The International Classification of The location of headache pain does not reliably predict the location of
Headache Disorders, third ed. Cephalalgia 38 (1), 1–211. https://doi. the underlying brain tumor (Valentinis et al., 2010).
org/10.1177/0333102417738202. Rapidly growing tumors are more likely to produce headache
than indolent lesions, but slowly enlarging lesions can eventually pro-
criteria for multiple entities that have not been sufficiently validated. If duce pain by compromising the ventricular system or exerting direct
better scientific data become available, some of these may move to the pressure on a pain-sensitive structure. When the CSF circulation is
main body of the classification in future revisions (IHS, 2018). Careful partially obstructed, resulting in high intracranial pressure (ICP),
definition of migraine subtypes and other primary headache disorders headache is often worse when supine, aggravated by coughing, strain-
has helped rid research and clinical publications of the confusing and ing, and Valsalva, and is often associated with nausea and vomiting.
often poorly defined terminology of earlier work. When tumors interfere with CSF flow and cause periodic increases
in ICP, the periods of elevated ICP may correlate with increasing
SECONDARY HEADACHES headache severity, vomiting, decreased consciousness, or a change in
respiration.
Headache Attributed to Nonvascular, Noninfectious Tumors growing in the ventricular system are rare, but they can
Intracranial Disorders manifest dramatically. The classic presentation of a colloid cyst of the
Intracranial lesions that occupy space, or “mass lesions,” produce head third ventricle is a sudden headache of great severity, rapidly accompa-
pain by traction on or compression of pain-sensitive veins, venous nied by nausea and vomiting and sometimes by loss of consciousness.
sinuses, arteries, cranial nerves, and possibly by causing inflammation Intraventricular meningiomas, choroid plexus papillomas, and other
around pain-sensitive structures in the head (Obermann et al., 2011). intraventricular tumors can present in this manner if they suddenly
The nature, location, and temporal profile of headache produced by obstruct the ventricular outflow pathways. A positional change may
an intracranial mass depend on many factors, including lesion loca- precipitate such an event; similarly, adoption of a different posture may
tion, rate of growth, effect on cerebrospinal fluid (CSF) pathways, and rapidly relieve the headache and other symptoms. Colloid cysts of the
any associated cerebral edema. The intracranial mass lesion may be third ventricle generally lead to slowly enlarging hydrocephalus that
neoplastic, inflammatory, or cystic. Mass lesions can result in either may result in a generalized and constant headache with superimposed
localized or generalized head pain. episodes of catastrophic increases in headache intensity. Headaches
that have a rapid onset and/or are associated with loss of consciousness
Tumors should lead the examiner to seek a secondary cause.
The estimated prevalence of headache in patients with brain tumors Infiltrating tumors such as gliomas can reach considerable size
(see Chapters 71 and 74) varies from 50% to 70%. The likelihood of without causing pain, because they may not deform or stretch the
developing headache is probably mediated by the tumor size, type, pain-sensitive vessels and nerves. Such lesions are more likely to pres-
and location, and on patient age and personal history of a preceding ent with focal neurological symptoms or with seizures rather than
headache disorder (Obermann et al., 2011; Valentinis et al., 2010). headache. Sudden worsening of the neurological state due to hemor-
Infratentorial tumors and intraventricular tumors might be more likely rhage into the tumor may present with sudden headache. Infarction of
to cause headache than supratentorial tumors. In gliomas, specifically, a tumor can cause edema and swelling that result in a similar dramatic
infratentorial and right-sided tumors are more frequently associated onset of head pain and neurological deficit.
publication.
CHAPTER 102 Headache and Other Craniofacial Pain 1747
Tumors that are intracranial but extraparenchymal (e.g., menin- consciousness, and increasing neurological deterioration. Slowly
gioma, acoustic neuroma, pinealoma, craniopharyngioma) and developing hydrocephalus may result in massively dilated ventricles
pituitary tumors can all produce headaches, but the clinician must and may be associated with little or no headache.
carefully consider whether the headaches and these tumors are caus- Congenital obstruction of the foramina of Luschka and Magendie
ally related or coincidental. When headaches are truly associated with (the Dandy-Walker syndrome) can lead to ballooning of the fourth ven-
these tumors, there are no specific headache patterns. Headaches can tricle and deformity of the cerebellum. Minor degrees of this malforma-
be near the lesion, referred to a more distant site in the cranium, or tion can remain asymptomatic until later in life and then manifest with
generalized when ICP increases. A family history of primary headaches obstructive hydrocephalus and headache. Similarly, the Chiari malfor-
and cavernous sinus invasion appear to be risk factors for headaches mation can obstruct free circulation of CSF and lead to hydrocephalus
associated with pituitary nonfunctioning adenomas (Yu et al., 2017). and headache and can cause symptoms via direct compression of the
Meningiomas and meningeal sarcomas can invade the skull and even brainstem by herniated cerebellum (Graxzzi and Andrasik, 2012). This
cause a mass externally by direct tumor spread or by overlying hyper- malformation can result in an occipital-suboccipital headache worsened
ostosis. Such tumors are often associated with localized head pain. or even initiated by a Valsalva maneuver during lifting, straining, or
Meningeal carcinomatosis (carcinomatous meningitis) produces a coughing. Thus, the Chiari malformation is one of the causes of an exer-
headache in most subjects, but the associated cranial nerve involve- tional or Valsalva maneuver–induced headache and cough headache.
ment and other neurological symptoms are generally more striking. Other symptoms of Chiari malformation include visual phenomena
The headache associated with other intracranial mass lesions such (e.g., wavy lines, flashing lights, scotoma), blurred vision, photophobia,
as cerebral abscess and intracranial granuloma is no more specific than dizziness, disequilibrium, pressure in the ears, tinnitus, decreased hear-
that due to a cerebral neoplasm. ing, nystagmus, dysphagia, and dysarthria. Other symptoms might be
Features that should serve as warnings that a patient’s headaches present if there is concurrent spinal cord syrinx. The clinician must be
may not be of benign origin and that raise the possibility of an intra- careful to differentiate between mild cerebellar tonsillar descent, a con-
cranial mass lesion are: subacute and progressive; new onset in adults; dition that is unlikely to cause symptoms, and a true Chiari malforma-
change in pattern; associated with nausea or vomiting; nocturnal or tion, a condition that can be associated with headache.
upon awakening in the morning; precipitated or worsened by changes In communicating hydrocephalus, free communication exists
in posture or Valsalva maneuver; associated with confusion, seizures, between the ventricular system and the subarachnoid space, but CSF
weakness, and/or abnormal neurological examination. circulation or absorption is impaired. Obstruction in the basal cisterns
or at the arachnoid granulations may follow subarachnoid hemorrhage
Syndrome of Transient Headache and Neurological Deficits and meningitis. Venous sinus occlusion can impair absorption of CSF.
With Cerebrospinal Fluid Lymphocytosis Headache may be a prominent symptom of both obstructive and
Although originally termed “migrainous syndrome with CSF pleo- communicating hydrocephalus, except in the case of normal-pressure
cytosis,” several later reports used various terms, including headache hydrocephalus, which is generally painless (see Chapter 86).
with neurological deficits, CSF lymphocytosis, and pseudomigraine
with temporary neurological symptoms and lymphocytic pleocy- Idiopathic Intracranial Hypertension
tosis. This self-limited syndrome consists of one to several episodes Idiopathic intracranial hypertension (IIH) is a condition of increased
of variable neurological deficits accompanied by moderate to severe intracranial pressure which typically manifests with papilledema and
headache and sometimes fever. Each episode lasts hours, with total headaches and has no identifiable cause.
duration of the syndrome being from 1 to 70 days. CSF abnormali- Symptoms and signs. In recent years, the IIH treatment trial
ties have included a lymphocytic pleocytosis varying from 10 to more (IIHTT) has extensively expanded the available data on this condition
than 700 cells/mm, elevation of CSF protein, and in some patients, (Friedman et al., 2014; Smith and Friedman, 2017). Analysis of
elevated opening pressure. MRI and CT are normal in the vast major- clinical profiles at baseline confirmed previous observations that IIH
ity of reported cases. Some patients may have evidence of gray-matter is almost exclusively a disease of obese young women. The mean age
swelling or hemispheric hypoperfusion (Quintas et al., 2018; Yilmaz was 29.0 years, 97.6% were women, and the average body mass index
et al., 2010). Results of microbiological studies are usually negative. was 39.9 kg/m2 (Wall et al., 2014). Headache was the most common
The cause of the syndrome is unclear, although an immune response initial symptom reported at study entry, followed by visual loss,
to a viral infection is speculated. No treatment alters the self-lim- pulsatile tinnitus, and diplopia, in that decreasing order. Frequency
ited course of this disorder. In contrast to this syndrome, episodes of most common symptoms at study entry was: headache in 84%,
of Mollaret meningitis (see Chapters 76 and 103) are separated by transient visual obscurations in 68%, back pain in 53%, and pulse
months to years and are typically not accompanied by focal neuro- synchronous tinnitus in 52% of patients. The headaches in IIH can
logical symptoms. be constant, daily, or intermittent and may or may not be classifiable
according to phenotypes of primary headaches. In the IIHTT, the most
Headaches Due To Elevated Intracranial Pressure common headache phenotypes were migraine in 52% and tension-
Lesions that prevent free egress of CSF from the ventricular system type headache in 22% of patients, with the rest not fulfilling complete
result in obstructive hydrocephalus. If this occurs before closure of the criteria for other primary headaches. Visual obscurations are a direct
cranial sutures, enlargement of the skull occurs, usually without pro- result of raised ICP leading to papilledema, while diplopia most often
ducing headache. Ventricular obstruction after closure of the sutures results from a lateral rectus palsy. Only 32% reported visual loss in the
leads to raised ICP and often to headache. The pain is often worse on IIHTT (Wall et al., 2014).
awakening, occipital in distribution, and associated with neck stiffness. Evaluation. Most IIH patients have papilledema, which should
Vomiting, blurred vision, and transitory obscuration of vision due to not be confused with pseudopapilledema (e.g., drusen). An
papilledema may follow, as well as failing vision due to optic atrophy. ophthalmologist should be involved in the diagnostic evaluation
Rapidly developing obstruction due to a posterior fossa mass lesion to confirm this and assess threat to vision if papilledema is present.
or a ball-valve tumor, such as a third ventricular colloid cyst, can One of the most common errors in diagnosing IIH is inaccurate
lead to a rapidly increasing headache followed by vomiting, impaired ophthalmoscopic examination (Fisayo et al., 2016). Brain
publication.
TABLE 102.1 Idiopathic Intracranial TABLE 102.2 Secondary “Pseudotumor

Hypertension Diagnostic Criteria Cerebri”
IIH Cerebral Venous Abnormalities
A. Papilledema • Cerebral venous sinus thrombosis
B. Normal neurological exam (except 6th cranial nerve palsy) • Bilateral jugular vein thrombosis or surgical ligation
C. Neuroimaging: normal brain parenchyma, venous thrombosis excluded. • Middle ear or mastoid infection
D. Normal CSF constituents • Increased right heart pressure
E. Elevated lumbar puncture pressure >25 cm • Superior vena cava syndrome
• Arteriovenous fistulas
IIH Without Papilledema (IIHWOP) • Decreased CSF absorption from previous intracranial infection or sub-
• Criteria B-E for IIH plus: unilateral or bilateral 6th cranial nerve palsy. arachnoid hemorrhage
CSF, Cerebrospinal fluid; IHH, idiopathic intracranial hypertension. • Hypercoagulable states
From Mollan, S.P., Davies, B., Silver, N.C., Shaw, S., Mallucci, C.L.,
Wakerley, B.R., et al., 2018. Idiopathic intracranial hypertension: con- Medications and Exposures
sensus guidelines on management. J. Neurol. Neurosurg. Psychiatry. • Antibiotics
89 (10), 1088–1100. https://doi.org/10.1136/jnnp-2017-317440. • Tetracycline, minocycline, doxycycline, nalidixic acid, sulfa drugs
• Vitamin A and retinoids
neuro imaging, ideally brain magnetic resonance imaging (MRI) • Hypervitaminosis A, isotretinoin, all-trans retinoic acid for promyelo-
with contrast, is mandatory before lumbar puncture (LP) to rule out cytic leukemia, excessive liver ingestion
an intracranial mass as the cause for symptoms and signs. Cerebral • Hormones
venography (usually with magnetic resonance venography [MRV]) • Human growth hormone, thyroxine (in children), leuprorelin acetate,
should also be pursued, if possible, to rule out cerebral venous sinus levonorgestrel (Norplant system), anabolic steroids
thrombosis (an IIH mimic) and to assess for bilateral distal transverse • Withdrawal from chronic corticosteroids
cerebral venous sinus stenoses, which are present in most if not all • Lithium
IIH patients and may aid the diagnostic evaluation. Whether these • Chlordecone
stenoses are the cause or a consequence of IIH remains a matter of
debate. It has been proposed, however, that bilateral transverse sinus Medical Conditions
stenosis (or stenosis of a dominant transverse venous sinus) might • Endocrine disorders
lead to the following sequence of events: decreased venous outflow • Addison disease
drainage, cerebral venous hypertension, impairment of CSF passive • Hypoparathyroidism
resorption, further incrementing CSF pressure resulting in external • Hypercapnia
compression of the transverse venous sinuses, leading to worsened • Sleep apnea
venous stenosis and vicious cycle perpetuation (Bidot et al., 2015). • Pickwickian syndrome
Other described brain MRI findings in IIH include: empty sella, • Anemia
posterior sclera flattening, optic nerve sheath distention, optic nerve • Renal failure
vertical tortuosity, and optic nerve head enhancement (Bidot et al., • Turner syndrome
2015). None of these brain MRV and MRI findings are specific • Down syndrome
for IIH, however; they can be seen in other causes of intracranial CSF, Cerebrospinal fluid.
hypertension. Normal subjects may also have bilateral cerebral From Friedman, D.I., Liu, G.T., Digre, K.B., 2013. Revised diagnostic crite-
venous sinus stenoses. ria for the pseudotumor cerebri syndrome in adults and children. Neurol-
Following the determination that there is no intracranial mass, ogy 81 (13), 1159–1165. https://doi.org/10.1212/WNL.0b013e3182a55f17.
ventricular system obstruction, or thrombosis of a dural venous sinus,
the high CSF pressure can be confirmed by LP manometry. Opening patients in the recent IIHTT tolerated >1 g/day for 6 months (ten
pressure via LP of at least 250 mm CSF (in adults) is required for the Hove et al., 2016). This trial has also provided support for the safe
diagnosis of IIH (Mollan et al., 2018). Importantly, pressure should use of acetazolamide up to 4 g daily with weight loss for effective
ideally be measured in lateral decubitus, which provides the most treatment of mild vision loss in IIH, with associated improvements in
accurate readings. Opening pressures obtained while the patient is papilledema, increased ICP, and quality of life (Smith and Friedman,
sitting are not valid. Pressures measured while prone during fluoros- 2017). Other diuretics and topiramate are used in patients who cannot
copy are typically difficult to interpret because of overestimation of take acetazolamide, although these have not been studied in controlled
pressure, although some suggest a table tilt while prone may improve fashion. The amount of weight loss required for IIH to remit is not
interpretation (Schwartz et al., 2013). CSF composition should be known, but up to 15% of weight loss has been reported (Mollan et al.,
normal in IIH. Removal of CSF to achieve a normal closing pressure 2018). An ophthalmologist should follow patients together with the
relieves the headache and temporarily prevents visual obscurations. neurologist to properly monitor vision. Headache is usually managed
Table 102.1 summarizes IIH diagnostic criteria. Importantly, IIH according to its phenotype (e.g., migraine or tension-type), when
mimics or “secondary pseudotumor cerebri” causes should be ruled present.
out prior to diagnosing IIH (Table 102.2). Patients who have significant visual field loss at presentation and
Management. Prevention of permanent visual field loss is the main those that have progressive visual field loss and/or progressive worsen-
goal of therapy. Once the diagnosis of IIH is established, treatment ing of visual acuity despite medical management may require surgical
in the absence of immediate threat for vision loss consists of weight intervention, traditionally CSF shunting or optic nerve sheath fenes-
loss and acetazolamide. Acetazolamide is typically started at 500 mg tration. Cerebral venous sinus stenting has been reported to improve
twice daily and is gradually increased if needed and tolerated. Most symptoms of intracranial hypertension. The role of neurovascular
publication.
stenting in IIH, however, has not yet been established. Stenting may be
useful for highly selected IIH patients with venous sinus stenosis with
an elevated pressure gradient in whom traditional therapies have not
been effective (Mollan et al., 2018).
Of note, headaches sometimes persist even after proper manage-
ment of IIH. In the IIHTT, 41% of patients reported a prior history
of migraine (Wall et al., 2014). In addition, 37% of headache suffer-
ers at baseline were overusing symptomatic headache medications
(Friedman et al., 2017). Possibly, in some cases, persistent head-
aches may occur on the basis of other processes (e.g., migraine with
or without medication overuse headache) different from intracranial
hypertension.
Headache Attributed to Low Cerebrospinal Fluid Pres-

sure
The headache of low CSF pressure/volume from spinal CSF leaks is
characteristically orthostatic, developing or worsening when a person
is upright and resolving or significantly improving with recumbency.
It most commonly occurs after a LP via loss of CSF volume due to
the removal of CSF for diagnostic purposes, and/or continued leak- Fig. 102.1 Axial T1-weighted magnetic resonance image with gadolin-
age of CSF through the hole in the arachnoid and dural layers left by ium in a patient with a spontaneous spinal cerebrospinal fluid leak and
the LP needle. Loss of CSF can result in brain sagging and traction orthostatic headache demonstrates diffuse pachymeningeal thickening
and enhancement.
on pain-sensitive structures such as bridging veins and sensory nerves.
Recumbency removes the effect of gravity, and the traction headache
is relieved. The headache that occurs after a spinal tap usually resolves
spontaneously within a few days. Spontaneous recovery is estimated
to occur in 24% of patients within the first 2 days, an additional 29%
of patients within 3–4 days, and an additional 19% within 5–7 days
(Turnbull and Shepherd, 2003). The healing process might be has-
tened when the patient has relative bed rest and good hydration. When
these conservative measures fail, relief can usually be obtained by the
application of an epidural blood patch. An epidural blood patch con-
sists of approximately 20 mL of the patient’s own venous blood being
injected into the epidural space close to the site of the original LP. The
resulting compression of the thecal sac and the presumed elevation of
subarachnoid pressure presumably explains the resulting headache
resolution. The increased pressure resulting from the epidural blood
patch presumably causes temporary cessation of the CSF leak, thereby
allowing the dura and arachnoid to heal. The success rate of a single
epidural blood patch is estimated between 70% and 98% (Turnbull
and Shepherd, 2003).
Similar low-CSF pressure/volume headaches can occur when a
spinal leak spontaneously develops, a condition still often referred to
as “spontaneous intracranial hypotension” by some. Although indeed
a significant number of patients with this condition have low (some-
times negative) CSF opening pressure when measured via LP, most
have normal pressures (Kranz et al., 2016b). Because low CSF volume Fig. 102.2 Coronal T1-weighted magnetic resonance image with gadolin-
may better explain the low pressure, headache, and neuroimaging ium of a patient with orthostatic headache secondary to a SSCSFL demon-
findings seen in spontaneous spinal CSF leaks, “CSF hypovolemia” strates subdural fluid collections and pachymeningeal enhancement.
has been proposed as an alternative term (Mokri, 1999). Skull-based
CSF leaks, however, rarely if ever present with the classic syndrome symptoms. Most commonly headache is orthostatic, but not infre-
in the setting of spontaneous spinal CSF leaks (Schievink et al., 2012). quently can be purely precipitated by Valsalva-like maneuvers (e.g.,
The remaining discussion pertains to “headaches secondary to spon- coughing, sneezing, laughing) or present as a combination of these
taneous spinal CSF leaks (SSCSFL),” the authors’ preferred term for two. A large series of SSCSFL specifically secondary to CSF-venous
this syndrome. fistula reported an even greater percentage of patients experienced
Spontaneous spinal CSF leaks are most commonly located in the Valsalva-induced headache exacerbation or precipitation compared
thoracic or cervico-thoracic regions. Three main types have been iden- to orthostatic headache, features that should raise suspicion for occult
tified in observational studies: the dural tear, the meningeal divertic- CSF-venous fistula (Duvall et al., 2019). Occasionally, headaches sec-
ulum, and the CSF-venous fistula (Schievink et al., 2016). Although a ondary to SSCSFL are preceded by a single “thunderclap headache.”
precipitating event for symptoms is often absent or uncertain, many Other common symptoms of SSCSFL include auditory muffling, tin-
patients with SSCSFL recall having a very minor injury, coughing, nitus, nausea and vomiting, and neck pain. Patients who have had the
sneezing, or performing a Valsalva maneuver just prior to onset of condition for a prolonged time can lose the orthostatic component
publication.
CHAPTER 102 Headache and Other Craniofacial Pain 1749.e1
eFig. 102.3 Sagittal T1-weighted magnetic resonance image demon-

strates brain descent made evident by low cerebellar tonsils, crowding
of the posterior fossa, small prepontine cistern, and inferior displace-
ment of the optic chiasm in a patient with a SSCSFL.
publication.
to their headache. Such patients might have constant headaches or Headache Attributed to Trauma or Injury to the Head
so-called “end-of-the-day” headaches (headache starting late in the and/or Neck
day and getting worse as the day goes on). As additional cases have Headaches are a common symptom following injuries to the head and
been reported in the literature, the clinical picture of CSF leaks has neck. Direct causality between the injury and headache is typically
been found to take many forms (Mokri, 2004). difficult to prove, since there are no headache characteristics that are
When a SSCSFL is suspected, the initial diagnostic test is brain MRI specific or sensitive for a diagnosis of posttraumatic headache. Thus,
with gadolinium. MRI findings supportive of a diagnosis of SSCSFL the interval between trauma and onset of headaches is relied upon for
include diffuse pachymeningeal gadolinium enhancement, brain sag- making a diagnosis of a posttraumatic headache. Although controver-
ging (i.e., cerebral and cerebellar tonsillar descent, inferior displace- sial, diagnostic criteria stipulate that headaches must begin within the
ment of the optic chiasm), flattening of the anterior aspect of the pons, first 7 days following trauma in order to be considered “posttraumatic”
and venous dilation (Figs. 102.1 and 102.2; eFig. 102.3). While an or within 7 days of regaining consciousness following a head injury
“acquired Chiari” from brain sagging can commonly be distinguished or within 7 days of discontinuing medications that impair the abil-
fairly easily from a congenital Chiari I malformation, sometimes this ity to sense or report headache following head injury (IHS, 2018). In
can be challenging. Subdural fluid collections (subdural hygromas addition, the diagnosis of headaches attributed to whiplash requires
and subdural hematomas) might occur in up to 50% of patients with that there is neck pain and/or headache at the time of whiplash.
SSCSFL (Schievink et al., 2005). The patient with classical symptoms Posttraumatic headaches are considered “acute” when they have been
of SSCSFL and classical brain MRI findings of the disorder might present for less than 3 months and “persistent” when they last longer
not need additional diagnostic tests prior to treatment with conser- than 3 months (IHS, 2018). Posttraumatic headaches can be due to
vative measures or epidural blood patch. However, increasing symp- direct or indirect forces to the head and/or neck.
tom duration associates with decreased prevalence of abnormal dural Headaches attributed to head injuries are typically subdivided into
enhancement; brain MRI can be normal in 20%–30% of cases (Kranz those associated with mild head injury and those associated with moder-
et al., 2016a). When the diagnosis is uncertain a complete spine MRI ate to severe injury. Headache is the most common symptom following
and/or radioisotope cisternography (RICG) may help establish the mild head injury and headaches might be more common following mild
presence of a SSCSFL although they rarely localize the exact leak site. traumatic brain injury compared to moderate or severe injury (Packard,
Spine MRI findings suggestive of CSF leak include dural enhancement, 2005). Other risk factors for the development of posttraumatic head-
dilated epidural veins, epidural venous plexus engorgement, and/or aches might include presence of pre-injury headaches, female sex, and
epidural fluid collections. Large longitudinal epidural fluid collections presence of comorbid psychiatric disorders (Stovner et al., 2009).
often suggest the presence of a high flow or “fast” SSCSFL. On RICG, Most often, posttraumatic headaches phenotypically resemble
delayed radioactive tracer ascent to cerebral convexities and/or early migraine or tension-type headaches and less often resemble cervico-
isotope tracer appearance in the urinary bladder are findings suggestive genic headache or occipital neuralgia (Lew et al., 2006). Headache may
of CSF leak. Although measurement of opening pressure via LP can be an isolated symptom following head trauma or can be part of the
aid diagnosis if low opening pressure is found, LP should be avoided post-concussion syndrome, a syndrome consisting of headache, dizzi-
when possible due to the risk of worsening symptoms following the ness, fatigue, cognitive dysfunction, psychomotor slowing, insomnia
procedure. Importantly, a normal CSF opening pressure does not rule and personality changes (Evans, 2004; Yang et al., 2009). When consid-
out a spontaneous CSF leak. If RICG is pursued, however, we typically ering a diagnosis of posttraumatic headache, it is essential to exclude
measure opening pressure during the LP part of the procedure. structural traumatic injuries such as cervical spine injuries, skull frac-
In patients with the typical clinical and radiographic features of tures, intracranial hemorrhages, cerebrospinal fluid leaks, and cervical
SSCSFL, treatment may be conservative with bed rest and hydration artery dissections.
for 1–2 weeks. If this is either impractical or ineffective, treatment with Treatment of post-concussion syndrome and posttraumatic head-
an epidural blood patch is warranted. If the CSF leak site is suspected, ache can be difficult, and an evidence base from which to select optimal
a “targeted” patch can be attempted close to the suspected leak site, but therapies is absent. Posttraumatic headaches are thus treated according
the patch is often done “blindly” in the lumbar spine when no clear to the primary headache disorder that they most resemble (e.g., a post-
leak site is known or suspected. Although epidural blood patches are traumatic headache that resembles migraine is treated with medica-
effective in a substantial number of patients, many require more than tions and other therapies typically used to treat migraine). Optimizing
one blood patch, and some require as many as four to six blood patches treatment requires that coexisting symptoms such as myofascial pain
(Mokri, 2004) with 1–2 months between individual attempts. and spasm, sleep disorders, and anxiety be recognized and addressed.
Patients with SSCSFL who fail to respond to conservative measures Nonpharmacological treatments (e.g., physical therapy, biobehavioral
are best investigated with myelography, the most effective study at pres- therapy) should be considered in addition to medication therapy.
ent to identify the precise spinal CSF leak site. Myelography can also be
pursued even prior to attempting epidural blood patching in patients Headache Attributed to Infection
with SSCSFL when a more precise diagnosis and a more definitive Inflammation of pain-sensitive structures such as the meninges and
treatment plan are desired. Conventional computed tomography (CT) intracranial vessels produces the severe headache frequently associated
myelography is often the first modality used. Dynamic CT myelogra- with both meningitis and meningoencephalitis. Headache is the most
phy is an alternative modality, particularly helpful to localize high-flow common symptom in acute bacterial meningitis, occurring in nearly
leaks. Digital subtraction myelography may be particularly helpful in 90% of cases (van de Beek et al., 2004). Acute bacterial meningitis char-
those with suspected occult CSF-venous fistula and in patients with acteristically produces a severe holocephalic headache with neck stiffness
SSCSFL with negative conventional CT myelogram. If myelography and other signs of meningismus, including photophobia and irritabil-
identifies the CSF leak site, targeted epidural blood patching can be ity. Pain may be retro-orbital and may worsen with eye movement. The
attempted. However, CSF-venous fistulas appear to respond poorly to presence of the classic triad of fever, neck stiffness, and altered mental
epidural blood patching (Duvall et al., 2019) and are often best managed status has a low sensitivity for the diagnosis of meningitis; however,
with surgical repair in centers with expertise. For other resistant leaks nearly all patients present with at least two of these symptoms and/or
that can be precisely localized, surgical repair may also be attempted. headache (van de Beek et al., 2004). Jolt accentuation of headache (i.e.,
publication.
worsening of headache with sudden movements) is a common feature detect the presence of subarachnoid blood. If the CT is normal, per-
of bacterial meningitis but its absence does not rule it out. form a LP, looking for blood or xanthochromia.
Chronic meningitis due to fungal or tuberculous infection may lead
to headache that may be severe and unrelenting. The headache of intra- Subarachnoid Hemorrhage and Thunderclap Headache
cranial infection is nonspecific but merits consideration, especially in The term thunderclap headache describes a severe headache occur-
immunocompromised patients. The diagnosis can be confirmed only ring with instantaneous onset (within seconds) and without warning,
by examination of the CSF. Further discussion of meningitis can be like a clap of thunder. While multiple processes can present like this,
found in Chapters 4, 75, 76, and 77. a subarachnoid hemorrhage is the most worrisome. Rupture of an
Sinusitis, mastoiditis, epidural or intraparenchymal abscess forma- intracranial aneurysm or AVM results in a subarachnoid hemorrhage,
tion, and osteomyelitis of the skull can all cause either focal or gen- with or without extension into the brain parenchyma. The headache
eralized headache. The diagnosis is usually suspected in the context of a subarachnoid hemorrhage is characteristically explosive in onset
of other associated symptoms and signs. After craniotomy, increasing and of overwhelming intensity. Patients may relate that they thought
pain and swelling in the operative site may be due to osteomyelitis of they were hit on the head. The headache rapidly generalizes and may
the bone flap. Plain skull roentgenograms may reveal the typical mot- quickly be accompanied by neck and back pain. Loss of consciousness
tled appearance of the infected bone, necessitating removal of the flap. may also occur, but many patients remain alert enough to complain of
Mollaret meningitis is a rare and recurrent aseptic meningitis (see the excruciating headache. Vomiting often accompanies the headache,
Chapters 76 and 103). The CSF cellular response includes large epithelioid which may aggravate the pain. Extension of blood into the ventricles
cells (Mollaret cells). The pathogenesis is unknown but may relate to the and basal cisterns or distortion of the midline structures can each con-
herpes simplex virus. The condition may recur every few days or every tribute to the rapid development of hydrocephalus, which frequently
few weeks for months or years. Headache, signs of meningismus, and low- worsens the headache.
grade fever accompany each attack. Treatment is mainly symptomatic. Suspicion of the diagnosis is easily confirmed by an unenhanced
Headache can accompany systemic infections due to viruses (e.g., CT scan that reveals blood in the subarachnoid cisterns or within the
influenza), bacteria (e.g., leptospirosis) and other infectious agents (e.g., parenchyma and often early hydrocephalus. When a CT unequivocally
Borrelia burgdorferi). These typically nonspecific headaches can be mild shows blood in the subarachnoid spaces it is not necessary or advisable
or can be a prominent symptom of the systemic infection (Gladstone and to perform a LP, because the resultant reduction of CSF pressure may
Bigal, 2010). Headaches attributable to systemic infections might be a cause herniation of the brain or may remotely induce further bleed-
result of the microorganisms activating pain-sensitive structures, release ing from the aneurysm. Demonstration of subarachnoid hemorrhage
of inflammatory mediators, presence of fever, and/or dehydration. generally indicates the need for cerebral angiography. The timing of
this procedure and the subsequent mode of treatment are detailed
Headache Attributed to Cranial or Cervical Vascular elsewhere (see Chapter 65). The headache that occurs after a subarach-
Disorders noid hemorrhage may be persistent, lasting up to 7–10 days. Rarely, a
Aneurysms and Arteriovenous Malformations chronic daily headache (CDH) may persist for months to years.
Intracranial aneurysms are rarely responsible for headache unless Movement aggravates a subarachnoid hemorrhage headache, and
they rupture or rapidly enlarge. Large aneurysms may produce pain photophobia and phonophobia are often associated. Therefore, these
by exerting pressure upon cranial nerves or other pain-sensitive struc- patients require a dark, quiet room, as well as comfort measures that
tures. Such pain is most commonly associated with aneurysms of the minimize straining with bowel movements, vomiting, and coughing.
internal carotid and posterior communicating arteries. Enlargement of Other conditions which can also manifest with thunderclap head-
an aneurysm may occur shortly before rupture, and the pain is there- ache in addition to subarachnoid hemorrhage include cerebral venous
fore an important clinical sign. sinus thrombosis, cervicocephalic arterial dissection, pituitary apo-
Parenchymal arteriovenous malformations (AVMs) should be con- plexy, acute hypertensive crisis, spontaneous spinal CSF leaks, men-
sidered in a patient presenting with a cranial bruit or the classic triad ingitis, embolic cerebellar infarcts, pheochromocytoma (Angus, 2013;
of migraine, seizures, and focal neurological deficits. Headache may be Heo et al., 2009), and reversible cerebral vasoconstriction syndromes
a presenting symptom in about 16% of patients and is often ipsilateral (RCVS) (Calabrese et al., 2007; Schwedt, 2013). These entities can be
to the AVM. Similar to aneurysms, the pain may increase in intensity associated with significant neurological morbidity and may not be eas-
and frequency before hemorrhage. Though photophobia and phono- ily seen on the initial CT image, thus underscoring the need for MRI
phobia are uncommon, large AVMs can be associated with ipsilateral and magnetic resonance angiography (MRA)/MRV in this group if
or bilateral throbbing cephalgia, resembling migraine. Occipital AVMs results of the initial workup are negative. There is also a rarely seen
may frequently have migraine characteristics, and it is thought that the category of thunderclap headache, referred to as primary thunderclap
occipital location may be linked with cortical spreading depression, headache, for which there is no underlying cause established (see the
causing secondary migraine headaches. The visual disturbances asso- section “Other Primary Headaches” later in the chapter).
ciated with occipital AVMs may resemble migrainous aura. MR or CT
angiography can usually exclude the presence of clinically significant Subdural Hematoma
aneurysms and AVMs. Bleeding into the subdural space is generally due to tearing of the bridg-
Both aneurysms and AVMs can produce mild subarachnoid hem- ing veins that cross the subarachnoid space to reach the venous sinuses.
orrhages that result in sentinel headaches. Such headaches may be Chronic subdural hematomas may cause headache via enlargement of
abrupt, mild, and short-lived. More catastrophic subarachnoid hem- the lesion and may present without serious neurological signs for a con-
orrhages classically present as the worst headache the patient has ever siderable time. Midline shift was the most influential factor for head-
had, all the more worrisome when associated with neck stiffness or ache in one study, which has led some to consider that the likely cause
pain, transient neurological symptoms (e.g., extraocular nerve palsy), of headache may be stretching or twisting of the pain-sensitive menin-
or fever. Patients having any suggestion of a sentinel bleeding episode ges and meningeal arteries or veins (Yamada et al., 2018). Changes in
or who describe a recent thunderclap-like headache (see thunderclap personality, alterations in cognitive abilities, subacute dementia, and
headache discussion below) require emergent examination and CT to nonspecific symptoms such as dizziness and excessive sleepiness may
publication.
be present for weeks or months. Focal seizures, focal weakness, sensory hyperemia subsides, headache generally eases, although in some,
changes, and ultimately, decreasing levels of consciousness may occur. headache following stroke becomes chronic and often resembles ten-
Symptoms of chronic subdural hematoma, including headache and sion-type headache (Hansen et al., 2015).
focal neurological symptoms, may fluctuate and occur intermittently, Paroxysmal visual and sensory disturbances commonly associated
thereby mimicking transient ischemic attacks (TIAs). Headache is the with migraine aura may mimic symptoms of cerebrovascular disease,
single most common symptom of subdural hematoma and often pres- occasionally making the differentiation between the two a challenge.
ents as a severe bitemporal pain. Headache due to subdural hematoma The visual aura of migraine is typically a positive phenomenon, per-
is more common in young people; the cerebral atrophy seen in many ceived with the eyes open or closed. Visual disturbances due to isch-
elderly patients may be protective in the setting of any space-occupy- emic lesions of the visual pathway or retina are usually associated with
ing intracranial lesion. Subdural hematoma should be considered in an negative phenomena such as vision loss or a negative scotoma; how-
elderly person with recent onset of headaches, especially in the context ever, emboli to the retinal artery can result in showers of bright flashes,
of a traumatic injury of even mild severity. Once suspected, exclude and calcarine ischemia can occasionally produce scintillating scotoma.
the presence of a subdural hematoma with CT or MRI. Treatment of While visual disturbances associated with stroke and TIA are usually
subdural hematomas is discussed in Chapter 60. Headaches tend to abrupt and fixed, the migraine aura tends to march across the visual
resolve after resolution of the bleed. field over the course of a few minutes and is generally followed by head-
ache after a latent interval. The headache associated with stroke and
Parenchymal Hemorrhage TIA typically has a more variable relationship to the visual disturbances.
A hemorrhage into the cerebral or cerebellar tissue is a potent source of
headache of rapid onset and increasing severity. The intraparenchymal Carotid and Vertebral Artery Dissection
mass causes headache by deforming and shifting the pain-sensitive vas- Dissection of the cervical portion of the carotid or vertebral arteries
cular, meningeal, and neural structures. As the hematoma enlarges, it is associated with headache, neck pain, or face pain in approximately
may obstruct the normal circulation of CSF and lead to increases in ICP. 80% of patients. The headache may be isolated or associated with
Initially, the pain of a cerebral hemorrhage is often ipsilateral, but it may an ipsilateral Horner syndrome or stroke symptoms. An ipsilateral
generalize in the presence of hydrocephalus and elevated ICP. Rupture Horner syndrome is more common in carotid than vertebral dissec-
of the hematoma into the subarachnoid space or leakage of the blood tions, and the sympathetic hypofunction may be due to interference
into the basal cisterns through the CSF pathways may cause the head- with the sympathetic fibers around the internal carotid artery as they
ache to intensify and may also be associated with neck stiffness and other ascend from the superior cervical ganglion to the intracranial struc-
signs of meningeal irritation. Disorders leading to cerebral and cerebellar tures. In internal carotid artery dissections, the headache is typically
hemorrhages are more thoroughly discussed elsewhere (see Chapter 64). unilateral and ipsilateral to dissection. Facial pain is common and ipsi-
Cerebellar hemorrhages account for about 10% of all intraparen- lateral cranial nerve palsies, especially of lower cranial nerves, are not
chymal bleeds and are neurological emergencies with potentially fatal infrequent. Cerebral or retinal ischemic symptoms are the initial mani-
outcomes. An enlarging hematoma in the cerebellum rapidly com- festations in a minority of patients. Vertebral artery dissections present
presses vital brainstem structures and obstructs the outflow of CSF most often with headache with or without neck pain, followed by a
from the ventricular system. This leads to occipital headache followed delay of focal CNS ischemic symptoms. In uncomplicated intracranial
rapidly by vomiting, impaired consciousness, and various combina- vertebral artery dissection, the headache usually is acute in onset with
tions of brainstem, cerebellar, and cranial nerve dysfunction. a persistent and temporal feature and in many cases the pain appears
to be throbbing and severe in the ipsilateral and occipitonuchal area.
Cerebral Ischemia Additionally, the headache often is aggravated by head flexion/ rotation
Cerebral infarctions and TIAs may be associated with transient head and relieved by head extension and being supine (Kim et al., 2015).
pain in up to 40% of patients. The headache may be either steady Cervicocephalic arterial dissections can result from intrinsic fac-
or throbbing and is rarely explosive or severe (Kropp et al., 2013). tors that predispose the vessel to dissection, including fibromuscular
The location of the pain is a poor predictor of the vascular terri- dysplasia, cystic medial necrosis, and other connective tissue disorders
tory involved, though unilateral headaches tend to be ipsilateral to such as Marfan syndrome or Ehlers-Danlos syndrome. Extrinsic fac-
the infarct. Cerebral ischemia-related headache is more common in tors such as trivial trauma may play a pathogenic role when superim-
younger patients and patients who are female. It is also more common posed on structurally abnormal arteries. Severe head and neck trauma
in patients with larger infarcts and infarcts in the posterior cerebral may occasionally be the proximate cause of dissection. Importantly,
and vertebrobasilar arterial distributions (Kropp et al., 2013). A recent in patients >60 years old, pain and mechanical triggers may be absent,
MRI voxel-based symptom lesion-mapping study suggests headache making the diagnosis of cervical artery dissection more challenging in
phenotypes may be related to specific ischemic lesion patterns (Seifert these older patients (Traenka et al., 2017). MRI or MRA usually con-
et al., 2018). In this study, pulsatile headache occurred with wide- firms the diagnosis of arterial dissection. At the level of involvement,
spread cortical/subcortical strokes, noise sensitivity was associated the lumen of the artery typically appears as a dark circle of flow void
with cerebellar lesions, nausea was associated with posterior circula- of smaller caliber than the original vessel, and the intramural clot
tion territory infarcts, and cranial-autonomic symptoms were related appears as a hyperintense and bright crescent or circle (in both T1- and
to parietal lobe, somatosensory cortex, and middle temporal cortical T2-weighted images) surrounding the flow void (eFig. 102.4). Catheter
lesions (Seifert et al., 2018). angiography is rarely required. The pain associated with cervicoce-
If a large cerebral or cerebellar infarct produces significant mass phalic dissections is of variable duration and may require treatment
effect as a result of edema, the associated headache may worsen. with potent analgesics. Patients with evidence of distal embolization
Obstruction of the ventricular system frequently results in hydroceph- are usually treated with either antiplatelet agents or anticoagulation.
alus and further aggravation of the pain. The pain may be pulsatile
and may worsen with straining or the head-low position. Hemorrhagic Giant-Cell Arteritis
transformation of an ischemic infarct may be associated with wors- Giant-cell arteritis is a vasculitis of elderly persons and is one of
ening of headache. As the infarct decreases in size and the phase of the most ominous causes of headache in this population. When
publication.
A B
eFig. 102.4 Magnetic resonance images of a patient with right internal carotid artery (ICA) dissection. Large
arrow in each figure points to right ICA, which has a smaller flow void than left ICA (small arrows), reflecting
narrowed vessel lumen. Region of flow void is surrounded by a hyperintense crescent representing the
intramural hematoma.
publication.
TABLE 102.3 Symptoms of Giant-Cell acute confusional state, and subacute stepwise cognitive deterioration
are rare manifestations.
Arteritis in 166 Patients*
Physical findings. About 49% of patients with histologically
Patients in verified giant-cell arteritis have physical signs of superficial temporal
whom it artery inflammation, including erythema, pain on palpation, arterial
Patients with was Initial nodularity and/or thickening, or reduced pulsation on the affected
Symptom Symptom (%) Symptom (%) side. Rarely, ischemic necrosis of the scalp and tongue occurs. Almost
Headache 72 33 a third of patients have large-artery bruits or diminished pulses, which
Polymyalgia rheumatica 58 25 usually affect the carotid artery. The upper-limb arteries are more
Malaise, fatigue 56 20 commonly affected than those in the lower limbs.
Jaw claudication 40 4 Ocular findings in giant-cell arteritis may be striking. In patients
Fever 35 11 with amaurosis fugax, sludging of blood in the retinal arterioles may
Cough 17 8 be observed. With infarction of the optic nerve, vision loss precedes the
Neuropathy 14 0 funduscopic signs of an anterior ischemic optic neuropathy by up to
Sore throat, dysphagia 11 2 36 hours. During the acute stage, there may be optic disc edema, optic
Amaurosis fugax 10 2 disc pallor, and resulting visual field defects which tend to be altitudi-
Permanent vision loss 8 3 nal. Optic disc edema is commonly followed by the gradual develop-
Claudication of limbs 8 0 ment of optic atrophy. Restrictions in eye movements may indicate
Transient ischemic attack/stroke 7 0 involvement of specific extraocular muscles. Oculosympathetic paresis
Neuro-otological disorder 7 0 (Horner syndrome) occasionally occurs.
Scintillating scotoma 5 0 Up to one-third of patients have clinically significant large-artery
Tongue claudication 4 0 disease. The most common causes of vasculitis-related death are cere-
Depression 3 0.6 bral and myocardial infarction. In fatal occurrences, vertebral, ophthal-
Diplopia 2 0 mic, and posterior ciliary arteries are involved as often and as severely
Tongue numbness 2 0 as the superficial temporal arteries. Rupture of the aorta is rare. In
Myelopathy 0.6 0 patients with peripheral neuropathic syndromes, ischemic infarction
of peripheral nerves due to vasculitis is demonstrable. Intracranial vas-
*Some patients had coincident onset of more than one symptom. cular involvement is rare.
Data from Caselli, R.J., Hunder, G.G., Whisnant, J.P., 1988. Neurologic Laboratory studies, and imaging. The laboratory abnormality
disease in biopsy-proven giant cell (temporal) arteritis. Neurology 38, most often associated with giant-cell arteritis is elevation of the
352–359.
erythrocyte sedimentation rate (ESR) (mean, 85 ± 32 mm in 1 hour
with the Westergren method), which has a sensitivity of about 84%.
unrecognized and untreated, it may lead to permanent blindness. C-reactive protein levels may be more sensitive than the ESR, though
Patients with this disorder most commonly see neurologists for new one study showed that both can be normal in 4% of biopsy-proven
headaches of unknown cause. patients (Kermani et al., 2012). Patients are usually anemic (mean
Clinical symptoms. The clinical manifestations of giant-cell hemoglobin value 11.7 ± 1.6 g/dL) and show a mild thrombocytosis
arteritis result from inflammation of medium and large arteries. (mean platelet count 427 ± 116 × 103/μL). As all of these laboratory
Table 102.3 summarizes clinical symptoms in 166 patients examined at tests are nonspecific, the confirmatory diagnosis rests on a temporal
the Mayo Clinic between 1981 and 1983 (Caselli et al., 1988). Headache artery biopsy. However, the sensitivity for this procedure is low, with
was the most common symptom, experienced by 72% of patients at a high false-negative rate of 15%–40% (Chong and Robertson, 2005).
some time and the initial symptom in 33%. The headache is most Imaging, particularly with temporal artery MRI or ultrasound, may
often throbbing, and many patients report scalp tenderness. Headache supplement the diagnostic investigation and may be helpful in decision
is associated with striking focal tenderness of the affected superficial making about proceeding to biopsy. The superficial cranial arteries
temporal or, less often, occipital artery. One-third of patients with along with the mural and luminal properties can be investigated with a
headache may have no objective signs of superficial temporal artery contrast-enhanced, high-resolution, temporal artery MRI (Bley et al.,
inflammation. 2005). Doppler ultrasound has been advocated by some, but its practi-
More than half of patients with giant-cell arteritis experience cal value is difficult to assess because of the heterogeneous study find-
polymyalgia rheumatica, which is the initial symptom in one-fourth. ings and high operator dependence for image acquisition (Bienvenu
Fatigue, malaise, and a general loss of energy occur in 56% of patients et al., 2016). Currently, temporal artery imaging is not considered to
and are the initial symptoms in 20%. Jaw claudication is common and support the diagnosis with as much certainty as temporal artery biopsy
the initial symptom in 4% of patients. Tongue claudication is rare. (Bienvenu et al., 2016). An angiogram of the aortic arch vessels may
Amaurosis fugax is one of the most ominous symptoms in giant- show long segments of smoothly tapered stenosis and occlusions of
cell arteritis; 50% of affected patients subsequently become partially subclavian, brachial, and axillary arteries. Fluorodeoxyglucose positron
or totally blind if untreated. In the Mayo Clinic series, 10% of patients emission tomography (FDG-PET)/CT may supplement the diagnostic
experienced amaurosis fugax, and 35% of those cases were bilateral. investigation by identifying vessel inflammation. The spatial resolution
Horizontal or vertical diplopia also occurs in giant-cell arteritis. of FDG-PET is best for vessels greater than 4 mm in diameter, so it is
Some 14% of patients have a neuropathy, which is a peripheral most useful when involvement of larger vessels, such as the aorta or the
polyneuropathy in 48%, multiple mononeuropathies in 39%, and an subclavian, vertebral, and carotid arteries, is suspected.
isolated mononeuropathy in 13%. Limb claudication occurs in 8% of Pathology. The histopathological features of arterial lesions include
patients and usually involves the upper limbs. TIAs and strokes occur intimal proliferation with consequent luminal stenosis, disruption of
in 7% of patients, and the ratio of carotid to vertebral events is 2 : 1. the internal elastic membrane by a mononuclear cell infiltrate, invasion
Vertigo and unilateral hearing loss can occur. An acute myelopathy, and necrosis of the media progressing to panarteritic involvement by
publication.
mononuclear cells, giant-cell formation with granulomata within the last effective dose and often boosting it temporarily to a higher level.
mononuclear cell infiltrate, and (variably) intravascular thrombosis Relapses generally reflect too rapid a taper, and resumption of a more
(eFig. 102.5). Involvement of an affected artery is patchy, with long slowly tapering regimen is indicated after the relapse has stabilized.
segments of the normal unaffected artery flanked by vasculitic foci Some patients may require continuation of low-dose (7.5–10 mg/day)
known as skip lesions, which may begin to normalize within days prednisone for several years, although complete withdrawal remains
after treatment. For these reasons, biopsy specimens of the superficial the eventual goal. There is some evidence that treatment with metho-
temporal artery should be generous (4- to 6-cm-long specimens), trexate 10 mg/wk may be an effective adjunctive treatment that allows
multiple histological sections should be taken, and bilateral biopsy for more rapid tapering of the prednisone dose. Recently, the US Food
considered. Employing these strategies may increase the diagnostic and Drug Administration (FDA) approved the use of tocilizumab as a
yield of temporal artery biopsy up to 86%. steroid-sparing agent for giant-cell arteritis treatment.
Immunology, etiology, and pathogenesis. Giant-cell arteritis is an The multitude of well-known adverse effects associated with exog-
idiopathic autoimmune disease. Although vasculitic processes are often enous corticosteroids (e.g., vertebral body compression fractures,
systemic, giant-cell arteritis is usually more focal than polyarteritis myopathy, a confusional state, among others) may influence manage-
nodosa and characterized by a mononuclear cell infiltrate with ment by prompting a more rapid taper, thereby exposing the patient to
giant-cell formation, suggesting differences in immunopathogenesis. the risks that accompany a relapse of the vasculitis.
No distinctive antigen has been identified to explain the particular Course and prognosis. The clinical onset of giant-cell arteritis
tropism of giant-cell arteritis, although the possibility that the immune may be acute, subacute, or chronic. Although the median duration
reaction is directed against the internal elastic lamina (which is absent of symptoms before diagnosis is 1 month, patients may rarely present
from cerebral vessels shortly after they pierce the dura) may explain with a history of up to several years of polymyalgia rheumatica.
the paucity of intracranial involvement. Lymphocytes sensitized to Within days of corticosteroid treatment, symptoms and labora-
the purported antigen infiltrate the internal elastic lamina and release tory abnormalities may begin to normalize. With tapering doses,
a host of lymphokines which attract a mononuclear cell infiltrate. relapses may occur and may present as a reactivation of prior
Activated macrophages release lysosomal proteases and may transform symptoms or with new symptoms altogether. Neurological com-
into epithelioid and multinucleate giant cells. T cells themselves, by plications, including neuropathies and cerebrovascular events, are
antibody-dependent cell-mediated cytotoxicity or natural killer not always preventable by corticosteroid administration and have
cell actions, may also be involved. In addition, the demonstration a median onset of 1 month after initiation of treatment. Similarly,
of antibody and complement deposits at the internal elastic lamina large-artery involvement can occur up to 7 months after initiation
suggests that humoral mechanisms are involved. of treatment.
Epidemiology. The incidence of biopsy-confirmed giant-cell Although the occurrence of amaurosis fugax often brings a
arteritis ranges between 9.5 and 29.1 per 100,000 per year, significantly patient with undiagnosed giant-cell arteritis to medical attention,
increases after 50 years of age, and peaks in the eighth decade permanent loss of vision rarely occurs with adequate treatment. In
(Gonzalez-Gay et al., 2009). It is the most common vasculitic process patients with acute and incomplete loss of vision, some visual func-
in both Europe and North America, appears to be most common tion may return with immediate institution of corticosteroid ther-
among individuals of Scandinavian descent, and is significantly less apy, but this is rare.
common among Asians. The reported female-to-male ratio in giant-
cell arteritis is as high as 4 : 1. Headache Associated With Disorders of Homeostasis
Treatment and management. Once giant-cell arteritis is Sleep apnea may result in both an independent headache type and
suspected, histological confirmation should be obtained, and may also be an aggravating factor among individuals with migraine.
treatment started immediately. Treatment consists of oral Individuals with nocturnal or morning-predominant headaches
corticosteroids given initially in high doses and gradually tapered should be asked about sleep apnea risk factors, such as snoring and
over months. Treatment should not be withheld pending the result observed apneic episodes. A body mass index greater than 35 kg/m2,
of temporal artery biopsy. Prednisone may be initiated at 40–60 mg/ and neck circumference greater than 40 cm, further increase the like-
day and continued for 1 month, after which time, start a cautious lihood of obstructive sleep apnea. The mechanism may involve hyper-
taper of less than 10% of the daily dose per week. If, at the time carbia and/or hypoxemia.
of presentation, ischemic complications are imminent or evolving, Despite common belief, mild to moderate hypertension does
parenteral high-dose corticosteroids should be given until these not directly cause headache, as demonstrated by a lack of correla-
complications stabilize. Intravenous (IV) pulse corticosteroids, tion between headache diaries and 24-hour ambulatory blood pres-
typically in the form of methylprednisolone 1000 mg/day for 3 days, sure analysis. Conversely, hypertensive emergency is commonly
has been advocated for patients with transient, partial, or complete associated with headache, where a diagnosis of posterior reversible
vision loss at presentation (Hoffman, 2016). Some studies have encephalopathy syndrome should also be considered. In a patient
shown antiplatelet therapy with low-dose aspirin to be associated with a short-duration headache associated with diaphoresis and
with a lower risk for developing visual loss and cerebrovascular palpitations, the possibility of pheochromocytoma should be pur-
infarcts (Nesher et al., 2004). A Cochrane review of the literature sued. Similarly, headache may be a sign of pre-eclampsia during
published in 2014, however, found that there is no evidence from pregnancy.
randomized controlled trials to determine the safety and efficacy of Cardiac cephalalgia occurs as a direct result of myocardial ischemia
low-dose aspirin as an adjunctive treatment in giant-cell arteritis and may present in the complete absence of chest pain. The headache
(Mollan et al. 2014). The adjunctive use of anticoagulants for is characteristically brought on by exertion, improved with rest, and
patients with ischemia may be tried, but their efficacy in this setting unlike most primary headache disorders, improved by nitroglycerin.
is unproven. Failure to identify this diagnostic entity may be associated with dire
Disease activity must be monitored both clinically and by moni- consequences. A cardiac evaluation should be considered in patients
toring the ESR. A flare of symptoms accompanied by an increase in over the age of 50 who present with new headaches (especially if exer-
the ESR mandates increasing the corticosteroid dose at least to the tional) and vascular risk factors.
publication.
eFig. 102.5 Transverse section of temporal artery showing narrowed

lumen (arrowhead) and giant cells (two arrows) in relation to the elas-
tic lamina (hematoxylin and eosin stain, ×100) (Micrograph courtesy R.
Jean Campbell, MBChB.)
publication.
45, after which spontaneous resolution is often seen. Mechanical dis-

Headache Caused by Disorders of the Cranium, Neck, orders of the joint, alterations in the way the upper and lower teeth
Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial relate, and congenital and acquired deformities of the jaw and man-
or Cranial Structures dible can all produce head and facial pain and are very occasionally
Ocular Causes of Headache responsible for the episodic and chronic pain syndromes seen by
In the absence of injection of the conjunctiva or other obvious signs neurologists.
of eye disease, headache and eye pain rarely have an ophthalmic cause. The neurologist evaluating head or facial pain should be familiar
The maxim is that a white eye is rarely the cause of a monosymptom- with the criteria for identification and localization of TMJ disorders.
atic painful eye. Acute angle-closure glaucoma is a rare but often dra- Temporomandibular joint pain should relate directly to jaw move-
matic event. The patient may present with extreme eye and frontal ments and mastication and commonly associates with tenderness in
head pain with associated vomiting. The sclera is injected, the cornea is the masticatory muscles or over the TMJ on palpation. Anesthetic
cloudy, the globe is stony hard, and unlike cluster headache, the pupil blocking of tender structures should confirm presence and location of
is fixed in mid-position. the pain source. A sudden change in occlusal relationship of the teeth,
Refractive errors, imbalance of external eye muscles, amblyopia, restriction of mandibular movement, and interference with mandib-
and “eyestrain” are not causes of headache in most instances. In chil- ular movement (clicking, incoordination, and crepitus) are all symp-
dren and teenagers, however, refractive errors, especially hyperopia, toms and signs suggestive of TMJ dysfunction.
can produce dull frontal and orbital headaches from straining to Bruxism, teeth clenching, and chronic gum chewing are import-
achieve accommodation at school. Myopic children are unaffected. ant in the production of pain in the masseter and temporalis muscles.
Trochleitis may produce a periorbital headache and be either idio- Arthritis and degenerative changes in the TMJ, loss of teeth, ill-fitting
pathic or secondary to an autoimmune disorder. The headache is char- dentures or lack of dentures, and other dental conditions can all lead
acteristically aggravated by vertical ductions of the eye, as the tendon of to the TMJ or myofascial pain dysfunction syndrome, which mani-
the superior oblique muscle runs through this structure. Cluster head- fests as facial and masticatory muscle pain. Head pain and facial pain,
ache, migraine, and other primary headaches, as well as carotid artery even when associated with the above-discussed criteria, require full
dissection, can cause orbital and retro-orbital pain. Each is discussed evaluation, which should include a detailed history and examination,
elsewhere in this chapter. appropriate radiographs, and laboratory studies to exclude other more
serious causes. If TMJ dysfunction is thought to be the source of pain,
Nasal Causes of Headache and Facial Pain further evaluation and treatment are in the province of the appropriate
Acute purulent rhinosinusitis causes local and referred pain. The dental specialist. Even when TMJ dysfunction is believed to be respon-
distribution of the pain depends on the sinuses involved. Maxillary sible for facial or head pain, conservative management with analgesics,
sinusitis causes pain and tenderness over the cheek. Frontal sinus dis- anti-inflammatory agents, application of local heat, and nonsurgical
ease produces frontal pain; sphenoid and ethmoidal sinusitis causes techniques to adjust the bite generally provide relief. Before using
pain behind and between the eyes, and the pain may refer to the ver- surgical modalities on the TMJ or mandibles, the diagnosis must be
tex. Acute rhinosinusitis is commonly associated with fever, puru- secure and other causes of head and facial pain excluded by appropri-
lent nasal discharge, and other constitutional symptoms. The pain is ate investigations.
worse when the patient bends forward and is often relieved as soon
as the infected material drains from the sinus. Chronic rhinosinusitis Other Dental Causes of Craniofacial Pain
is considered to be a risk factor for CDH, where the headache most Pulpitis and root abscess generally produce dental pain that a patient
often resembles chronic tension-type headache in features (Aaseth can localize. The cracked tooth syndrome results from an incomplete
et al., 2010). Intracranial infections may occur as a complication of tooth fracture, most commonly involving a lower molar. The initial
untreated sinusitis. Acute infection involving the sphenoid sinus can pain is usually sharp and well localized, but thereafter the pain is often
be especially dangerous because of its close proximity to the cavernous diffuse and hard to locate. After a fracture, the tooth is sensitive to
sinus. cold. Pain may be felt in the head and face ipsilateral to the damaged
Commonly, migraine headaches are erroneously diagnosed as sinus tooth. With time, infection develops in the pulp, leading to extreme
headaches, because they are associated with cranial autonomic symp- and well-localized pain. Confirmation of the diagnosis and treatment
toms, have prominent facial involvement, and/or are triggered (e.g., of the cracked tooth require the expertise of a dentist.
by a change in altitude/weather, an exposure to pollens, or a seasonal
predilection). Most patients with a diagnosis of “sinus headaches” have Headaches and the Cervical Spine
migraine headaches (Cady et al., 2005). Cervicogenic headache is often a controversial diagnosis with
Malignant tumors of the sinuses and nasopharynx can produce potential medicolegal implications. Many common cervical spine
deep-seated facial and head pain before involving cranial nerves or pathologies, such as degenerative spondylosis, occur just as often in
otherwise becoming obvious. Trigeminal sensory loss is an important individuals with or without headache. Therefore, the diagnosis rests
neurological sign which is associated with neurological involvement, on establishing the cervical spine as a pain generator either through
often by perineural spread. MRI scanning is the optimal technique for clinical signs, or a diagnostic nerve block. Cervicogenic headache
detecting these cryptic lesions. should be strongly suspected as a diagnosis when there is occipital
headache, especially when unilateral, and associated with constant
Temporomandibular Joint Disorders neck pain.
In 1934, Costen first drew attention to the temporomandibular joint Migraine in particular frequently presents with pain in the occip-
(TMJ) as a cause of facial and head pain. Until recently, Costen syn- ital and nuchal regions, which are innervated by the greater occip-
drome was a rare diagnosis. During the past 2 decades, however, ital nerve. Furthermore, muscle hypersensitivity and tenderness,
interest in disorders of the TMJ, the muscles of mastication, and the restriction of neck movements, and hyperalgesia may accompany
bite as they relate to headaches has been increasing. Painful temporo- the pain. Similarly, pain of cervical origin or cervicogenic headache
mandibular dysfunction is most common between the ages of 35 and is prominent in the occipital region but may also spread to trigeminal
publication.
territories. The referral of pain observed in cervicogenic headache the RVM in favor of a pro-nociceptive increased descending facilitation
and migraine reflects the convergence of trigeminal and cervical from the RVM (Meng and Harasawa, 2007; Okada-Ogawa et al., 2009).
afferents onto the same neurons in the trigeminal-cervical complex. Similar neural adaptations may contribute to opiate-induced MOH in
Despite this anatomical overlap, the provocation or exacerbation of humans by increasing the responsiveness of the nociceptive system,
the headache by neck movement, a persistent rather than intermittent as well as increasing the transmission of pain signals at the medullary
headache, and lack of photophobia, phonophobia, and nausea, are dorsal horn (De Felice and Porreca, 2009). Animal studies have found
features that may be helpful in distinguishing cervicogenic headache that sustained or repeated administration of triptans can also induce
from migraine. Diagnostic blocks performed accurately and under pro-nociceptive neural adaptations, enhance responses to established
controlled conditions are the only currently available means by which triggers of migraine headache, and lower cortical spreading depression
a cervical source of pain can be established. A positive response to threshold, the latter of which can increase the activation of the trigem-
occipital nerve block should be interpreted with caution, however, inal nucleus caudalis (De Felice et al., 2010; Green et al., 2014). Some
given the fact that many primary headaches, including migraine and individuals may possess a genetically determined liability to medi-
cluster headache, may respond to this procedure. The use of intra-ar- cation overuse. A FDG-PET study in patients with chronic analgesic
ticular steroids and long-acting anesthetics may provide relief that can overuse in migraine sufferers demonstrated persistent hypometabo-
last several months, and complete relief of headache can occasionally lism of the orbitofrontal cortex (especially in patients overusing com-
be achieved by radiofrequency neurotomy in patients whose head- bination analgesics) even after withdrawal of the overused medication.
ache stems from the C2 to C3 zygapophysial joint (Bogduk, 2004). Persistent orbitofrontal hypofunction is known to occur in substance
Physical therapy may also be helpful in the treatment of cervicogenic abuse (Fumal et al., 2006).
headache. Treatment of MOH is challenging and requires aggressive non-
pharmacological and appropriate acute and preventive headache
Medication Overuse Headache treatment. Rigorous controlled data are lacking, with current evi-
Overuse of acute medications by patients with frequent headache may dence supporting preventive therapy alone, withdrawal of overuse
lead to a daily headache syndrome, now known as medication overuse analgesics alone, and the combination of the two. It is generally con-
headache (MOH). Previously referred to as rebound or medication- sidered that lifestyle modifications such as limiting or eliminating
induced headache, this syndrome is induced and maintained by the caffeine consumption, exercise, and establishing regular mealtimes
very medications used to relieve the pain. Diagnostic criteria accord- and sleep schedules can be beneficial for some patients. Depression,
ing to ICHD-3 are designed to improve sensitivity, requiring only the anxiety, and sleep disturbances occur in more than half of patients
presence of chronic daily headache (CDH) in the setting of exposure to and must be addressed. Training in relaxation techniques and bio-
an overused analgesic (IHS, 2018). The risk for development of med- feedback may be helpful, especially if stress or anxiety is a frequent
ication overuse headache varies with individual substances. Opioids, provocative trigger. Patients should always be provided with support
butalbital-containing compounds, and some combination analgesics and close follow-up, particularly during the first 8 weeks after treat-
appear to have the highest risk; triptans carry moderate risk, and non- ment is initiated.
steroidal antiinflammatory drugs (NSAIDs) the lowest risk. In fact, Pharmacological treatment involves tapering or discontinuing
migraine prevention guidelines include recommendations for daily the overused medication. Abrupt drug withdrawal is the treatment of
NSAID exposure in the preventive treatment of migraine (Silberstein choice except with barbiturates, benzodiazepines, and opioids. Typical
et al., 2012). Further, there is longitudinal epidemiological evidence withdrawal symptoms last 2–10 days (mean 3.5 days) but may persist
that NSAID use among individuals with <10 headache days per month for 2–4 weeks. In most patients, the withdrawal can be managed on
is associated with a dose-dependent reduction in the development of an outpatient basis. Patients with coexistent medical or psychiatric ill-
chronic migraine (Lipton et al., 2013). nesses and overuse of agents containing opioids, benzodiazepines, and
The population prevalence of CDH associated with acute med- barbiturates may need hospitalization or withdrawal in a controlled
ication overuse has been estimated to be 1.4% (Colas et al., 2004). environment. Prednisone 60 mg daily for 5 days as a transitional and
The proportion of patients in the population with CDH who overuse short-term treatment during the withdrawal phase to reduce with-
acute medications ranges from 18% to 33%, indicating that medica- drawal symptoms can be considered and may decrease the need for
tion overuse is not necessary for the development of CDH, nor is the acute treatment during this time (Evers and Jensen, 2011; Rabe et al.,
overuse of acute medication synonymous with MOH. In other words, 2013). Preventive medication aimed at the underlying primary head-
tapering and discontinuing the overused medication does not always ache disorder should be started from the outset while initiating the
return the patient to an episodic pattern of headache. taper of the overused substance.
The most frequently overused acute medications include analge- Studies have indicated a high rate of relapse following withdrawal
sics, opioids, butalbital-containing products, ergotamine, and triptans, of acute headache medications in patients with presumed MOH. One
alone or in combination. The delay between the frequent intake of prospective study reported a relapse rate of 41% in the first year and
these medications and the development of CDH appears to be shortest 45% after 4 years (Katsarava et al., 2005). In another report with 4
for triptans (1.7 years), longer for ergots (2.7 years), and longest for years of follow-up, only one-third of patients initially treated for CDH
analgesics (4.8 years). The duration of withdrawal symptoms after dis- and analgesic overuse were successful in refraining from chronic over-
continuation and the recidivism rate are also shortest/lowest for trip- use of medication.
tans and longest/highest for analgesics. To avoid MOH relapse, in general, it is best to avoid the use of
The pathogenesis of MOH is unclear. A leading hypothesis sug- opioids and/or butalbital for the regular management of primary
gests facilitation of central trigeminal sensitization caused by a med- headache disorders. To prevent relapse, limit NSAIDs, aspirin, or acet-
ication-induced impairment of descending inhibition of nociceptive aminophen use to ≤14 days/month and limit combination analgesics,
trafficking. In rats, chronic morphine exposure increases the pain, triptans, ergot derivatives, or opioids to ≤9 days/month. Although
facilitating “on” cell activation in the rostral ventromedial medulla data are limited, the effectiveness of headache preventive medications
(RVM) that may alter the balance between the descending inhibition may be decreased by overuse of acute medications (Mathew et al.,
from the nucleus reticularis dorsalis (NRD) and the facilitation from 1990).
publication.
PRIMARY HEADACHES than 15 days per month. However, 2% of the general population has
“chronic migraine,” meaning that they have headaches on at least 15
Migraine days per month, including at least 8 days per month on which they
Definition and Classification have symptoms of full-blown migraine attacks (Natoli et al., 2010).
The term migraine derives from the ancient Greek word hemikranios, On average, people with chronic migraine have 22 headache days per
which means “half head,” underscoring the unilateral distribution of month. An estimated 7.5% of patients with episodic migraine when
head pain that is present in about 60%–75% of people with migraine followed quarterly will meet criteria for chronic migraine at least once
(Kelman, 2005; Wober-Bingol et al., 2004). Although not all people within a 15-month period, as compared to the 2.5% transformation
with migraine experience all potential phases of a migraine attack, rate observed when patients are evaluated annually (Bigal et al., 2008b;
the migraine attack can consist of up to four phases: the premoni- Serrano et al., 2017).
tory phase, aura, headache phase, and postdrome. In addition to head
pain, the “headache phase” consists of a combination of photophobia, Triggers of the Migraine Attack
phonophobia, osmophobia, cutaneous allodynia, nausea, and vomit- At least three-quarters of migraineurs can identify triggers of their
ing. Although osmophobia is not part of the formal diagnostic criteria migraine attacks (Kelman, 2007). However, it seems that the suscepti-
for migraine, when present, is considered to be highly specific for the bility of the migraine brain to potential migraine attack triggers fluctu-
disorder (Chalmer et al., 2018). Box 102.2 shows the classification of ates from day to day. Thus, many migraineurs will find that exposure
different encountered forms of migraine, including episodic migraine to a potential trigger does in fact trigger a migraine attack on some days
with aura, episodic migraine without aura, and chronic migraine (IHS, and does not on other days. The most commonly identified migraine
2018). attack triggers include emotional stress, fluctuating female hormones,
missed meals, weather factors, sleep disturbance, odors, certain visual
Epidemiology stimuli, alcohol, muscle tension, physical exercise, and being over-
A survey of a sample of 20,000 households estimated 27.9 million heated (Kelman, 2007). It has been noted that self-reported triggers are
migraine patients in the United States. More than 90% of patients not consistently validated when formally studied experimentally. For
report an impaired ability to function during migraine attacks, and example, photophobia, a hallmark of migraine often present during
53% report severe disability requiring bed rest. Approximately 31% the prodrome, may be misinterpreted by a patient as light triggering
of patients with migraine missed at least 1 day from work or school their headache.
in the preceding 3 months due to migraine (Lipton et al., 2001).
Indirect costs of migraine related to decreased productivity and lost The Migraine Attack
days of work have been calculated to be $13 billion per year; estimates Migraine prodrome. Many patients with migraine report that
are that the equivalent of 112 million bedridden days per year are due a prodromal phase precedes the headache, typically starting 1–2
to migraine (Hu et al., 1999). The World Health Organization has hours prior to onset of migraine headache (Kelman, 2004). The
declared migraine to be among the most disabling medical conditions most frequent prodromal symptoms include fatigue, mild cognitive
experienced worldwide. dysfunction, irritability, neck pain, light and noise sensitivity, blurred
Migraine has a 1-year prevalence of 12% in the general popula- vision, excessive yawning, and excessive thirst. When premonitory
tion, including 18% of women and 6% of men (Lipton et al., 2007; symptoms are observed by the migraineur, a migraine develops within
Rasmussen, 1995). Migraine afflicts prepubescent boys and girls with the next several days about three-quarters of the time.
a similar frequency. At puberty, the incidence of migraine increases Migraine aura. Migraine auras occur in about one-third of
sharply in both boys and girls, but preferentially so in girls. Peak migraine patients (Cutrer and Huerter, 2007). Most patients who
migraine prevalence for both sexes occurs in the fourth decade of have migraine attacks with aura also have attacks without aura,
life, during which time approximately 24% of women and 7% of men with only one-fifth of migraine-with-aura patients having aura with
have migraine (Lipton et al., 2007). Migraine tends to manifest with every migraine attack. Typical aura symptoms develop and progress
fluctuating frequencies of attacks throughout one’s life, with a typical gradually over several minutes and then resolve within 60 minutes.
trend towards milder and less frequent migraines late in life. The life- The resolution of aura symptoms often coincides with the onset of
time prevalence of migraine is about 33% in women and 13% in men headache. Much less commonly, aura symptoms can occur during the
(Launer et al., 1999). headache phase of the migraine attack, after the headache phase, or
Due to headache and other migraine symptoms, migraine causes in the absence of headache altogether (“acephalgic migraine” or “aura
substantial pain and disability. During a migraine attack, the vast without headache”). Individual aura symptoms may occur in isolation
majority of migraineurs have at least mild disability and about half during an individual migraine attack or more than one aura symptom
have severe disability, often requiring rest in a dark and quiet room may occur sequentially.
(Lipton et al., 2007). Overall, migraineurs have lower physical, emo- Visual phenomena are the most common aura symptom, reported
tional, and social quality of life. by over 80% of patients with migraine aura (Eriksen et al., 2004;
There is a genetic predisposition for developing migraine. Russell and Olesen, 1996). Like all migraine aura symptoms, visual
Compared to the general population, first-degree relatives of people symptoms progress slowly, moving across the visual field. Visual
who have migraine without aura are about twice as likely to develop auras consist of positive symptoms such as seeing flashing lights and
migraine without aura, while first-degree relatives of people who have wavy lines (“scintillating scotoma”), often followed by negative sco-
migraine with aura are about four times more likely to have migraine tomas within the same distribution of the preceding positive visual
with aura (Russell and Olesen, 1995). phenomena.
Sensory aura, the second most common aura type, is, like the visual
Migraine Attack Frequency aura, characterized by positive symptoms (paresthesias) followed
The majority of people with migraine have attacks 1–4 times per by negative symptoms (numbness), which slowly spread or migrate
month (Lipton et al., 2007). These migraineurs are considered to (Eriksen et al., 2004; Russell and Olesen, 1996). Sensory aura is usually
have “episodic migraine,” meaning they have headaches on fewer unilateral and has a predilection for the hand, arm, shoulder, and face.
publication.
This may be due to the large representation of these structures in the described as throbbing/pulsating, but other pain qualities are also
sensory cortex or thalamus. Commonly, sensory symptoms begin in common. Headache intensity increases over approximately 90 min-
the hand and then slowly spread up the ipsilateral arm to the shoulder utes before reaching moderate to severe intensity. Pain is intensified by
and face with perioral and tongue involvement. The rate of spread of physical activity in the majority of patients.
a sensory aura is important to help distinguish it from a sensory sei- During a migraine attack there is a hypersensitivity to visual,
zure and the sensory disturbance of a TIA. Just as a visual aura spreads auditory, cutaneous, and olfactory stimuli. Most migraineurs have
across the visual field slowly, taking as long as 20 minutes to reach hypersensitivity to light and visual patterns, exposure to which results
maximum, the paresthesias may take 10–20 minutes to spread from in generalized discomfort, visual discomfort, and worsening head-
the point at which they are first felt to their maximal distribution. This ache. Similarly, exposure to normal and loud volume sound results
is slower than the spread of a sensory seizure and much slower than in discomfort and worsening headache intensity in most migraineurs.
the spread of sensory symptoms associated with TIA. A migrainous Increased sensitivity to odors is present in a minority of migraineurs.
sensory aura generally resolves over the course of 20–60 minutes, most Scents that more commonly result in olfactory hypersensitivity include
often within 30 minutes. perfumes, food smells, and cigarette smoke.
After sensory aura, the next most common type is a language aura The experience of nonpainful stimuli (e.g., washing the face,
(Eriksen et al., 2004; Russell and Oleson, 1996). Expressive dysphasias, combing the hair) as painful on the skin is known as cutaneous allo-
including paraphasic errors, are the most common language symp- dynia, which develops in about two-thirds of migraineurs during a
toms of migraine aura, with receptive dysphasias being less common. migraine attack (Ashkenazi et al., 2007; Bigal et al., 2008a; Lipton
Language symptoms of migraine aura are typically of mild severity. et al., 2008). The allodynic migraineur experiences pain or dis-
When unilateral motor weakness is present with migraine aura, comfort with normally nonnoxious stimulation of the skin, such as
the diagnosis is “hemiplegic migraine.” Hemiplegic migraine can be occurs with light touch of the face or scalp, wearing eyeglasses, shav-
“familial” or “sporadic.” Motor weakness of hemiplegic migraine most ing the face, and wearing a tight collar or necklace. Although allody-
often involves the hand and arm. Although the term “-plegia” suggests nia symptoms are most commonly noted within the trigeminal nerve
paralysis, the motor symptom of hemiplegic migraine is usually weak- distribution, about one-fourth of migraineurs develop extracephalic
ness as opposed to true paralysis. In addition to the hemiparesis, there allodynia, typically involving the upper extremity (Mathew et al.,
must be at least one other aura symptom, including a visual, sensory, 2004). The identification of this feature is highly clinically relevant.
or language/speech symptom. Like with all migraine auras, the aura The presence of allodynia during an attack tends to predict a less
symptoms of hemiplegic migraine have a slow spreading onset over robust response to acute treatments (Lipton et al., 2017). Further,
several minutes, with each symptom resolving within 60 minutes. a history of allodynia increases ones risk of developing chronic
However, the motor weakness of hemiplegic migraine can endure for migraine (Louter et al., 2013), but then also predicts having a more
several days. The genetics of familial hemiplegic migraine are discussed favorable response to treatment with onabotulinumtoxinA (Mathew
further under Migraine Genetics. et al., 2008b).
When aura consists of at least two brainstem symptoms but no Nausea is present during the migraine attack in the majority of
motor or retinal symptoms, the diagnosis is “migraine with brainstem patients and vomiting occurs in about half. Besides the obvious dis-
aura” (previously called “basilar migraine”). Migraine with brainstem comfort of vomiting itself, vomiting can complicate the migraine
aura consists of a combination of fully reversible visual, sensory, and attack by leading to dehydration and preventing the absorption of
language/speech symptoms with at least two brainstem symptoms orally administered medications. Even when vomiting is absent,
including dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, and the absorption of orally administered migraine medications might
decreased level of consciousness. Each aura symptom resolves within be unpredictable due to the presence of gastric stasis (Aurora et al.,
60 minutes. 2006).
When a migraine aura is not followed by a headache, the episode Untreated, the migraine headache phase usually lasts from 4 to 72
is termed migraine aura without headache, a migraine equivalent, or hours, with the majority subsiding within a day or after a night’s sleep.
acephalgic migraine. Most commonly encountered in patients who When the migraine attack is debilitating and endures for longer than
have a past history of migraine with aura, the episodes can begin de 72 hours, “status migrainosus” is diagnosed.
novo, usually after 40 years of age, but they can occur at almost any age. Migraine postdrome. The majority of migraineurs continue to
Migraine equivalents are easily recognizable when the attacks occur on have migraine symptoms for up to 24 hours following resolution of the
a background of migraine with aura. In the absence of such a history, migraine headache (Kelman, 2006). The constellation of symptoms,
the transitory disturbance may be difficult to distinguish from an epi- commonly referred to by patients as the “migraine hangover,” is very
sode of transient cerebral or brainstem ischemia, and thus diagnostic similar to those symptoms experienced during the premonitory phase
tests might be required. of the migraine attack. Symptoms often include fatigue, mild cognitive
Headache phase. The headache of migraine is typically a dysfunction, atypical mood, generalized weakness, feeling dizzy,
moderate to severe unilateral throbbing pain that is exacerbated neck stiffness, light and sound hypersensitivity, and excessive thirst
by routine physical activities. In addition to the headache, patients (Kelman, 2006).
are hypersensitive to visual, auditory, olfactory, and somatosensory
stimuli, often resulting in the migraine patient desiring rest in a Physical Findings
dark and quiet room. Nausea, vomiting, and neck pain are frequent Between attacks, the migraineur should have a normal neurologi-
accompaniments. cal examination, with abnormalities on examination increasing
A migraine headache can be felt anywhere throughout the head, the suspicion for a secondary headache disorder. In addition to the
including retro- and periorbital locations, frontal, occipital, temporal, usual physical and neurological examinations, attention should be
vertex, and parietal regions. Pain is unilateral in 60%–75% of patients paid to examination of the temporal arteries, fundoscopy, cervi-
and bilateral in others (Kelman, 2005; Russell et al., 1996; Wober- cal and cranial muscles, and temporomandibular joint. During an
Bingol et al., 2004). Often, pain starts unilaterally and then becomes attack of migraine, the scalp vessels may be distended and tender.
bilateral as the migraine attack endures. Pain is most commonly The blood pressure is likely to be elevated due to the pain. Many
publication.
of the sodium-potassium ATPase pump (De Fusco et al., 2003). FHM3

BOX 102.2 Migraine
is associated with a mutation in the gene SCN1A on chromosome
Migraine without aura 2q24, SCN1A encoding the α subunit of a neuronal voltage-gated
Migraine with aura: sodium channel (Dichgans et al., 2005). Although FHM is a rare
Migraine with typical aura genetic subtype of migraine with aura, the clinical similarities (with
Migraine with brainstem aura typical migraine, with and without aura) suggest at least the possibility
Hemiplegic migraine of a shared pathophysiology. The discovery of a genetic locus for FHM
Retinal migraine has generated considerable interest and prompted a large effort in the
Chronic migraine field of molecular genetics to find the fundamental defects in the more
Complications of migraine: common forms of migraine.
Status migrainosus Common forms of migraine (e.g., migraine without aura, migraine
Persistent aura without infarction with aura) have complex underlying genetic profiles. It is estimated
Migrainous infarction that about half of the underlying propensity toward developing
Migraine aura-triggered seizure migraine is due to additive gene effects, while the other half is attrib-
Probable migraine: utable to environmental factors (Gasparini et al., 2013; Silberstein and
Probable migraine without aura Dodick, 2013). A meta-analysis of migraine genome-wide association
Probable migraine with aura studies (GWAS), including 375,000 individuals, revealed 44 genetic
Episodic syndromes that may be associated with migraine: variants involving 38 distinct loci across the genome that are associated
Recurrent gastrointestinal disturbance with either increased or decreased susceptibility to migraine (Gormley
Benign paroxysmal vertigo et al., 2016). Incredibly, both genes with previously known roles in
Benign paroxysmal torticollis nociception and ion channels were uncommon among the GWAS sus-
ceptibility loci. The identified genes were demonstrated to be enriched
Adapted from Headache Classification Committee of the International
predominantly in smooth and vascular tissue, as well as certain brain
Headache Society (IHS). 2018. The International Classification of
Headache Disorders, third ed. Cephalalgia 38 (1), 1–211. https://doi.
regions. Known functions of identified genes are diverse and include
org/10.1177/0333102417738202. cell–cell interactions, vascular biology, and synaptic regulation.
Given that susceptibility loci identified through GWAS each confer
only a very small individual effect size, researchers have used polygenic
patients are pale and clammy during the attack, especially if nause- risk scores to understand the cumulative impact of these common
ated. The patient is likely to object to the lights of the examination genetic variants. Interestingly, polygenic risk scores are larger in cases
room and try to avoid the glare of the ophthalmoscope during the of familial migraine than in individual population cases, indicating
eye examination. that an aggregation of common variants contribute to the genetic
architecture seen in families with migraine (Gormley et al., 2018).
Diagnostic Testing An accumulation of common variants is observed to an even greater
The majority of patients presenting with migraine do not require diag- extent among families with typical aura than without, and most prom-
nostic testing. There are no tests that help to rule in the migraine diag- inently in cases of hemiplegic migraine. Polygenic risk scores are also
nosis. Diagnostic tests may be needed to evaluate for other headache being studied in migraine to understand pleiotropy—where a single
causes when a patient has atypical or worrisome features identified genetic variant contributes to two distinct phenotypes. One example
during the patient interview and when there are unexplained abnor- of this was a demonstration of shared genetic susceptibility between
malities on the neurological examination. Although such investiga- migraine and stroke, which may, in part, account for the observed clin-
tions must be chosen based upon the clinician’s suspicions for specific ical comorbidity (Malik et al., 2015).
causes for a secondary headache, testing may include blood tests (e.g.,
thyroid stimulating hormone, ESR), MRI of the brain in non-acute Pathophysiology
settings, imaging of the cervical and intracranial arteries, imaging of Vascular versus neuronal. Whereas the migraine attack was once
the intracranial venous sinuses, cervical spine imaging, LP, sleep stud- considered attributable to vascular dysfunction, the migraine attack is
ies, and others. now considered to be primarily due to brain dysfunction, perhaps with
secondary vascular effects. Historically, the migraine aura was thought
Migraine Genetics to be due to cerebral vasoconstriction while the headache was thought
Although prior familial migraine studies have shown no clear to be due to cerebral vasodilation. However, there has been evidence
Mendelian inheritance patterns, recent genetic epidemiological sur- building against the role of the intracranial vasculature in generating
veys and large national registry-based twin studies strongly support the migraine attack. First, there is solid evidence from functional MRI
the hypothesis of a genetic contribution. Perhaps the most striking studies that a phase of focal hyperemia precedes the phase of oligemia
evidence of a genetic basis for migraine has come to us over the past during the migraine aura. Second, headache may begin while cortical
decade from investigation of familial hemiplegic migraine. blood flow remains reduced, thereby rendering obsolete the theory
Familial hemiplegic migraine (FHM) is a rare autosomal dominant that vasodilatation is the sole mechanism of the pain. The oligemia
subtype of migraine with aura in which, in the context of otherwise that spreads across the cerebral cortex at a rate of 2–4 mm/min during
typical migraine attacks, patients experience hemiplegia. Thus far, migraine aura does not conform to discrete vascular territories, making
three genes for FHM have been identified: CACNA1A, ATP1A2, and it also unlikely that vasospasm of individual cerebral arteries, with
SCNA1A. A mutation in CACNA1A, a gene located on chromosome subsequent cerebral ischemia, is the source of the aura. Furthermore,
19p13 that codes for the α1 subunit of a brain-specific voltage-gated a MRA study of nitroglycerin-triggered migraine attacks showed
P/Q-type calcium channel, is associated with FHM1 (Ophoff et al., no change in cerebral artery diameters during the migraine attack
1996). The gene mutation for FHM2 is on chromosome 1q23 in the (Schoonman et al., 2008). Thus, the current prevailing theory is that
ATP1A2 gene, a gene that encodes the α2 isoform of the major subunit the migraine attack is due to an alteration in normal brain function.
publication.
Atypical brain function during migraine likely involves widespread activation followed by the period of brain deactivation might corre-
areas of the brain, including regions within several different functional spond with the pattern of “positive” symptoms (e.g., visual scintilla-
networks that are responsible for processing pain, visual stimuli, tions) followed by “negative” symptoms (e.g., visual scotoma) typical
auditory stimuli, olfactory stimuli, regulating sleep and wakefulness, of the migraine aura, a notion supported by another more recent func-
and awareness (Charles, 2013). Atypical activity within these functional tional imaging study (Arngrim et al., 2017). The cortical spreading
networks and atypical interactions between them could associate with depression wave is not confined within the distribution of any partic-
migraine symptoms such as headache, allodynia, photosensitivity, ular cerebral artery, but crosses the areas perfused by the middle and
phonosensitivity, olfactory hypersensitivity, fatigue, and decreased posterior cerebral arteries while advancing with a distinct wave front
ability to concentrate. until some major change in cortical cellular architecture is reached
A migraine generator. The existence of a “migraine generator,” (e.g., at the central sulcus).
a brain region that is responsible for triggering the migraine attack, It is debated whether or not cortical spreading depression can
is a matter of debate. Searches for a migraine generator typically lead to activation of the trigeminocervical system and thus trigger the
center around pain-modulating regions of the brainstem and on the headache phase of the migraine attack (Burstein et al., 2012). Some
hypothalamus. In support of a brainstem region serving as a possible data suggest that cortical spreading depression evokes a series of
migraine generator, functional MRI studies performed during cortical, meningeal, and brainstem events consistent with the devel-
migraine attacks have demonstrated activation of brainstem regions opment of headache. In rat models, focal stimulation of the visual
(e.g., dorsal rostral pons) prior to activation of cortical regions and cortex induced CSD, and approximately 14 minutes later, triggered
prior to onset of migraine symptoms (Stankewitz and May, 2011). long-lasting activation of the meningeal nociceptors (Zhang et al.,
The hypothalamus has also been considered a possible migraine 2010). Some believe that this activation of meningeal nociceptors
generator, since many symptoms of the premonitory phase (e.g., mood triggers dura mater protein extravasation and release of vasoactive
changes, thirst, food cravings, excessive yawning, and drowsiness) are neuropeptides such as calcitonin gene-related peptide (CGRP) and
suggestive of hypothalamic dysfunction. A PET study of nitroglycerin- pituitary adenylate cyclase-activating polypeptide (PACAP), con-
triggered migraine attacks found premonitory phase activations in tributing to signaling along the trigeminovascular pathway (Dodick,
posterolateral hypothalamus, several brainstem regions (e.g., midbrain 2018).
tegmental area, periaqueductal gray, dorsal pons), and several cortical Interestingly, blockade of the trigeminal ganglion does not appear
areas (Maniyar et al., 2014). Another study used daily functional MRI to disrupt the CSD-induced activation of second-order neurons in
in one patient over 31 days and was able to capture three migraine the trigeminal nucleus caudalis (Lambert et al., 2011), suggesting
attacks. This showed increased activity in the hypothalamus 24 hours peripheral stimulation of this trigeminocervical system may not be
prior to the onset of headache pain, as well as functional coupling of the only mechanism by which the headache phase of the migraine
the hypothalamus with spinal trigeminal nuclei and with the dorsal attack is triggered. Furthermore, the majority of patients do not have
rostral pons (Schulte and May, 2016). migraine aura, or may experience aura without headache, or aura after
While a single brain region might generate the migraine attack, the headache phase has begun. Although there is some evidence to the
or functional alteration within a single brain region might reduce the contrary, presumably CSD does not occur prior to onset of migraine
threshold for the migraine attack to be generated, it seems probable without aura attacks. Thus, other mechanisms for trigeminocervical
that there is not a single “migraine generator” shared by all people activation and development of migraine headache likely exist. It may
with migraine and that there is not a single “migraine generator” be that physiological events during the premonitory phase contribute
within individuals from attack to attack. Migraine symptoms are quite to both the aura and migraine attack in genetically susceptible individ-
variable from attack to attack and from patient to patient. There is uals (Dodick, 2018).
not a specific symptom that is reliably identified as the first symptom The trigeminocervical system and migraine headache. The
from migraine attack to migraine attack. In fact, during the migraine trigeminocervical system is the basic anatomical system that underlies
attack there is substantial co-occurrence of symptoms, meaning that the migraine attack. The trigeminocervical system consists of the
multiple symptoms are present in an overlapping pattern, as opposed trigeminal and cervical sensory afferents from the pain-sensitive
to there being a linear cascade of one symptom leading to the next. intracranial and extracranial structures (e.g., dura mater, cerebral and
These clinical features of the migraine attack might suggest “parallel meningeal blood vessels, and posterior head/neck); the projections to
alteration” in the functional activity of several different brain regions the trigeminal ganglion and trigeminal nucleus caudalis (extending
and/or networks, as opposed to a “linear cascade” of dysfunction in caudally to include input from C2 and C3 nerve roots); ascending
one region leading to dysfunction in subsequent regions (Charles, fibers from the trigeminal nucleus caudalis to multiple brainstem,
2013). thalamic, hypothalamic, and basal ganglia nuclei; and the projections
Cortical spreading depression. Cortical spreading depression from these nuclei to higher-order cortical areas.
(CSD) is considered the electrophysiological substrate of the migraine Activation of the trigeminocervical system results in transmission
aura. CSD tends to start in the occipital lobe and spreads forward over of impulses centrally toward the first synapse within laminae I and IIo
the cerebral hemisphere at a rate of about 2–4 mm/min. The CSD wave of the trigeminal nucleus caudalis. From this point, nerve impulses
causes disruption in ionic gradients contributing to depolarization travel rostrally to the cortex via thalamic relay centers. Activation
followed by a period of hyperpolarization. Secondary to this CSD of the trigeminocervical system leads to release of vasoactive neuro-
wave, there is a corresponding initial phase of hyperemia followed by peptides from sensory afferents that innervate the major intracranial
oligemia. arteries, a process termed “neurogenic inflammation” (Akerman
In humans, CSD has been studied indirectly using functional imag- et al., 2013). Neuropeptides that are released include CGRP, substance
ing. One study using blood oxygenation level–dependent (BOLD) P, vasoactive intestinal polypeptide (VIP), nitric oxide (NO), and
functional MRI during visual aura was able to demonstrate waves of PACAP (Gasparini et al., 2013). Release of these vasoactive neuropep-
increased BOLD response followed by diminished BOLD signal, trav- tides results in vasodilation, plasma protein extravasation, inflamma-
elling over the occipital cortex at 3.5 mm/min, a rate similar to the tion, and likely contributes to causing the headache of the migraine
CSD in animal models (Hadjikhani et al., 2001). The period of brain attack.
publication.
The hyperexcitable migraine brain. The migraine brain has agents if possible. Use of estrogens and oral contraceptives should be
exuberant responses to sensory stimuli, a hyperexcitability likely linked discontinued if they are suspected of contributing to the headaches,
to the allodynia, photosensitivity, phonosensitivity, and olfactory although in some patients this may not be possible. Exercise programs
hypersensitivity of migraine. Functional MRI studies consistently to promote well-being, correction of dietary excesses, and avoidance of
show the migraine brain to have greater stimulus-inducted activations prolonged fasts and irregular sleeping habits can be helpful.
of regions that facilitate the perception of stimuli compared to the The topic of dietary factors in migraine is difficult. Radical alter-
nonmigraine brain (Datta et al., 2013; Moulton et al., 2011; Schwedt ations in the diet are rarely justified and seldom effective. A diet
et al., 2015). It is not yet clear whether these exuberant activations favoring both an increase in omega-3 and reduction in omega-6 fatty
are attributable to intrinsic cortical excitability, a lack of cortical acid intake is both healthy and may be useful in longitudinal head-
inhibition, or a combination of both processes (Diener et al., 2012). ache reduction (Ramsden et al., 2013). Avoidance of foods contain-
In the migraine brain, brainstem regions that are primarily pain ing nitrites (e.g., hot dogs, preserved cold cuts) and prepared foods
inhibiting have been demonstrated to hypoactivate in response to pain, containing monosodium glutamate can be helpful. Avoiding mono-
further enhancing the migraine pain experience (Moulton et al., 2008). sodium glutamate can be difficult because it is a constituent of many
Furthermore, electrophysiological and functional imaging studies have canned and prepared foods and is widely used in restaurants, especially
shown that the interictal migraine brain lacks the normal habituating in the preparation of Chinese dishes. Ripened cheeses, fermented food
response to recurrent or prolonged stimuli, making the migraine items, red wine, chocolate, chicken liver, pork, and many other foods
patient less likely to acclimate to such stimuli (Stankewitz et al., 2013). have been suspected of precipitating headaches. These foods mostly
Recurrent and/or prolonged activation of the trigeminocervical contain tyramine, phenylethylamine, and octopamine. An occasional
system can lead to peripheral and central sensitization. Sensitized patient identifies an offending foodstuff, but in our experience, dietary
neurons have lower thresholds for activation, increased spontaneous precipitation of migraine is uncommon. Other headache authorities
activity, and receptive field expansion. Approximately three-fourths disagree. In some migraineurs, strong odors, especially of the perfume
of people with migraine have evidence of central sensitization (e.g., or aromatic type, precipitate attacks. Avoiding the use of strong-smell-
reduced pain thresholds within trigeminal nerve and extratrigeminal ing soaps, shampoos, perfumes, and other substances can be helpful
nerve territories) during the migraine attack (Burstein et al., 2000). for some individuals.
Approximately two-thirds of all people with migraine develop cuta- Persons with migraine may note that stress is a trigger for attacks
neous allodynia during a migraine attack, a clinical manifestation of but helping them deal with or avoid stress is difficult. Long-term stress
sensitization (Ashkenazi et al., 2007; Bigal et al., 2008a; Lipton et al., management may require the help of a psychologist or other appropri-
2008). Existence of sensitization during a migraine attack results in ately trained professional. Useful self-management techniques include
increased pain and discomfort and might reduce the effectiveness of biofeedback, relaxation training, hypnosis, and cognitive behavioral
migraine abortive therapies. training.
Pharmacotherapy. Medical therapy can be administered
Treatment and Management prophylactically to prevent attacks of migraine or symptomatically
The nature of the disorder should be explained to the patient and to relieve the pain, nausea, and vomiting of an attack. Prophylactic
reassurance given that although it is a painful and potentially dis- therapy is needed when the frequency or duration of attacks seriously
abling disorder, migraine has an overall favorable prognosis. Explain interferes with the patient’s lifestyle. Other indications for prophylaxis
that migraine is now thought of as a genetic disorder of the brain that include severe or prolonged neurological symptoms or lack of
causes headache and sensitivity to the environment. Explain that a cure response to symptomatic treatment. In general, prophylaxis should be
for migraine is lacking, but management is available. It is important considered if attacks occur as often as 1–2 days a week. Patients with
that patients feel the physician understands that their headaches rep- frequent migraine headaches commonly need both symptomatic and
resent a medical problem and does not consider them to arise from prophylactic treatments.
psychological factors. In fact, physicians underestimate that an expla-
nation of the condition may be a primary outcome the patient wants Symptomatic Treatment
out of the visit. A normal head CT or MRI scan may offer considerable An individualized strategy for migraine treatment is necessary because
reassurance. Some patients are more interested in knowing that they no single approach is effective for all patients. Symptomatic treatment
do not have a brain tumor or other potentially lethal condition than should start as early in the development of an attack as possible. If an
they are in obtaining relief from the pain. aura is recognized, patients should take medications during it rather
Avoidance of trigger factors, especially those that are noxious in than waiting for the pain to begin. An evidence assessment of acute
nature (e.g., strong perfumes, gasoline) is important in the management migraine pharmacotherapies from the American Headache Society
of migraine, but simply advising a patient to avoid stress and relax more (AHS) has been published (Marmura et al., 2015). Limits should be
is usually meaningless. In fact, the standard advice to avoid triggers explained regarding frequency of acute treatment use to guard against
has been challenged by a clinical trial demonstrating that habituation medication overuse headache (see Medication Overuse Headache sec-
strategies to certain triggers (e.g., bright lights) are associated with pro- tion, previously).
spective reductions in headache days, as opposed to avoidance (Martin For many, nonspecific medications such as simple oral analgesics
et al., 2014). The concept is highlighted by the common experience of (e.g., aspirin, acetaminophen, naproxen, ibuprofen), or an analgesic
perceiving bright lights upon exiting a dark movie theater, where avoid- combination with caffeine, may be effective if pain is not very severe.
ance of light causes a maladaptive increased sensitivity over time. Caffeine aids absorption, helps induce vasoconstriction, and may
Advice to reduce excessive caffeine intake, to stop smoking, and reduce the firing of serotonergic brainstem neurons. Another nonspe-
to reduce alcohol intake is often useful. Medication use should be cific combination analgesic which may be useful in the symptomatic
reviewed and modified if necessary. The use of drugs known to cause treatment of migraine is the sympathomimetic agent isometheptene
headaches (e.g., proton-pump inhibitors, reserpine, nifedipine, the- mucate. It is available in proprietary preparations combined with acet-
ophylline derivatives, caffeine, vasodilators [including long-acting aminophen and dichloralphenazone and has the advantages of not
nitrates], alcohol) should be discontinued, or substituted for other increasing nausea and being well-tolerated, but it may fail to give relief
publication.
for severe attacks. Table 102.4 lists some commonly used nonspecific and an antiemetic with dopamine receptor type 2 antagonist prop-
acute migraine treatments. Certain aromatic oils (e.g., lavender) may erties (e.g., prochlorperazine, metoclopramide) targets multiple sub-
provide relief. The patient may need rest in a dark, quiet room with an strates of acute migraine pathophysiology. A randomized clinical trial
ice pack on the head. This provides the best situation for the analgesic has demonstrated superiority of stratified (medication choice based
to relieve the pain. If sleep occurs, the patient often awakens headache on attack severity and disability) over step (always taking NSAID first
free. and waiting to take a triptan) care in the acute treatment of migraine
Migraine-specific drugs (triptans and ergot derivatives) can be used (Lipton et al., 2000). Across 6 attacks, more favorable outcomes for
if nonspecific analgesics do not provide adequate relief or if pain is stratified treatment were reported for headache response rates, head-
severe from onset, these are discussed below. Migraine-specific drugs ache disability, and direct costs of care.
are more efficacious than nonspecific analgesics, particularly when Symptomatic treatment of migraine with typical aura is essentially
migraine headaches are disabling. Triptans are easier to use and have the same as that described previously, although some data suggest sub-
fewer adverse effects than dihydroergotamine. Lasmiditan, a selective cutaneous sumatriptan may not be effective if taken during the aura
5-HT1F agonist without vasoconstrictive properties has shown compa- phase before headache onset. This, however, remains an unsettled con-
rable efficacy to triptans in phase III clinical trials. troversy. Modification of the aura is rarely possible or needed.
It must be recalled, that once the migraine attack is fully developed, Triptans. The development of sumatriptan heralded a new class of
oral preparations are almost always less effective because of decreased antimigraine agents that are highly selective at certain 5-HT receptors.
gastrointestinal motility and poor absorption. If severe nausea or These agents, collectively called triptans, together with the less-selective
vomiting develops, nonoral routes of administration are often nec- ergot preparations, have strong agonist activity at the 5-HT1B receptor,
essary (suppository, intranasal, and/or injections). Antiemetics may which mediates cranial vessel constriction, and at the 5-HT1D receptor,
be needed as adjunctive treatment, in addition to nonspecific and/or which leads to inhibition of the release of sensory neuropeptides from
migraine-specific medications when nausea and vomiting are present. perivascular trigeminal afferents. Experiments show that activation of
Combining acute treatments with different mechanisms of action 5-HT1B/5-HT1D receptors can attenuate the excitability of cells in the
(e.g., rationale polytherapy) is more effective than a single agent. In TNC, which receives input from the trigeminal nerve. Accordingly,
the case of migraine, a combination of an NSAID, triptan or ergot, 5-HT1B/5-HT1D agonists may act at central as well as peripheral
components of the trigeminal vascular system, and at least part of their
clinical action may be centrally mediated.
TABLE 102.4 Some Commonly Used Oral
Administration of sumatriptan can be oral, intranasal, and by
Nonspecific Acute Migraine Treatments subcutaneous injection (Table 102.5, eTables 102.6 and 102.7). Self-
Agent Single Dose administered as a 6-mg subcutaneous injection, either using the manu-
Acetaminophen 1000 mg facturer’s auto-injector device or conventional subcutaneous injection,
Aspirin 500–1000 mg sumatriptan results in significant pain relief at 1- and 2-hour time
Ibuprofen 200–400 mg points after drug administration (see eTable 102.6). For patients who
Naproxen sodium 550 mg had no significant pain relief after 1 hour, administration of a second
Diclofenac potassium 50–100 mg dose of 6 mg provided little further benefit. Side effects of sumatrip-
Ketoprofen 75–100 mg tan by injection include local reaction at the injection site, usually of
Flurbiprofen 100 mg mild or moderate severity, and a transient tingling or flushed sensa-
Acetaminophen/aspirin/caffeine 500/500/130 mg tion that may localize or generalize. A more unpleasant sense of heavi-
Acetaminophen 325 mg/isometheptene 2 CAP, then 1 CAP q 1 h PRN; ness or pressure in the neck or chest occurs in a small percentage of
mucate 65 mg/dichloralphenazone 100 mg maximum 5 CAP/12 h recipients. It rarely lasts more than a few minutes and is generally not
associated with electrocardiogram (ECG) changes or other evidence of
TABLE 102.5 Serotonin (5-HT) Agonists Used in Acute Migraine Treatment

May Repeat Doses if Maximum Dose
Drug Route(s) Dose Headache Recurs (h) per 24 h (mg)
Dihydroergotamine IV 0.5, 1 mg 1 3
(DHE-45) IM 0.5, 1 mg 1 3
SQ 0.5, 1 mg 1 3
(Migranal) Nasal spray 2 mg (0.5 mg/spray) one spray in each 3
nostril, repeat in 15 min
Almotriptan (Axert) Oral 6.25, 12.5 mg 2 25
Eletriptan (Relpax) Oral 20, 40 mg 2 80
Frovatriptan (Frova) Oral 2.5 mg 2 7.5
Naratriptan (Amerge) Oral 1 mg, 2.5 mg* 4 5
Rizatriptan (Maxalt) Oral 5 mg, 10 mg* 2 30
Sumatriptan (Imitrex) Oral 25 mg, 50 mg, 100 mg 2 200
SQ 4, 6 mg 1 12
Intranasal 5 mg, 20 mg* 2 40
Zolmitriptan (Zomig) Oral 2.5 mg,* 5 mg 2 10
Intranasal 5 mg 2 10
IM, Intramuscular; IV, intravenous; SQ, subcutaneous.
*These are the recommended starting dosages based on efficacy and tolerability.
publication.
myocardial ischemia. However, because sumatriptan has been shown tartrate and may prevent vomiting. For patients who are close to vom-
to produce a minor reduction in coronary artery diameter, it should iting or who are vomiting, an antiemetic suppository such as chlor-
be used with caution in patients who have significant risk factors for promazine (25–100 mg) or prochlorperazine (25 mg) can be helpful.
coronary artery disease and should not be given to patients with any If more than 6 mg of ergotamine is required per week, use an alterna-
history suggestive of coronary insufficiency. It is also contraindicated tive preparation.
in patients with untreated hypertension, ischemic or vaso-occlusive Ergotamine must be used cautiously by patients with hypertension
cerebrovascular disease, peripheral vascular disease, and in those using and those with peripheral vascular disease. It is contraindicated in
ergot preparations. It is contraindicated in women during pregnancy patients with coronary artery disease and in women who are pregnant.
and in patients with hemiplegic migraine or migraine with brainstem It is unwise to administer ergotamine to patients in whom the aura is
aura (previously “basilar-type migraine”). Per the American Academy particularly prolonged or characterized by a major neurological deficit.
of Pediatrics, at present, sumatriptan belongs to the group of medica- The fear of potentiating the vasospasm to the point of cerebral infarc-
tions usually compatible with breast feeding. tion may be unjustified but avoid the potential risk by withholding
Seven triptans are now available in the United States. All seem to potent vasoconstrictors.
have a beneficial effect on migraine-associated symptoms, including Dihydroergotamine (DHE) has been a treatment for migraine
nausea, photophobia, and phonophobia, which also improves the since the 1940s. Its poor oral bioavailability limits its administration
patient’s ability to return to normal functioning. eTable 102.7 provides to the parenteral and intranasal routes (see Table 102.5 and eTable
a comparison of the currently available oral triptans. The potential side 102.6). Patients can self-administer this drug by each of these routes.
effects are quite similar: tingling, flushing, and a feeling of fullness in This medication should be considered when nausea and vomiting
the head, neck, or chest. In general, the indications and contraindica- limit the use of oral medications or when other medications are
tions for all 5-HT1 agonists are similar. They are not safe when admin- ineffective. Although DHE’s effects are slower than sumatriptan (see
istered within 24 hours of ergot preparations or other members of the eTable 102.6), efficacy after 2 hours is similar, and the drug is asso-
triptan class. ciated with a lower recurrence of headache in 24 hours. Increased
At this time, no evidence exists to allow accurate prediction of nausea in some patients may require combination with an antiemetic
which of these agents will be most effective in a given patient. A few agent. When given intravenously in an acute medical care setting,
practical guidelines are available, based on the clinical situation and use of an antiemetic is mandatory. A new inhaled formulation of
knowledge about available agents. If severe nausea or vomiting occurs DHE is currently being evaluated for US FDA approval. This new
early in an attack, the parenteral or intranasal routes should be used. formulation may provide a means of administering DHE without IV
Some patients may prefer nasal or injectable routes (sumatriptan infusion.
and zolmitriptan). Zolmitriptan is available as an oral and intrana- Status migrainosus. For many patients, an attack of migraine
sal preparation. For patients with benign but intolerable side effects becomes a harrowing experience. After a variable period, they go to
from this group of medications, consider naratriptan, almotriptan, or an emergency room or physician’s office for further treatment. Status
frovatriptan, given their favorable side-effect profiles. Recurrence of migrainosus is described as a debilitating migraine attack lasting
headache after initial relief may necessitate a repeat dose. With future for more than 72 hours (IHS, 2018). While there are no concrete
attacks, a higher dose (if available) may be used, or the triptan can guidelines currently available for status migrainosus treatment, several
be combined with an NSAID and/or an antiemetic. If one agent fails, strategies have been used by some in the past. At our institution we
it seems reasonable, barring major side effects, to try another agent have developed consensus among headache specialists for adult status
in the class. Since there is evidence that some of these agents have a migrainosus management recommendations based on available
lower oral bioavailability when taken by patients with migraine, both evidence, guidelines, and clinical experience (Fig. 102.6; Garza and
during an attack and interictally (Aurora et al., 2006), it is logical to Cutrer, n.d.). These do not replace clinical judgment but may assist the
consider combining them with metoclopramide to improve gastric provider with decision making when encountering status migrainosus.
emptying. Although, strictly defined, status migrainosus is a migraine headache
Ergots. Although increasingly less available and supplanted in lasting >72 hours, treatment often needs to start earlier if associated
many cases by newer agents, ergot preparations still have a role in with significant uncontrolled vomiting and/or dehydration. In this
the symptomatic treatment of migraine. The actions of ergotamine model, if IV access is present, initial treatment consists of IV hydration,
tartrate and other ergot preparations are complex. They are both IV ketorolac 30 mg, and a neuroleptic antiemetic of choice (commonly
vasoconstrictors and vasodilators, depending on the dose and the prochlorperazine, metoclopramide, or promethazine) as needed.
resting tone of the target vessels, and probably exert their effects on Specific status migrainosus treatment protocols using neuroleptic
migraine via agonist activity at 5-HT receptors. Oral preparations are antiemetics have been published (Bell et al., 1990; Fisher, 1995; Lane
far less effective than those given rectally or parenterally. et al., 1989; McEwen et al., 1987; Richman et al., 2002; Tek et al., 1990;
If selected for use, 2 mg of ergotamine tartrate by mouth should Wang et al., 1997). To avoid extrapyramidal reactions with neuroleptic
be taken as soon as the patient recognizes the symptoms of an acute antiemetics, consideration can be given to pretreating with 1 mg oral
migraine attack. This dose, combined with a simple oral analgesic-caf- (PO), intramuscular (IM), or IV benztropine mesylate. Benztropine is
feine combination, can be taken again in 1 hour. Possibly a better typically given to patients with a history of an extrapyramidal reaction
regimen, but inconvenient and unpleasant to some patients, is ergot- to the chosen antiemetic, but not routinely. If IV access is not available,
amine tartrate by rectal suppository. The patient should be instructed IM ketorolac with or without promethazine may be a good alternative.
to insert a 1- or 2-mg rectal suppository of ergotamine tartrate at Patients with significant dehydration, complex coexisting medical
the onset of the aura or pain and take a simple analgesic orally. The problems and those requiring prolonged parenteral treatment may need
ergot preparation can be repeated in 60 minutes if needed. Experience to be hospitalized (Garza and Cutrer, n.d.). If initial measures fail and
over the course of several attacks is useful to determine the amount proper expertise is available, consideration can be given to extracranial
of ergotamine needed to obtain relief. With subsequent attacks, the nerve blocks directed to the area or areas of pain such as occipital,
entire dose can be taken at onset. If nausea is troublesome, metoclo- supraorbital, or auriculotemporal nerves and/or the sphenopalatine
pramide in doses of 10 mg orally aids absorption of the ergotamine ganglion. If DHE is needed for a patient in a short-term stay setting
publication.
eTABLE 102.6 Subcutaneous and Intranasal Serotonin (5-HT) Agonists

HEADACHE RESPONSE (%)*
Recurrence of
Drug Dose (mg) 1h 2h 4h Headache (%)†
Dihydroergotamine
Subcutaneous 1 57 73 85 18
Intranasal 2 46 47–61 56–70 14
Sumatriptan
Subcutaneous 6 70 75 83 35–40
Intranasal 20 55 60 NA 35–40
Zolmitriptan
Intranasal 5 55 70 78 25
NA, Not available.
*Headache response is defined as a reduction of headache severity from moderate or severe pain to mild or no pain.
†Recurrence of headache within 24 h after initial headache response.
eTABLE 102.7 Oral Serotonin (5-HT) Agonists

HEADACHE RESPONSE (%)*
Recurrence of
Drug Dose (mg) 1h 2h 4h Headache (%)†
Almotriptan 12.5 35 57 NA 23
Eletriptan 20 20 49 NA 30
40 30 60 NA 22
Frovatriptan 2.5 NA 42 61 10–25
Naratriptan 1 19 42 51 17–28
2.5 21 48 67 2.5
Rizatriptan 5 30 60 NA 30–35
10 37 67–77 NA 10
Sumatriptan 25 NA 52 68 35–40
50 NA 50 70 50
100 NA 56 75 100
Zolmitriptan 2.5 38 64 75 31
5 44 66 77 5
Note: Composite data from product information inserts and literature.
NA, Not available.
*Headache response is defined as a reduction in headache severity from moderate or severe pain to mild or no pain.
†Recurrence of headache within 24 h after initial headache response.
publication.
Status migrainosus
confirmed
Initial treatment
Yes
Dismiss and
Resolved?
outpatient follow-up
No
Consider extracranial
nerve clocks
Yes
Dismiss and
Resolved?
No
Administer DHE No
Contraindications to
according to clinical dihydroergotamine
setting (DHE)?
Yes
No
Resolved? IV valproic acid
Yes Yes
Dismiss and
Resolved?
Dismiss and
outpatient follow-up No
Current Yes
opioid Neurology consult
overuse?
IV opiate of choice
Yes
Dismiss and
Resolved?
No
Neurology consult
Fig. 102.6 Status Migrainosus Management Recommendations for Adult Patients at our Institution.
IV, Intravenous.(Adapted from (Garza and Cutrer, n.d.). Used with permission of Mayo Foundation for Medi-
cal Education and Research, all rights reserved.)
such as the emergency room, it is administered as a 0.5 mg IV test dose DHE initiates at 3 mg in 1000 mL normal saline and is administered
and if tolerated may repeat DHE 0.5 mg IV 30–60 minutes later (total IV at 42 mL/h but if significant nausea the rate is reduced to 21–30
1 mg). If inpatient, however, DHE is administered instead with IV 0.5– mL/h (may continue up to 7 days if needed). Patients getting IV DHE
1.0 mg doses (depending on tolerance every 8 hours as needed (“Raskin are commonly pretreated with IV metoclopramide (with or without
protocol”) (Raskin, 1990) for up to 2–5 days or via continuous IV benztropine mesylate as discussed above) if no other antiemetic has
DHE infusion (“Ford protocol”) (Ford and Ford, 1997). In the latter, been given, and the antiemetic is repeated as needed while on IV DHE
publication.
treatment. When used, IV valproic acid starts with a loading dose of 15 β-Adrenergic blockers. β-Adrenergic antagonists are widely used for
mg/kg in D5W (5% dextrose in water) or normal saline at 20 mg/min prophylaxis of migraine headaches (Silberstein et al., 2012). Propranolol
and is followed by 5 mg/kg every 8 hours as needed (Schwartz et al., in doses of 80–240 mg/day, if tolerated, should be given a trial of 2–3
2002). An alternative IV valproic acid protocol is 1 g in 250 mL normal months. Compliance increases with the use of a long-acting form of
saline over 1 hour (Edwards et al., 2001). A very common valproic propranolol given once daily. Side effects are not usually severe. Lethargy
acid IV dosing, however, is 500 mg at 20 mg/min × 1 dose (after 1000 or depression may occur and may be a reason for discontinuation
mL normal saline) (Garza and Cutrer, n.d.). One of the main goals of of the medication. Hypotension, bradycardia, impotence, insomnia,
this approach is to avoid opiate/opioid use as much as possible when and nightmares can all occur. As with all β-adrenergic blocking
managing status migrainosus, to minimize the risk of medication agents, propranolol should be discontinued slowly to avoid cardiac
overuse headache. Dexamethasone (10 mg IV) may be given prior to complications. It is contraindicated in persons with a history of asthma
dismissal to help prevent headache recurrence (Garza and Cutrer, n.d.). or severe depression and should be used with caution in patients using
insulin or oral hypoglycemic agents, because it may mask the adrenergic
Prophylactic Treatment symptoms of hypoglycemia. Timolol, nadolol, atenolol, and metoprolol
A preventive program is appropriate when attacks occur weekly or sev- probably have approximately the same benefit in migraine as propranolol.
eral times a month, or when they occur less often but are very prolonged The mechanism of action is not known. The only pharmacological trait
and debilitating. The most effective prophylactic agents available typi- that separates β-adrenergic blocking agents effective in migraine from
cally reduce headache frequency by at least 50% in approximately 50% those that are not is a lack of sympathomimetic activity.
of patients. Calcium channel blockers. Although the relevant mechanism
Preventive medications are generally titrated gradually to the min- by which calcium channel antagonists affect migraine is not known,
imum effective or maximum tolerated dosage. This target dosage is their use in migraine was originally based on their ability to prevent
maintained for at least 3 months, and if there is a beneficial response, vasoconstriction and on their other actions, including prevention of
the medication is continued until there has been clinical stabilization platelet aggregation and alterations in release and reuptake of serotonin.
for at least 6–12 months. The full benefit of a preventive medication Several clinical trials have indicated some benefit for verapamil and
may take up to 6 months to be realized. In a clinical trial evaluating the flunarizine in preventing recurrent migraine. Little evidence exists to
impact of discontinuing preventive therapy, patients taking topiramate support the use of nimodipine. Verapamil in doses of 80–160 mg three
were randomized for 6-months to either continue topiramate or switch times a day reduces the incidence of migraine with aura, but it is not
to a placebo (Diener et al., 2007a). Remarkably, although patients con- as useful in migraine without aura. Experience with diltiazem is too
tinuing topiramate tended to have overall better headache outcomes, limited to permit an assessment of its value at this time.
patients switching to placebo maintained improvements, compared to Antidepressants. Amitriptyline and other tricyclic antidepressants
their pre-treatment baseline. Therefore, a discussion regarding treatment can be helpful in migraine prophylaxis (Silberstein et al., 2012).
discontinuation is reasonable after 6 months if patients are doing well. The benefit seems to be independent of their antidepressant action,
Multiple guidelines exist for the selection of preventive therapies which typically requires doses higher than that used for migraine.
for episodic migraine, including the American Academy of Neurology Used in doses of 10–150 mg at night, amitriptyline, nortriptyline,
(AAN)/American Headache Society (AHS), Canadian Headache imipramine, or desipramine may all provide some reduction in
Society and the European Federation of Neurological Societies (Loder attacks of migraine, although evidence of efficacy in clinical trials is
et al., 2012). The levels of recommendation made by the AAN/AHS available only for amitriptyline. Protriptyline is an alternative without
are based on the strength of efficacy data alone, while the Canadian sedating properties, although there is no support in the literature for
and European guidelines factor in a balance of potential benefits and its use in chronic migraine. Side effects can be rather troublesome.
harms. First-line therapies, including topiramate, divalproex, metop- Morning drowsiness, dryness of mouth, weight gain, tachycardia,
rolol, and propranolol are given first-line recommendation status by and constipation are common. The anticholinergic side effects may
all guidelines (Loder et al., 2012). In our practice, a process of shared decrease with time. If tolerated, give the tricyclic agents a trial of at
decision making with consideration for the strength of available clin- least 3 months after reaching a therapeutic dose. The optimal dose
ical trial data, potential side effects, and individual patient treatment for migraine prophylaxis is determined by titration to the effective or
preferences and goals is employed. Table 102.8 lists some commonly maximum tolerated dose within the therapeutic range (e.g. usually
used migraine preventive medications in our practice. 50–150 mg for amitriptyline and nortriptyline).
TABLE 102.8 Some Commonly Used Migraine Preventive Medications

Drug Initial Dose (mg) Typical Daily Dose Range Common Adverse Effects Serious Adverse Effects
Amitriptyline 10–25 25–150 Weight gain, constipation, sedation Cardiac dysrhythmias
Nortriptyline 10–25 25–150 Weight gain, constipation, sedation Cardiac dysrhythmias
Protriptyline 5–10 10–30 Constipation, sedation Cardiac dysrhythmias
Topiramate 15–25 75–200 Paresthesias, fatigue, weight loss, cognitive Glaucoma, hyperthermia, meta-
impairment bolic acidosis, nephrolithiasis
Divalproex 250–500 750–1500 Alopecia, weight gain, tremor, nausea Pancreatitis, liver failure,
sodium thrombocytopenia
Gabapentin 300 900–2400 Dizziness, fatigue, edema, sedation
Propranolol 40–60 40–240 Depression, fatigue Bradyarrhythmia
Atenolol 25 50–100 Depression, fatigue Bradyarrhythmia
Verapamil 80–160 160–480 Edema, constipation Hypotension, dysrhythmias
Adapted from Garza, I., Swanson, J.W., 2006. Prophylaxis of migraine. Neuropsychiatr. Dis. Treat. 2 (3), 281–291.
publication.
Selective serotonin reuptake inhibitors have not consistently central serotonin agonist, is no longer available in the United States
proven to be effective for migraine prophylaxis and in some cases and Canada. Historically, it was a very useful agent despite its potential
may elicit or aggravate headaches. Given the frequent comorbidity of for producing serious complications.
generalized anxiety disorder and panic disorder, a serotonin-norepi- Two small clinical trials have demonstrated efficacy of an extract of
nephrine reuptake inhibitor such as venlafaxine may be considered if butterbur root in migraine prophylaxis, at a total daily dose of 150 mg
a single agent is desired. Venlafaxine is probably used less commonly daily (in two or three divided doses). The treatment is well tolerated,
than the tricyclic antidepressants discussed above. Nonetheless, ven- but gastrointestinal symptoms may occur. Recently, the safety of but-
lafaxine was found to be effective in a placebo-controlled trial and terbur root has come into question due to potential for hepatotoxicity
remains an option which may prevent migraine headaches in some. and carcinogenesis.
Among patients with comorbid generalized anxiety disorder, venlafax- Riboflavin administered orally in a dose of 400 mg/day has been
ine may be an appropriate weight-neutral treatment option to facilitate shown by Schoenen to be effective in migraine prophylaxis in a pro-
dual treatment. spective randomized controlled study that enrolled a relatively small
There are uncontrolled studies to support the use of the mono- number of subjects. Its effect on the frequency of attacks was not statis-
amine oxidase inhibitor (MAOI) phenelzine for migraine prophylaxis. tically significant until the third month of the trial. There are minimal
Unfortunately, the dietary restrictions that must be carefully followed side effects associated with this agent.
if a hypertensive crisis is to be avoided limit the widespread use of Evidence is mixed regarding the efficacy of magnesium in migraine
these inhibitors for prevention of migraine. Dangerous drug interac- prophylaxis. Oral magnesium supplementation with 600 mg of a
tions can occur with preparations such as sympathomimetic agents, chelated or slow-release preparation is the recommended dosage.
central anticholinergics, tricyclic antidepressants, and opioids, espe- Magnesium-induced diarrhea and gastric irritation are the most com-
cially meperidine. Side effects of MAOIs include hypotension as well mon side effects.
as hypertension, agitation, hallucinations, retention of urine, and inhi- Aspirin, 325 mg, taken every other day for the prevention of cardio-
bition of ejaculation. vascular disease, may slightly reduce the frequency of migraine. NSAIDs
Anticonvulsants. Antiepileptic medications are in general a highly are being increasingly recognized as having benefit in migraine pro-
efficacious class of prophylactic treatment. Their mechanisms of action phylaxis and may be associated with reduced risk of chronic migraine
in migraine prophylaxis are unknown. development in individuals with less than 10 headache days per month
In the early 1990s, several blinded placebo-controlled studies based on epidemiological studies (Lipton et al., 2013).
showed a beneficial effect of valproate in the prophylactic treatment OnabotulinumtoxinA injection in the treatment of chronic migraine
of migraine; 50% of patients showed a response with a 50% or bet- is now supported by two large multicenter placebo-controlled random-
ter reduction in migraine incidence. Valproic acid, given in the form ized clinical trials and is currently the only FDA-approved treatment
of divalproex sodium, is generally effective (Silberstein et al., 2012) specifically for chronic migraine (Dodick et al., 2010) (see chronic
at a range of 500–1750 mg/day, taken in divided doses. Side effects migraine discussion). OnabotulinumtoxinA is established as ineffective
include sedation, dizziness, increased appetite, increased bleeding and should not be offered for episodic migraine (Simpson et al., 2016).
time, increased fragility of hair, and an asymptomatic increase in liver Candesartan (angiotensin II receptor blocker), at a dose up to 16 mg
function test values. Valproate is contraindicated in women who are at daily, and lisinopril (angiotensin converting enzyme inhibitor), at a dose
risk for becoming pregnant, because it is associated with an increased from 10 to 20 mg daily, are antihypertensives that are probably used less
risk for neural tube defects. While only limited evidence is available to often than other blood-pressure medications discussed here previously.
support its use, gabapentin does appear to be effective in the reduction Nonetheless, both have been found to be effective as migraine preven-
of migraine frequency in clinical practice. It also has beneficial effects tives in randomized controlled trials and remain an option when other
in somatic pain and may be a good choice if a patient has neck pain, more commonly used preventives fail or are not tolerated.
back pain, or painful peripheral neuropathy as well as migraine. It
appears relatively well tolerated, although dizziness and sedation may Neurostimulation
limit its use in some patients. The usual therapeutic dose range for gab- In March 2014, a transcutaneous supraorbital nerve stimulator was
apentin is 900–2400 mg/day. Topiramate’s efficacy for migraine was approved by the FDA for migraine prevention following a small
demonstrated in pivotal large randomized trials (Brandes et al., 2004). clinical trial showing modest benefit among patients with episodic
Topiramate has effects not only on γ-aminobutyric acid (GABA) but migraine (Schoenen et al., 2013b). The device is considered to be safe;
also on non-N-methyl-d-aspartate glutamate and carbonic anhydrase however, efficacy has not been independently confirmed by other
activity. It may have prominent sedating and cognitive side effects, investigators.
making a slow gradual titration of the drug (15–25 mg/wk initially) Transcranial magnetic stimulation (TMS), a noninvasive technique
to the therapeutic range of 75–200 mg/day the most successful strat- utilizing a magnetic pulse hypothesized to disrupt cortical spreading
egy. Too rapid a titration schedule increases the risk of precipitating depression, has now been approved by the FDA for the symptomatic
depression, especially if there is a personal or family history (Mula treatment of migraine with aura. Single-pulse TMS (sTMS) was stud-
et al., 2009). Other side effects include paresthesia and weight loss, ied in a randomized, double-blinded, sham-controlled study, where
the latter making topiramate a particularly attractive choice for many greater pain-free responses were observed at 2 hours, with a sustained
patients. It is also associated with a mildly increased risk for calcium effect noted at 24 and 48 hours after treatment of migraine with aura
phosphate kidney stones. Zonisamide may be a good alternative in (Lipton et al., 2010). In a prospective, open-label study of 263 patients
topiramate-intolerant patients who had previously experienced a good with migraine with or without aura, scheduled twice-daily treatment
response (Mohammadianinejad et al., 2011). with sTMS for 3 months, 46% of the patients reduced their headache
Other prophylactic agents. Cyproheptadine is a peripheral frequency by half or more, and no serious adverse effects were observed
serotonin antagonist, typically used in pediatric patients. For younger (Starling et al., 2018).
patients unable to swallow pills, cyproheptadine is available in a syrup A noninvasive vagal nerve stimulator was evaluated for acute treat-
formulation. At all ages, it causes drowsiness and may cause significant ment of migraine in a double-blind, randomized, sham-controlled trial
weight gain. Methysergide, a peripheral serotonin antagonist and (Tassorelli et al., 2018). When attacks were initially treated within 20
publication.
minutes, superior efficacy for pain freedom was observed at early (30- been proposed that PMM be defined as attacks that occur between days
and 60-minute) time points, but not at a later (2-hour) time point. No −2 and +3 of the menstrual cycle. The prevalence of PMM according
serious adverse events were observed. to this definition is about 7%. More commonly, migraine attacks
occur throughout the cycle but increase in frequency or intensity at the
Calcitonin Gene-Related Peptide Targeted Therapies time of menstruation (menstrually related migraine). This association
There has been a long-standing literature documenting a fundamental occurs in up to 60% of female migraineurs. Menstrual migraines have
role for CGRP in the pathophysiology of migraine (Edvinsson, 2017). a tendency to be more severe, disabling, and treatment-refractory.
Along these lines, elevated levels of CGRP can be measured in the Aura is uncommon. Finally, headache may be a symptom of the
internal jugular vein during an acute attack of migraine, which then premenstrual syndrome, where depression, irritability, fatigue, appetite
normalize with treatment with sumatriptan. Further, experimental changes, bloating, backache, breast tenderness, and nausea characterize
infusion of CGRP triggers migraine in patients with migraine but not the disorder. These different relationships between migraine and the
controls. The development of oral CGRP antagonists (“-gepants”) menstrual cycle can be determined by reviewing headache diaries, and
have largely been hampered by hepatotoxicity in clinical trials; how- their distinction is important because the pathophysiology may differ,
ever, at least two agents (rimegepant and ubrogepant) have demon- as would the therapeutic approach.
strated efficacy and safety in phase III clinical trials for acute treatment Numerous mechanisms have been proposed to explain the
of migraine. pathogenesis of menstrual migraine. There is abundant clinical and
Four different monoclonal antibodies have demonstrated safety experimental evidence to support the theory that estrogen with-
and efficacy for preventive treatment of migraine in phase III trials. drawal before menstruation is a trigger for migraine in some women.
Prospective data indicate that these medications remain effective even Estrogen withdrawal may modulate hypothalamic β-endorphin,
among patients who have failed up to four prior preventive trials. dopamine, β-adrenergic, and serotonin receptors. This complex rela-
Injection site discomfort is the most common side effect, with small tionship causes significant downstream effects such as a reduction in
numbers of patients also reporting constipation. Three of these mono- central opioid tone, dopamine receptor hypersensitivity, increased
clonal antibodies have been licensed in the United States: erenumab trigeminal mechanoreceptor receptor fields, and increased cerebro-
which targets the CGRP receptor, and fremanezumab and galcane- vascular reactivity to serotonin. These changes, which occur during
zumab, both of which target CGRP. the luteal phase of the cycle, may be germane to the pathogenesis of
The AHS has released a consensus statement offering guidance menstrual migraine.
as to how to incorporate CGRP-based immunotherapies into clini- Several lines of investigation have implicated both prostaglan-
cal practice (American Headache Society, 2019) based on number of dins and melatonin in the pathogenesis of menstrual migraine.
headache days per month and headache-related disability, as mea- Prostaglandins and melatonin are important mediators of nociception
sured by the Migraine Disability Assessment Scale or the Headache and analgesia, respectively, in the CNS. The concentrations of prosta-
Impact Test. For patients reporting 4–7 monthly headache days glandin F2 and nocturnal melatonin secretion increase and decrease,
and at least moderate disability despite at least two 6-week trials of respectively, during menstruation in female migraineurs. These obser-
AAN level A or B preventive therapies, CGRP-based immunotherapy vations are the basis for the clinical use of NSAIDs and melatonin for
would be indicated. For patients reporting 8–14 monthly headache menstrual migraine prophylaxis.
days, a CGRP-based immunotherapy is indicated at any disability
level if at least two 6-week trials of preventive therapies have not been Management of Menstrual Migraine
successful. Finally, CGRP-based immunotherapies are indicated for To establish a direct link between menstruation and headache attacks,
patients with chronic migraine if they have not responded to either ask the patient to keep a diary of migraine attacks and menstrual peri-
two 6-week oral preventive trials or two quarterly injection cycles of ods for at least 3 consecutive months. The nature of this relationship
onabotulinumtoxinA. determines subsequent therapy. For example, for patients who have
Despite general enthusiasm for the availability of a novel class of both menstrual and nonmenstrual migraine, a standard prophylactic
pharmacotherapy with a benign side-effect profile, significant pre-clin- medication might be used throughout the cycle rather than the peri
ical concerns warrant caution pending longer term post-marketing menstrual use of a prophylactic agent. Clearly outline the goals of
experience. Specifically, CGRP is known to exert several protective therapy in addition to the dosages, benefits, and side-effect profile of
physiological roles including vasodilation, raising concerns that worse each recommended medication. Ideally, the headache diary can help
outcomes could be observed if a patient exposed to treatment were to identify other nonhormonal triggers. Biofeedback and relaxation ther-
experience a vascular event (Deen et al., 2017). Nonetheless, open-la- apy can be helpful in selected patients and should be used whenever
bel experience now reported out to 3 years fortunately has not docu- possible.
mented such adverse outcomes. Acute menstrual migraine therapy. The goal of acute menstrual
migraine therapy is to decrease the severity and duration of pain as well
Hormones and Migraine as the associated symptoms of an individual migraine attack, including
Migraine occurs equally in both sexes before puberty, but it becomes nausea, vomiting, photophobia, and phonophobia. Some women
three times more common in women after menarche. Approximately may control attacks of menstrual migraine quite adequately with
25% of women have migraine during their reproductive years. The abortive therapy only (see Migraine/Symptomatic Treatment section,
changing hormonal environment throughout a woman’s life cycle, previously). The acute management of menstrual migraine does not
including menarche, menstruation, oral contraceptive use, pregnancy, differ from the treatment of migraine unassociated with menstruation
menopause, and hormone replacement therapy (HRT), can have a (see Migraine/Symptomatic Treatment section, discussed previously).
profound effect on the course of migraine. Prophylactic menstrual migraine therapy. Prophylaxis may either
Menstrual migraine. Migraine attacks are generally associated be perimenstrual (cyclic) (Box 102.3) or continuous (noncyclic, see
with menses in one of two ways. The attacks may occur exclusively Migraine/Prophylactic Treatment section, discussed previously). Many
during menstruation and at no other time during the cycle. This of the regimens suggested for perimenstrual migraine prophylaxis
association is referred to as pure menstrual migraine (PMM), and it has depend on regular menstruation and the ability to predict headache
publication.
the unfavorable effects of surgical menopause on migraine. Therefore,

BOX 102.3 Cyclic (Perimenstrual)
until convincing evidence demonstrates otherwise, hysterectomy with
Prophylaxis for Menstrual Migraine or without oophorectomy is not currently a recommendation for
Nonsteroidal anti-inflammatory drugs (days −3 through +3): women with menstrual migraine.
Naproxen sodium, 550 mg bid
Mefenamic acid, 250 mg tid Oral Contraception in Female Migraineurs
Ketoprofen, 75 mg tid Migraine prevalence is highest in women during their reproductive
Ergots (days −3 through +3): years, the very population who use oral contraceptive therapy. Oral
Ergotamine tartrate + caffeine (Wigraine), 1 mg qhs or bid contraceptives have a variable effect on migraine. Migraine may begin
Dihydroergotamine, 0.5–1 mg (subcutaneous, intramuscular, or intranasal) de novo after a woman starts taking oral contraceptives, pre-existing
bid migraine may worsen in severity or frequency, or the characteristics
Triptans: of the migraine attack may change (e.g., development of aura symp-
Naratriptan, 1 mg bid for 5 days toms in a woman who for years had migraine without aura). Migraine
Frovatriptan, 2.5 bid for 6 days attacks may also lessen after starting an oral contraceptive, particu-
Zolmitriptan, 2.5 mg bid or tid for 7 days larly in women whose migraine attacks had a very close relationship
to menstruation. In the majority of women, however, the pattern of
bid, Twice daily; qhs, every day at bedtime; tid, three times daily. migraine does not change appreciably after they start taking an oral
contraceptive, particularly with the lower doses of estrogen and pro-
onset in relationship to menses. Perimenstrual prophylaxis commences gestin now found in most oral contraceptives.
a few days before the period is expected and continues until the end The concern about the use of synthetic estrogen in women with
of menstruation. In women whose cycles are difficult to predict, migraine pertains to the increased risk for ischemic stroke in this pop-
continuous prophylaxis with standard migraine prophylactic agents ulation, relative to age-matched women without migraine. There is
is called for (see Migraine/Prophylactic Treatment section, discussed now convincing evidence that female migraineurs have a small, but
previously). measurably increased risk of experiencing ischemic stroke. A 1995
NSAIDs are considered first-line agents for perimenstrual prophy- case-control study found migraine to be strongly associated with
lactic therapy in patients with either menstrual-associated migraine, the risk for ischemic stroke in young women (odds ratio [OR], 3.5),
or PMM, when the timing of menstruation is predictable. Different and this association was independent of other vascular risk factors.
classes of NSAIDs should be tried because response may vary in a The risk for ischemic stroke was particularly increased in women
given individual. Ergot derivatives can also be effective when used as with migraine who were using oral contraceptives (OR, 13.9), were
perimenstrual prophylactic drugs around the time of menstruation. heavy smokers (OR, 10.2), or who had migraine with aura (OR, 6.2).
Risks for rebound headaches are minimal, given the limited dura- The estimated incidence of ischemic stroke in young women with
tion of treatment when drugs are used perimenstrually. Frovatriptan, migraine with aura who use oral contraceptives is 28 per 100,000
naratriptan, and zolmitriptan have been found to be effective for per- women aged 25–34, and 78 per 100,000 aged 35–44. This is in con-
imenstrual prophylaxis and are included in the AAN and AHS guide- trast to the incidence of ischemic stroke of approximately 4 and 11
lines on migraine prophylaxis (Silberstein et al., 2012). It is worth per 100,000 women in the general population in the same respective
noting that severe menstrually related migraine may respond better to age groups. Although the relative risk for ischemic stroke is increased
short-term or perimenstrual prophylaxis while on a chronic (continu- in this group, it is important to bear in mind that the absolute risks
ous, noncyclic) preventive agent. are still small. Further, there is no convincing evidence that exposure
Other treatments. For those with PMM, attacks are also to very low dose estrogen (<20 μg ethinyl estradiol) confers addi-
preventable by stabilizing estrogen levels during the late luteal phase of tional risk to individuals with migraine, who do not smoke and are
the cycle. Estrogen levels can be stabilized by maintaining high levels normotensive.
with estrogen supplements. These should be directed by the patient’s The International Headache Society Task Force developed evi-
gynecologist. dence-based recommendations for the use of oral contraceptives and
The use of magnesium for acute and prophylactic treatment of HRT in migraineurs (Bousser et al., 2000). When prescribing combi-
migraine and menstrual migraine may be considered. Women with nation oral contraceptives (COCs) in women with migraine, their rec-
menstrual migraine have low levels of systemic magnesium, and MRS ommendations were as follows:
studies have demonstrated reduced levels of intracellular magne- • Identify and evaluate risk factors.
sium in the cerebral cortex of migraineurs. Low levels of intracellular • Diagnose migraine type, particularly the presence of aura.
magnesium may lead to neuronal hyperexcitability and spontaneous • Women with migraine should stop smoking before starting COCs.
depolarization, which may be the central process initiating a migraine • Treat other conditions such as hypertension and hyperlipidemia.
attack. This has led some investigators to study the effect of magne- • Consider non–ethinyl estradiol methods in women at increased
sium on menstrual migraine management. risk for ischemic stroke. Progestogen-only hormonal contraception
Some physicians still advocate the use of hysterectomy and oopho- may not increase ischemic stroke risk.
rectomy in women with intractable PMS and menstrual migraine • High-dose COCs (50 μg ethinyl estradiol) are not recommended for
whose headaches respond to medical ovariectomy. No long-term fol- routine use.
low-up or controlled studies exist that conclusively substantiate this • Low-dose formulations (<50 μg ethinyl estradiol) containing either
position. Because no study has been placebo controlled, the positive second- or third-generation progestogens should be used when
results seen in some studies may reflect the daily postoperative use possible.
of estrogen. Although two-thirds of women who have physiological Migraine symptoms that may necessitate further evaluation or ces-
menopause experience migraine relief, the opposite effect may occur sation of COC include new persisting headache, new onset of migraine
with surgical menopause with bilateral oophorectomy. In a retrospec- aura, increased headache frequency or intensity, and/or development
tive study of 1300 women, Granella and colleagues also demonstrated of unusual aura symptoms, particularly prolonged aura.
publication.
With respect to contraindications for the use of HRT, the Task more suitable delivery systems for women with migraine or for those
Force concluded that there was no evidence proving that migraine is whose headaches worsen by oral estrogen replacement therapy. Also,
a risk factor for ischemic stroke in women older than age 45. In addi- continuous rather than interrupted HRT may be more effective in
tion, there are insufficient data to support an increased risk for isch- female migraineurs whose headaches had been associated with estro-
emic stroke in women with any type of migraine who are using HRT. gen withdrawal.
Consequently, the usual indications and contraindications for HRT Cyclic progestins may worsen migraine. For women who require
should apply. combined estrogen and progesterone therapy after hysterectomy, a
Migraine and pregnancy. Pregnancy has a variable effect on transdermal progestin patch usually circumvents this problem.
migraine (see Chapter 111) Although approximately 70% of women
experience improvement or remission of migraine symptoms during Chronic Daily Headache
pregnancy, the attacks can either remain unchanged or worsen. Chronic daily headache (CDH) is a descriptive term that encom-
Moreover, migraine may begin for the first time during pregnancy. passes several different specific headache diagnoses. The designation
Remission or improvement occurs more often in women with pre- of “chronic” in CDH refers either to the frequency of headaches or
existing menstrual migraine, whereas worsening is more common in to the duration of the disease, depending on the specific headache
those with a history of migraine with aura. Most women who develop type. For example, in chronic tension-type headache and chronic
migraine during pregnancy have migraine with aura. Although there migraine, “chronic” indicates a headache frequency of at least
is a trend for improvement in the second and third trimesters, there 15 days per month. In chronic cluster headache and chronic par-
is no significant correlation between improvement or worsening of oxysmal hemicrania, however, “chronic” refers to a duration of at
migraine and a specific trimester. least 1 year without remission or with remissions lasting less than
If remission occurs during pregnancy, migraine often recurs in the 3 months. In keeping with the Headache Classification Committee
postpartum period, particularly in those with a history of menstrual of the International Headache Society (IHS, 2018) and conventional
migraine or migraine associated with estrogen withdrawal. Postpartum clinical standards, clinicians must distinguish between primary and
migraine occurs most often 3–6 days after delivery. Migraine may be secondary headache disorders that present with more than 15 head-
experienced for the first time in the postpartum period, but this is a ache days per month. The disorders that can present with secondary
very rare occurrence. CDH are numerous and include disorders of CSF dynamics (e.g.,
The use of medication to treat migraine during pregnancy should idiopathic intracranial hypertension, spontaneous spine CSF leaks),
be limited. For most mild to moderate attacks, use nonpharmacolog- intracranial space-occupying lesions, inflammatory disorders (e.g.,
ical treatment, including biofeedback, rest, and relaxation therapy. giant-cell arteritis), cerebrovascular disease, cervicogenic headache,
Acetaminophen may be combined with codeine, but the indiscrimi- TMJ disorders, trauma, infections including chronic meningitis, and
nate use of codeine may present a risk to the fetus during the first or medication overuse headache, among others. The development of
second trimester. progressively frequent and severe headaches within 3 months, neu-
For patients with severe attacks or status migrainosus, the risk to rological symptoms, focal or lateralizing neurological signs, pap-
the developing fetus may be greater than the judicious use of medi- illedema, headaches aggravated or relieved by assuming upright or
cations. The IV use of neuroleptics, supplemented with either IV opi- supine posture, headaches provoked by a Valsalva maneuver (cough,
oids or corticosteroids, can be an effective strategy. Chlorpromazine sneeze), systemic symptoms (e.g., weight loss, fever, myalgias), a his-
or prochlorperazine (10 mg) delivered in 4 mL of crystalloid or 50 mL tory of sudden-onset headache, and onset after age 50 years are fea-
of normal saline as a bolus over 10–15 minutes can be effective for the tures that should prompt a diagnostic investigation with appropriate
headache as well as the nausea and vomiting associated with a severe laboratory tests and imaging. Because these disorders are covered
attack. Methylprednisolone (50–250 mg) delivered IV can also be an elsewhere in this chapter, this discussion will focus on primary CDH
effective method to terminate a severe acute migraine attack or status disorders.
migrainosus during pregnancy. Intravenous magnesium sulfate (1 g) If a secondary cause of headache is excluded, efforts are then
may be an effective alternative. focused on diagnosing the primary CDH subtype so that a treat-
Cefaly, a wearable device, can likely be used safely as both a; pre- ment strategy can be established. The first decision point in mak-
ventive and abortive treatment during migraine. If the benefits of ing a diagnosis of a specific primary CDH disorder is to determine
treatment outweigh any potential risks to the fetus then propran- whether there are distinct episodes of headache with intervening
olol or amitriptyline could be considered for migraine prophylaxis headache-free periods. When discrete headache episodes are pres-
(Pringsheim et al., 2012). ent, the usual duration of individual episodes and their frequency
Migraine in menopause. Just as with pregnancy, the effect of and timing must be determined. CDH disorders of short duration,
menopause on the course of migraine is somewhat unpredictable. usually defined as less than 4 hours, include cluster headache, par-
In two-thirds of women with a previous history, migraine decreases oxysmal hemicrania (PH), hypnic headache, SUNCT/SUNA and
with a physiological menopause, but it can either regress or worsen primary exertional and cough headache. These disorders are covered
at menopause; in a minority of women, migraine or its functional elsewhere in this chapter.
equivalents may begin after menopause. Primary CDH disorders of long duration in which individual
Women with menopausal symptoms resulting from erratic or headache episodes last longer than 4 hours include chronic migraine
diminished estrogen secretion may benefit from hormone replace- (CM), chronic tension-type headache, hemicrania continua, and new
ment therapy (HRT), but consider potential risks. Few published stud- daily persistent headache. Indeed, patients who suffer from any of
ies have assessed the effects of HRT on migraine in perimenopausal these disorders may have a continuous background daily headache
women, but the available evidence appears to highlight the importance with superimposed bouts of severe and disabling headache. CM and
of both route and method of administration. With any preparation medication overuse headache (MOH) are the most common types
of estrogen, use the lowest effective dose. In general, parenteral or of CDH encountered in clinical practice. Although strictly speaking,
transdermal preparations provide a physiological ratio of estradiol MOH is not a primary subtype of CDH, it frequently coexists with CM
to estrone and a steady-state concentration of estrogen. They are also (see Medication Overuse Headache section, in Secondary Headaches
publication.
section) and warrants simultaneous management along that of chronic prevention of migraine. All of the CGRP monoclonal antibodies have
migraine. Risk factors for the development of CM identified in pop- been studied in chronic migraine and have shown favorable results.
ulation-based and clinic-based prospective studies include baseline While not rigorously studied for the treatment of CM, gabapen-
high attack frequency, obesity, stressful life events, snoring, cutaneous tin, divalproex sodium, amitriptyline, and β-adrenergic blockers
allodynia, and overuse of certain classes of medications, particularly among other preventives used for episodic migraine prophylaxis
opioid and barbiturate combination products (Lipton, 2009; Louter are also frequently used in CM prevention, based on evidence for
et al., 2013). These risk factors may help clinicians identify those who their effectiveness in patients with episodic migraine and a long
may be at highest risk for the development of CM. It is important to clinical experience with these medications for migraine prevention
recognize and address coexistent sleep and mood disorders that can (for more details, see Migraine/Prophylactic Treatment section,
lead to exacerbation of the underlying headache condition. earlier).
Similarly to episodic migraine management (see previous discus-
Chronic Migraine sion), preventive medications are generally titrated to the minimum
Chronic migraine, previously referred to as transformed migraine, effective or maximum tolerated dosage over the course of 1–2 months.
is characterized by headaches (tension-type and/or migraine) on 15 This target dosage is maintained for at least 3 months, and if there is
or more days per month in a patient with prior migraine history, a beneficial response (>50% reduction in headache days), the medica-
with at least 8 days per month being migraine for at least 3 months tion is continued until there has been clinical stabilization for at least
(IHS, 2018). 6–12 months. It must be remembered that the full benefit of a preven-
Patients with CM usually have a history of episodic migraine that tive medication may take up to 6 months to be realized. An attempt
began in their second or third decade of life. In the majority, the evo- to taper and discontinue the preventive medication is reasonable, but
lution from episodic migraine to chronic migraine is gradual, but the only after consultation with the patient and after a reasonable period
transition can be abrupt in about 30% of patients. Population studies of stability (>6–12 months).
estimate that patients with episodic migraine will transition to CM at Patients with chronic migraine should limit acute treatment use to
the rate of approximately 2.5% per year (Lipton, 2009). For the patient prevent development of medication overuse headache (see Medication
with CM, on some days the headaches and associated symptoms Overuse Headache section, previously).
(nausea, photo/phonophobia) may retain characteristics of migraine,
whereas on other days, symptoms may be indistinguishable from a Cluster Headache
tension-type headache. These patients do not have “mixed” or “com- Among the many painful conditions that affect the head and face,
bined tension-vascular headaches,” antiquated terms that are still used cluster headache is without doubt the most painful recurrent head-
(Dodick, 2006). ache, and the one that produces the most stereotyped attacks. In epi-
Treatment of CM requires preventive medications and judicious sodic cluster headache, attacks of pain occur in periods lasting 7 days
use of acute medications. Only topiramate, onabotulinumtoxinA, to 1 year, separated by pain-free periods lasting 3 months or longer.
and, more recently, erenumab, fremanezumab, galcanezumab, and In chronic cluster headache, attacks of pain occur for more than 1
eptinezumab have been studied specifically in chronic migraine via year without remission or with remissions lasting less than 3 months
controlled studies. Two randomized double-blind placebo-controlled (IHS, 2018). This chronic form of the disease may develop de novo
studies demonstrated that topiramate was effective and achieved signif- or may evolve from episodic cluster headache. Approximately 90%
icant reductions in migraine frequency (Diener et al, 2007b; Silberstein of patients have episodic cluster headache, and 10% have the chronic
et al., 2007). A pooled analysis of results from two large phase-III pla- form.
cebo-controlled studies (PREEMPT 1 and 2) demonstrated a mean
decrease from baseline in frequency of headache days, with statistically Epidemiology
significant between-group differences favoring onabotulinumtox- Compared with tension headache and migraine, the syndrome of clus-
inA over placebo at week 24 (−8.4 vs. −6.6; P < .001) (Dodick et al., ter headaches is considerably less common. In many headache clinic
2010). While the therapeutic gain over placebo for this and many of populations, migraine is 10–50 times more common than cluster
the PREEMPT trials’ outcomes appeared to be modest, onabotulinum- headache. The prevalence of cluster headache is about 1 person per
toxinA has been found to significantly reduce chronic migraine impact 500. It occurs approximately three times more often in men than in
and improve quality of life (Lipton et al., 2011). Botulinum toxin blocks women but is clinically identical in both genders. Although not uni-
the release of glutamate from nociceptive terminals and therefore may versally observed, there is a tendency for cluster headache symptoms
reduce or inhibit the development of peripheral and central trigeminal to remit with age (May, 2005). Unlike migraine, cluster headache has
sensitization. The mechanism of action may be referable to the obser- not been considered until recently to be an inherited condition. Several
vation that single trigeminal afferents may have both dural and extra- twin studies have demonstrated 100% concordance in monozygotic
cranial projections (Schueler et al., 2013). The excellent tolerability of twins. Two genetic epidemiological surveys suggest that first-degree
onabotulinumtoxinA makes it an extremely attractive alternative for relatives may have up to an 18-times higher risk and second-degree
patients who fail to tolerate oral prophylactics. The injection proto- relatives a 1- to 3-times higher risk of cluster headache than the general
col used in the PREEMPT trials is currently the most widely accepted population. The increased familial risk of cluster headaches suggests a
method of administration (Blumenfeld et al., 2010). The injections genetic underpinning. Inheritance is likely to be autosomal dominant
are given every 12 weeks and at least 2–3 cycles are recommended to with variable penetrance; nonetheless, in some families it may be auto-
determine response (Silberstein et al., 2015). In onabotulinumtoxinA somal recessive or multifactorial (Russell, 2004).
responders, commonly a continued need and a cumulative benefit
is observed over time (Aurora et al., 2014). Monoclonal antibodies Clinical Features
targeting the CGRP receptor (erenumab) and the CGRP molecule Onset typically begins in the third decade of life, although it has been
(fremanezumab, galcanezumab, and eptinezumab) have now been described as early as 1 year of age and as late as the seventh decade.
developed. At the time of this publication erenumab, fremanezumab, Periodicity is a cardinal feature of cluster headache. In most patients,
galcanezumab, and eptinezumab have been FDA approved for the the first cluster of attacks, the cluster period, persists on average for
publication.
6–12 weeks and is followed by a remission lasting for months or even localized swelling of the palate ipsilateral to the pain can be observed.
years. The duration of the cluster period is often strikingly consistent Cluster headache patients tend to have coarse facial skin, deep naso-
for a given patient. A common pattern is one or two cluster periods per labial folds, and an increased incidence of hazel eye color. Many of
year. With time, however, the clusters may become seasonal and then the patients are heavy cigarette smokers and tend to use more alcohol
occur more often and last longer. During a cluster, patients typically than age- and sex-matched control subjects. Most patients, however,
experience from 1 to 3 or more attacks in 24 hours. The attacks com- abstain from alcohol during a cluster period, since it commonly trig-
monly occur at similar times throughout the 24 hours for several weeks gers attacks.
to months. Onset during the night, or 1–2 hours after falling asleep, is
common. In some patients, these may occur at the onset of rapid eye Pathophysiology
movement (REM) sleep. At times, several attacks per night can result The pathogenesis of cluster headache is not entirely understood. While
in sleep deprivation in patients with chronic cluster headache, partic- the pain is likely mediated by activation of the trigeminal nerve path-
ularly when they avoid sleep for fear of inducing a further attack. With ways, the autonomic symptoms are due to parasympathetic outflow
increasing age, the distinct clustering pattern may be less recognizable. and sympathetic dysfunction. The periodicity suggests a defect in CNS
The attacks of pain are similar among individuals. The pain is cycling mechanisms that is likely related to hypothalamic dysfunction.
strictly unilateral and almost always remains on the same side of the The most direct evidence in support of a role of the hypothalamus
head from cluster to cluster. Rarely it may switch to the opposite in cluster headache comes from neuroimaging. PET imaging studies
side in a subsequent cluster or even (less frequently) during a single have shown activation in the ipsilateral ventral diencephalon during
attack (Capobianco and Dodick, 2006). The pain is generally felt in nitroglycerin-induced cluster attacks. In addition, a morphometric
the retro-orbital and temporal regions (upper syndrome) but may be study of MRI scanning technology has shown an increase in volume
maximal in the cheek or jaw (lower syndrome). It is usually described in the diencephalon. Asymmetric facilitation of trigeminal nociceptive
as steady or boring and of terrible intensity (so-called suicide head- processing predominantly at a brainstem level has been detected in
ache). Graphic descriptions of feeling the eye being pushed out or an patients with cluster headache (Holle et al., 2012).
auger or hot poker going through the eye are common. Although vasodilatation has been generally believed to be respon-
Onset is usually abrupt or preceded by a brief sensation of pressure sible for the pain, PET studies have shown that carotid artery dilation
in the soon-to-be-painful area. An occasional patient may describe is not specific for cluster headache but is seen with other types of oph-
tension and discomfort in the limbs and neck ipsilateral to the pain, thalmic division pain; it appears to be an epiphenomenon of a primary
either during the attack or just preceding it. Infrequently, aura symp- neural process.
toms (as seen in migraine) may precede cluster attacks. The pain inten- In 1993, Moskowitz emphasized the role of the trigeminovascular
sifies very rapidly, peaking in 5–10 minutes and usually persisting for connections and substance P in the pathogenesis of vascular head pain.
45 minutes to 2 hours. Toward the end of this time, brief periods of Further evidence suggested activation of the trigeminovascular system
relief may be followed by several transient peaks of pain before the as manifested by increased levels of CGRP in blood sampled from the
attack subsides over a few minutes. Occasionally, attacks last twice as external jugular vein ipsilateral to an acute spontaneous attack of clus-
long or, less commonly, attacks may seem to merge together, produc- ter headache. Vasoactive intestinal polypeptide levels were similarly
ing 12 or more hours of pain. After the attack, the patient is pain free elevated in the cranial venous blood during a cluster attack, demon-
but exhausted; however, the respite may be transient because another strating activation of the cranial parasympathetic nervous system.
attack may occur shortly. Parasympathetic activation is believed to be responsible for the ipsilat-
During the pain, patients almost invariably avoid the recumbent eral conjunctival injection, lacrimation, nasal congestion, rhinorrhea,
position because doing so increases pain intensity. Unlike patients with and/or eyelid edema. Trigeminal-parasympathetic overactivity may
migraine, they are restless and prefer to pace or sit during an attack. result in perivascular edema compromising the carotid canal, leading
Some remain outdoors even in freezing weather for the duration of the to neurapraxic injury of postganglionic sympathetic fibers and hence
attack. Interestingly, some may find relief or even abort an attack with a Horner syndrome manifested in ptosis and miosis (May, 2005). The
physical exertion such as push-ups. Otherwise rational persons may fact that low-frequency sphenopalatine ganglion (SPG) stimulation
strike their heads against a wall or hurt themselves in some other way can provoke cluster-like headaches with autonomic features suggests
as a distraction from the intense head pain. Most patients prefer to be efferent parasympathetic outflow from this ganglion may give rise
alone during the attack. Some apply ice to the painful region, others to autonomic symptoms and activate the trigeminovascular sensory
prefer hot applications; almost all press on the scalp or the eye to try afferents which may initiate pain (Schytz et al., 2013).
to obtain relief. During the pain, some patients consider suicide; a few
attempt it. Investigations
During the pain of cluster headache, the nostril on the side of the In most patients, the diagnosis is certain on clinical grounds alone.
pain is generally blocked; this blockage in turn can be followed by ipsi- However, imaging studies are recommended for all patients at the
lateral lacrimation. The conjunctiva may be injected ipsilaterally, and time of diagnosis, particularly for those presenting with an atypical
the superficial temporal artery may be visibly distended. Profuse sweat- episodic cluster (“cluster-like”) headache or for patients with head-
ing and facial flushing on the side of the headache have been described ache in the chronic phase. “Cluster-like” headaches can be associated
but are rare. Nasal drainage usually signals the end of the attack. Ptosis with underlying intracranial or neck structural lesions such as neo-
and miosis on the side of the pain may occur. This Horner syndrome plasms, paranasal sinus disease, vascular malformations, and cervico-
may persist between attacks and is believed to be due to compression cephalic arterial aneurysms or dissections (Capobianco and Dodick,
of the sympathetic plexus secondary to vasodilatation or other changes 2006). Therefore, as part of the evaluation, a contrast-enhanced brain
in the region of the carotid siphon. Migrainous symptoms such as MRI scan is recommended to help reassure the patient, their rela-
nausea, photophobia, phonophobia, and/or osmophobia commonly tives, and physicians that the extremely painful attacks are not due
accompany cluster headache (Bahra et al., 2002). Facial swelling, most to some major abnormality. Clinical judgment guides the necessity
often periorbital, may develop with repeated attacks. Rarely, transient for further testing.
publication.
Differential Diagnosis that the beneficial response is mediated through its effects on the
The diagnosis of cluster headache is essentially clinical. It is helpful parasympathetic outflow via the facial/greater petrosal nerve, with
to have confirmation from the spouse or relatives of the periodic- no direct effect on trigeminal afferents (Akerman et al., 2009).
ity, rapidity of onset and resolution, and presence of conjunctival Although portable regulators are available, the major drawbacks to
injection, rhinorrhea, ptosis, and altered behavior during the attack. oxygen use are the inconvenience, lack of accessibility, and need to
Despite the stereotyped nature of the attacks from episode to episode have a regulator and canister available at all times. Unfortunately,
and from patient to patient, the diagnosis is often missed for several in some cases, oxygen merely delays an attack rather than aborting
years. Conditions that cause episodic unilateral head and facial pain it (Capobianco and Dodick, 2006).
should be considered, but they are easy to exclude. Trigeminal neu- Administration of sumatriptan by subcutaneous injection in a
ralgia, sinusitis, dental disease, and glaucoma may superficially mimic dose of 4–6 mg is an effective means of aborting an individual cluster
the pain of cluster headache, but, in each, the temporal profile, lack attack. Sumatriptan nasal spray is less effective than the subcutaneous
of associated autonomic features, and past history allow easy differ- formulation.
entiation. Similarly, migraine, temporal arteritis, and the headache of DHE is available in injectable and intranasal formulations. DHE-45
intracranial space-occupying lesions should not be difficult to differ- administered IV provides prompt and effective relief of a cluster attack.
entiate from cluster headache. Orbital, retro-orbital, and frontal pain The intramuscular and subcutaneous routes of administration provide
associated with Horner syndrome can result from ipsilateral dissection slower relief. The potential role of intranasal DHE (2 mg) has not been
of the carotid artery; unlike the pain of cluster headache, however, it validated in a controlled fashion.
is not episodic and does not produce the restlessness so characteris- Other potential symptomatic options include zolmitriptan nasal
tic of this condition. The pain associated with Tolosa-Hunt syndrome spray, octreotide, and intranasal lidocaine administered by dripping
and Raeder paratrigeminal syndrome is accompanied by oculomotor 4% viscous lidocaine into the nostril ipsilateral to the pain.
or trigeminal nerve dysfunction, a feature that should easily prevent Preventive pharmacotherapy. Use of an effective preventive
confusion with cluster headache. Similarly, pain from compression of regimen cannot be overemphasized. The goals of preventive therapy
the third cranial nerve by an aneurysm should be easy to distinguish are to produce a rapid suppression of attacks and maintain remission
from cluster headache pain, especially when partial or complete third over the expected duration of the cluster period. Preventive therapy
cranial nerve palsy is detected. in cluster headache can be divided into transitional and maintenance
Cluster headache is a member of the primary headache syndromes prophylaxis.
collectively referred to as the trigeminal-autonomic cephalalgias Transitional p rophylaxis. Transitional prophylaxis involves the
(TACs); the other TACs have to be differentiated from cluster head- short-term use of corticosteroids, occipital nerve blocks, ergotamine,
ache, since their management is usually different. These are discussed or DHE. This typically induces a rapid suppression of attacks while one
elsewhere in this chapter. of the maintenance agents can take effect.
During the initial cluster or when the patient’s past history sug-
Treatment and Management gests that a cluster will be of limited duration, relief can usually be
The patient should be reassured that the syndrome, even though obtained by administering a short course of corticosteroids. Several
unbearably painful, is benign and not life threatening. Pain reduction regimens are effective, such as 60 mg of prednisone as a single daily
but not cure should be promised. dose for 3–4 days, followed by a 10-mg reduction after every third
The frequency, severity, and brevity of individual attacks of clus- or fourth day, to thereby taper the dose to zero over 18 or 24 days.
ter headache and their lack of response to many symptomatic mea- Alternatively, an intramuscular injection of triamcinolone (80 mg)
sures necessitate the use of a prophylactic treatment regimen for most or methylprednisolone (80–120 mg) can be used to give a tapering
patients. The treatment plan is determined by several factors, including corticosteroid blood level. Whichever treatment regimen is used,
whether the phase is episodic or chronic and whether other disease the patient usually obtains relief from the headaches until the lower
states such as hypertension and coronary or peripheral vascular insuf- doses or blood levels of corticosteroids are approached. The course
ficiency are present. can be repeated several times, but thereafter the risk for side effects
Pharmacological management suggests that an alternative prophylactic regimen should be used if
Acute (symptomatic) therapy. Given the rapid onset and the cluster has not run its course.
short time to peak intensity of the pain of cluster attacks, fast- Ergotamine tartrate can be given orally or by rectal suppository
acting symptomatic treatment is imperative. Oxygen, subcutaneous on retiring to prevent nocturnal attacks of headache. This approach
sumatriptan, and subcutaneous or intramuscular DHE provide may only postpone the attack until morning, when it may be more
the most rapid, effective, and consistent relief for cluster headache troublesome if it occurs when the patient is at work. Prophylactic
attacks. use of ergotamine tartrate can nevertheless be valuable, but great
Oxygen inhalation is one of the most effective symptomatic care must be taken to regulate the dose if chronic ergotism is to
treatments for cluster headache. Its advantages are that it has no be avoided. Most patients with cluster headache can be given 2
established adverse effects, it can be administered several times mg of ergotamine tartrate daily for several days without adverse
daily, it can be combined with other treatments, and it is inexpen- effects; however, caution must be used with ergotamine, triptans,
sive. Inhaled oxygen at 100% for 15–20 minutes via a nonrebreath- and analgesics to avoid the development of MOH (Paemeleire et
ing face mask can be dramatically effective for aborting a cluster al., 2006). DHE is a well-tolerated ergot derivative that can be given
attack. Rates of oxygen delivered at 12 L/min have been demon- in a dose of 0.5–1 mg every 6–8 hours in an attempt to prevent
strated to be effective (Cohen et al., 2009). Flow rates of 15 L/min headaches, but this dose should be continued for only a few days
may be effective when lower rates are not (Rozen, 2009). The best to avoid ergotism.
position for oxygen inhalation is sitting on the edge of a chair or In addition, an occipital nerve block ipsilateral to the cluster head-
bed and leaning forward with arms on knees. The mechanism of ache may be useful as a transitional measure in some patients when the
action of oxygen remains to be fully elucidated; recent data suggest use of other medications may be contraindicated or poorly tolerated.
publication.
Repeating this every 3 months may benefit some with chronic cluster headache. Corticosteroids can be useful in chronic cluster headache
headache (Lambru et al., 2014a). to provide brief remissions for fixed periods. Nonetheless, long-term
Maintenance prophylaxis. Maintenance prophylaxis refers to use of corticosteroids in patients with chronic cluster headache must
the use of preventive medications throughout the anticipated dura- be resisted. Given the role that CGRP plays in cluster headache, the
tion of the cluster period. The preventive medication is initiated at monoclonal antibodies targeting CGRP or its receptor could prove to
the onset of the cluster period, typically in conjunction with cortico- be viable options in the prophylaxis of headache. Only galcanezumab
steroids, and is continued after the initial suppressive medication is has been studied in cluster headache, but as of this publication has not
discontinued. been FDA-approved for cluster headache.
The calcium channel blockers (Leone et al., 2009), particularly ver- In patients for whom conventional first-line therapy is inef-
apamil, are considered first-line preventive therapy for both episodic fective, poorly tolerated, or contraindicated, one may consider
and chronic cluster headache. They are generally well tolerated and adjunctive therapy with a number of potential agents including
can be used safely in conjunction with ergotamine, sumatriptan, cor- melatonin, baclofen, and intranasal civamide (Francis et al., 2010;
ticosteroids, and other preventive agents. The initial starting dose of May et al., 2006).
verapamil is 80 mg three times a day after a normal ECG has been Surgical treatment. Surgery is a last resort for medication-
demonstrated. The authors have encountered several patients who resistant chronic cluster headache, an option to be considered when all
appear to have an improved response with the nonsustained release pharmacological treatment options have been thoroughly exhausted
formulation. The daily dose can be increased in 40- to 80-mg incre- (Leone et al., 2009). Ablative procedures reported as potentially
ments every 7–14 days until the attacks disappear, adverse effects successful include radiofrequency thermocoagulation of the gasserian
occur, or the maximum daily dose of 720 mg is achieved (Leone et al., ganglion, trigeminal sensory rhizotomy, microvascular decompression
2009). Doses as high as 960 mg daily may be required (Goadsby, 2012). of the trigeminal nerve, and sphenopalatine ganglion radiofrequency
These doses are considerably higher than those used for hypertension ablation (Leone et al., 2009; Narouze et al., 2009). Unfortunately,
and heart disease (Rozen, 2009). If a patient requires more than 240 adverse events of these procedures can be severe and include corneal
mg/day, an ECG is recommended before each dose increment, 2 weeks anesthesia, keratitis, and anesthesia dolorosa. Furthermore, the benefit
after the last adjustment, and periodically thereafter if verapamil is may be less than robust and short-lived. These procedures have
used long term (Cohen et al., 2007). The most common side effect of therefore been for the most part abandoned and are now used only
verapamil is constipation, but lightheadedness, hypotension, fatigue, rarely.
peripheral edema, and bradycardia can also occur. Neurostimulation procedures involving central or peripheral ner-
Methysergide can be effective for reducing or preventing cluster vous system targets have been employed to treat refractory chronic
headache in about 60% of patients, but it is no longer available in the cluster headache (Leone et al., 2009). At present, these are preferred
United States or Canada. over the previously discussed interventions but should only be con-
For patients who have chronic cluster headache with attacks that sidered in patients with medically intractable CH in tertiary head-
occur daily for years, relief may be obtained with lithium. Lithium car- ache centers, and the least invasive options should be considered first
bonate, 300 mg three times a day, can be given initially and the dose (Martelletti et al., 2013).
adjusted at 2 weeks to obtain a serum lithium level of about 1 mEq/L. In 2003, Franzini and colleagues reported a complete response
Side effects at this level include a mild tremor of the limbs, gastroin five patients with medically refractory chronic cluster headache
intestinal distress, and increased thirst. The therapeutic range is very after stereotactic implantation of a stimulating electrode into the
narrow, and blood levels of more than 1.5 mEq/L are to be avoided. periventricular hypothalamus. The rationale for this procedure is
Nephrotoxicity, goiter formation, and a permanent diabetes insipi- based on the activation of the periventricular hypothalamus seen on
dus-like state have been reported after lithium treatment. In chronic PET scanning of patients during attacks of cluster headache. Sixteen
cluster headache, lithium may have a beneficial effect within 1 week, patients with intractable chronic cluster headache were successfully
but the response is typically delayed for several weeks. Although treated by hypothalamic stimulation, with no significant adverse
attacks may recur after some months, a renewed response to lithium events in this series (Leone et al., 2005). At a mean follow-up of 23
may occur if the drug is withdrawn and then reintroduced after a few months, 13 of the 16 patients were persistently pain free or almost
weeks. In patients whose headaches respond to lithium, use of the drug pain free, while the rest were improved (Leone et al., 2006). Similar
should be discontinued every few months to determine whether the results from approximately 60 treated patients have been reported
cluster headaches have subsided. While lithium is being given, it is thus far. Hypothalamic deep brain stimulation may therefore be an
necessary to monitor the blood level at regular intervals to avoid the efficacious procedure to relieve intractable chronic cluster headache.
development of serious side effects. Thiazide diuretics should not be There have been, however, several intracranial hemorrhages reported
used concurrently because they can cause a rapid elevation of blood with this procedure, including one death from such a hemorrhage.
levels of lithium. Less-invasive interventions are therefore favored prior to considering
Despite the available treatments, management of patients with deep brain stimulation.
chronic cluster headache can be extremely difficult because many of Peripheral stimulation of the occipital nerve has been employed in
their headaches do not respond or respond only briefly to the treat- several open-label trials of patients with medically intractable cluster
ment regimens already described. In such patients, a combination of headache. One used bilateral stimulators in eight patients (Burns et al.,
several medications may give relief. On the basis of clinical experience, 2007), and the other used unilateral stimulation (side ipsilateral to
the combination of verapamil and topiramate or verapamil and lith- headaches) in eight patients (Magis et al., 2007). Substantial improve-
ium can prove effective. For particularly resistant headaches, triple ment occurred in a majority of individuals in each study, which was
therapy may be necessary, consisting of verapamil with either topira- durable for a mean follow-up of 20 months and 15 months, respec-
mate or valproate plus lithium. The authors have had some success tively. The favorable outcome of 14 patients with medically intracta-
with onabotulinumtoxinA injections for chronic cluster headache, ble chronic cluster headache implanted with bilateral electrodes in the
although there are no controlled studies available for its use in cluster suboccipital region was published (Burns et al., 2009). Others have
publication.
reported similar outcomes (Leone et al., 2017; Miller et al., 2017). and consider an alternative diagnosis. If there is an absolute response
This approach deserves additional study via prospective randomized to the indomethacin trial, however, indomethacin is continued as
controlled trials to further determine its role in cluster headache man- long as it is tolerated. The headache usually resolves within 1–2 days
agement. Factors predictive of a beneficial response to occipital nerve of initiating the effective dose. Dose adjustments are often needed to
stimulation have failed to be elucidated; pain relief after greater occipi- address clinical fluctuations. Skipping or delaying doses may result
tal nerve block does not predict efficacy (Leone et al., 2009). in recurrence of the headache. Efforts should be placed for patients
Schytz has shown that high-frequency stimulation of the SPG to find the lowest dose possible that controls the pain. We typically
can abort cluster headaches (Schytz et al., 2013). Of very recent place patients on gastric mucosa protective agents while they take daily
interest are the encouraging results from a randomized, sham-con- indomethacin. In patients with episodic PH, the indomethacin can be
trolled study stimulating the SPG in medically refractory chronic continued for roughly 2 weeks beyond the typical headache bout dura-
cluster headache. Throughout a period up to 8 weeks, 19 of 28 tion, and then a trial of tapering can be undertaken. Some patients
(68%) patients had a clinically significant improvement: seven are able to discontinue indomethacin without recurrence (presum-
(25%) achieved pain relief in ≥50% of treated attacks, 10 (36%) a ably representing a transition from chronic to episodic PH), so treat-
≥50% reduction in attack frequency, and two (7%), both. Results ment should be tapered periodically to ensure that patients are still
suggest a potential dual benefit (acute pain relief and attack presymptomatic. During this taper, we usually decrease the indometha-
vention) (Schoenen et al., 2013a). Other studies are necessary to cin dose by 25 mg every 3 days until either the headache recurs or the
confirm these findings. patient gets completely off indomethacin. Despite the differences in
typical attack frequency and duration between cluster headache and
Other Trigeminal Autonomic Cephalalgias PH, in some circumstances cluster headache and PH can be clinically
Paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform indistinguishable. Thus, any patient presenting with what appears to
headache attacks (SUNCT/SUNA), and hemicrania continua (HC) be cluster headache but is refractory to usual cluster headache treat-
are all classified along with cluster headache as trigeminal autonomic ments should have an indomethacin trial. The therapeutic response
cephalalgias by the Headache Classification Committee (IHS, 2018). to indomethacin is the most reliable differential diagnostic criterion
PH and SUNCT/SUNA are distinguished from cluster headache by for cluster headache and PH. Other treatments reported to be effec-
having shorter attack durations and higher attack frequencies. PH tive in PH include celecoxib, rofecoxib, botulinum toxin A, verapamil,
and HC (the most prolonged TAC), respond completely to preventive nicardipine, flunarizine, ibuprofen, ketoprofen, aspirin, piroxicam,
treatment with indomethacin, which is not the circumstance in cluster naproxen, diclofenac, phenylbutazone, acetazolamide, topiramate,
headache or SUNCT/SUNA. Although rare, the occurrence of con- prednisone, lithium, ergotamine, sumatriptan, oxygen, greater occip-
comitant different TACs may manifest in single individuals (Totzeck ital nerve block, occipital nerve stimulation, and hypothalamic stimu-
et al., 2014). lation (Boes and Swanson, 2006; Goadsby et al., 2010).
Paroxysmal Hemicrania Short-Lasting Unilateral Neuralgiform Headache Attacks

Paroxysmal hemicrania has a typical onset in the third decade of life. Short-lasting unilateral neuralgiform headache attacks are attacks of
The female-to-male ratio is approximately 1:1, which contrasts with moderate or severe, strictly unilateral head pain lasting seconds to
cluster headache, for which there is an overwhelming male predom- minutes, occurring at least once a day and usually associated with
inance (Cittadini et al., 2008). Chronic PH and episodic PH differ in prominent lacrimation and redness of the ipsilateral eye. This disor-
their temporal profile. In chronic PH, attacks occur for more than a der has two clinical phenotypes. When the attacks are associated with
year without remission or with remission periods lasting less than 3 both conjunctival injection and lacrimation (tearing) it is referred to
months. Episodic PH is characterized by bouts of attacks occurring in as SUNCT (short-lasting unilateral neuralgiform headache with con-
periods lasting from 7 days to 1 year and separated by pain-free remis- junctival injection and tearing). When only one or neither of con-
sion periods lasting at least 3 months (IHS, 2018). The headache bouts junctival injection or lacrimation is present it is diagnosed as SUNA
can range from 4 to 24 weeks, and remission periods can last 12–376 (short-lasting unilateral neuralgiform headache attacks with cranial
weeks. While active, both disorders are associated with daily attacks autonomic symptoms) (IHS, 2018). SUNCT and SUNA are rare disor-
of severe short-lived unilateral pain, which is often maximally felt in ders and their treatment is entirely prophylactic, in general using the
the orbital/retro-orbital or temporal region, although extra-trigemi- same medications.
nal pain in the occiput can occur. The mean attack frequency in one Knowledge of SUNCT is more ample when compared to SUNA,
study was 11 in 24 hours, with a median of 9 attacks in 24 hours and as the latter has been described more recently. SUNCT’s painful par-
a range from 2 to 50 attacks per day (Cittadini et al., 2008). The mean oxysms are usually felt in or around the eye and can sometimes be
length of attacks was 17 minutes, with a median of 19 minutes and a triggered by cutaneous stimuli. Single stabs last on average 58 seconds,
range from 10 seconds to 4 hours. Similar to cluster headache, each groups of stabs usually last 396 seconds, and a sawtooth attack (many
paroxysm is accompanied by at least one robust ipsilateral autonomic stabs between which the pain does not totally resolve) typically lasts
feature, which may include lacrimation, miosis, ptosis, eyelid edema, 1160 seconds (Cohen et al., 2006). Attacks may occur 2–600 times
conjunctival injection, nasal congestion, rhinorrhea, or forehead/facial a day, with a mean of 59 attacks per day. The associated ipsilateral
sweating. Numerous cases of secondary PH have been reported and conjunctival injection and lacrimation are very prominent. Unlike
underline the importance of MRI of the brain in every case. PH typi- trigeminal neuralgia, most of the pain in SUNCT is in a V1 distribu-
cally responds completely to indomethacin. The dose required ranges tion, and tears often run down the face. Only 4% of patients with tri-
from 25 to 300 mg/day. Most patients require around 150 mg/day. In a geminal neuralgia have pain in the ophthalmic division alone (Boes
patient with suspected PH, the usual indomethacin trial includes indo- and Swanson, 2006). Unlike trigeminal neuralgia, 95% of SUNCT
methacin 25 mg 3 times a day for 3 days, then 50 mg 3 times a day for patients have no refractory period. The brevity and high frequency
3 days, and then finally 75 mg 3 times a day for 3 days. If at the end of of attacks in SUNCT should make the distinction from cluster head-
this trial there is minimal or no response, discontinue indomethacin ache quite clear. Numerous cases of secondary SUNCT have been
publication.
reported and underline the importance of MRI of the brain in every acemethacin, acetaminophen with caffeine, lamotrigine, gabapentin,
case. Lamotrigine has been effective in several patients when given in topiramate, melatonin, valproic acid, verapamil, onabotulinumtoxinA,
an open fashion. Topiramate, carbamazepine, and gabapentin are all and lithium have been reported to be effective in some cases. Other
reasonable alternatives to consider. Other options with uncontrolled treatments include occipital or supraorbital nerve blocks and occipital
evidence include oxcarbazepine, verapamil, clomiphene, zonisamide, nerve stimulation.
onabotulinumtoxinA, corticosteroids, and IV lidocaine. Indomethacin
has no effect. The role of neurosurgical intervention directed at the Other Primary Headaches
trigeminal nerve in the treatment of SUNCT is unclear, and it should Tension-Type Headache
only be considered as a last resort. Other treatments reported to be Almost everyone has a headache at some time when stressed, over-
effective in SUNCT include occipital nerve block, opioid blockade of worked, anxious, or subject to prolonged muscular strain. Such head-
the superior cervical ganglion, hypothalamic stimulation, and surgical aches rapidly subside with relaxation, sleep, or ingestion of simple
removal of a pituitary microadenoma. analgesics. Tension-type headaches have historically been ascribed to
Both SUNCT and SUNA have been reported to respond to trigemi- persistent contraction of scalp, neck, and jaw musculature. However,
nal nerve microvascular decompression (Williams et al., 2010). Out of the concept of muscle contraction causing headache has been ques-
16 patients, 75% have become pain free for up to 32 months (Favoni tioned. Electromyographic (EMG) studies and other observations
et al., 2013). Of more recent interest in medically refractory SUNCT have led some to believe tension-type headache and migraine may be
and SUNA is the possible role of bilateral occipital nerve stimulation extreme ends of a spectrum.
(ONS). Out of nine patients in a recent study, all but one obtained In the past, the term “tension” had been tacitly taken to mean
substantial relief. Because ONS is not cranially invasive or neurally either emotional or muscle tension, thus implying both pathogenesis
destructive, it might be considered the surgical treatment of choice for and pain mechanism. The current classification places the word “type”
medically intractable SUNCT and SUNA (Lambru et al., 2014b). The after “tension,” and the term tension-type headache is now used to
precise role these two interventions may have in the management of bring attention to the fact that actual muscle tension may not be a key
medically refractory SUNCT/SUNA remains to be determined. factor in the pathophysiology.
The prevalence of tension-type headache ranges in the general pop-
Hemicrania Continua ulation from 30% to 78% (IHS, 2018). In the United States, an epide-
As the name implies, hemicrania continua is characterized by a con- miological study showed a higher prevalence in Caucasian women and
tinuous unilateral headache of moderate intensity that may involve the in patients aged 30–39 (Schwartz et al., 1998).
entire hemicranium or simply be confined to a focal area. The female- Tension-type headaches can begin at any age, are generally bilat-
to-male ratio is approximately 2:1, and the average age of onset is 28 eral, and are often described as a sense of pressure or wearing a tight
years (range, 5–67 years). Although invariably continuous, this disor- band around the head. The pain is of mild to moderate intensity, tends
der may sometimes resemble a prolonged unilateral migraine attack to not be aggravated by routine physical activity, and may wax and
lasting several days to weeks, with headache-free remissions. The con- wane throughout the day or may be present and steady for days, weeks,
tinuous headache is typically punctuated by painful unilateral exacer- or even years at a time. Tension headaches have no associated nausea
bations lasting 20 minutes to several days. These periods of increasing or vomiting and are much less commonly associated with light and
pain intensity are accompanied by one or more autonomic features sound sensitivity than migraine.
that are usually subtler than those seen in PH or cluster headache and The pathophysiology of tension-type headache is incompletely
about two-thirds report a sense of restlessness or agitation (Cittadini understood. That emotional tension leads to muscle tension and
and Goadsby, 2010). Primary stabbing headache (“icepick headache”) hence to headache is too simplistic. A far more complex central
is often a feature of this disorder, usually on the ipsilateral side and mechanism is likely responsible for the pain, likely involving inter-
usually during a period of exacerbation. About a third report an ipsi- action between peripheral myofascial input and sensitization of sec-
lateral eye itch and most have migrainous features including photo- ond-order nociceptive neurons in the trigeminal nucleus and spinal
and phonophobia (unilateral in half of patients) and motion sensitivity dorsal horn (Fumal and Schoenen, 2008). A lower-pressure pain
(Cittadini and Goadsby, 2010). Because of its daily persistence, hemi- tolerance threshold has been shown in the fingers of patients with
crania continua may be seen in the context of medication overuse, chronic tension-type headache compared to healthy controls, sug-
which may alter the clinical features. Therefore, a higher index of gesting the presence of allodynia and hyperalgesia in patients with
suspicion may be required in these cases. It is reasonable to consider this disorder.
a trial of indomethacin in any patient with a chronic unilateral daily Physical examination in acute tension-type headache is generally
headache that does not respond to other conventional medications, unrevealing. Chronic tension-type headache may be associated with
especially if autonomic features are present. Several cases of secondary craniocervical musculature tenderness. In elderly patients, the ESR
hemicrania continua have been reported, highlighting the importance should be determined to help exclude giant-cell arteritis. If the head-
of brain MRI in the evaluation of these patients. Hemicrania continua ache is new or progressively worsening, a CT or MRI of the brain can
patients respond completely to prophylactic indomethacin. The indo- help rule out serious structural intracranial diseases mimicking ten-
methacin regimen is similar to that described for PH. Unfortunately, sion-type headache. Cervical spine imaging may be needed to rule out
about a fourth of patients do not tolerate indomethacin, mainly from secondary causes of sustained contraction of the cervical and scalp
gastrointestinal side effects. Without indomethacin, treatment can muscles. Patients with obstructive sleep apnea (OSA) have a higher
be challenging. Cases of hemicrania continua have been reported likelihood of developing tension-type headache than patients without
that have not recurred after stopping indomethacin. It is therefore it. (Chiu et al., 2015). We routinely screen for OSA in patients with
reasonable to periodically withdraw treatment (Boes and Swanson, frequent or chronic tension-type headache.
2006). Complete response to rofecoxib, celecoxib, aspirin, naproxen, For occasional mild tension-type headache, treatment with
ibuprofen, diclofenac, and piroxicam in hemicrania continua has aspirin, acetaminophen, or NSAIDs may be sufficient. More severe
been reported. Dihydroergotamine, methysergide, corticosteroids, headaches usually require a prescription analgesic, but no specific
publication.
preparation has been shown to be better than another. The combina- of effort (like a Valsalva maneuver) that may trigger primary cough
tion of acetaminophen with isometheptene and dichloralphenazone headache, though the two headaches may occasionally co-occur in the
may be useful for moderately severe headaches. The frequent use of same patient (IHS, 2018; Sjaastad and Bakketeig, 2002). The headache
combination analgesics with codeine, propoxyphene, or butalbital is not explosive in onset but rather builds in intensity and lasts between
with or without caffeine should be avoided to prevent nedication 5 minutes and 48 hours. The headache can be prevented by avoiding
overuse headache. excessive exertion, particularly in hot weather or at high altitude. In
The most effective prophylactic drug is possibly amitriptyline. one prospective study, the average age at onset for primary exertional
Controlled trials have shown more than 50% improvement in over headache was 40 years, whereas the average age at onset for primary
65% of patients. The usual dose is 50–150 mg/day. The drug is better cough headache was 60 years (Pascual et al., 2008). Similar to cough
tolerated if given as a single bedtime dose. Other tricyclic antidepres- headache, this disorder can be benign or symptomatic of an underlying
sants, gabapentin, mirtazapine, sodium valproate, or topiramate may cause. In one series, 12 of 28 patients with exertional headache were
be used as prophylactics if amitriptyline is not tolerated or contra- found to have underlying causes (Pascual et al., 1996). These patients,
indicated. Techniques to promote relaxation of the scalp and neck however, were older (mean age 42 vs. 24 years), developed acute severe
muscles (e.g., biofeedback, neck massage) can help in the short term, bilateral headaches lasting 1 day to 1 month, and developed accom-
but their long-term benefit has not been established (Fumal and panying symptoms of vomiting, diplopia, or neck rigidity. Potential
Schoenen, 2008). causes of secondary exertional headache include subarachnoid hem-
In contradistinction to the infrequent variety, chronic tension-type orrhage, cerebral metastases, intracranial hypertension, pansinusitis,
headache (more than 15 headache days a month) can persist for years and pheochromocytoma. Exercise-induced cardiac ischemic pain can
and can be difficult to manage. refer to the head and neck and is referred to as cardiac cephalalgia. A
patient with risk factors for coronary artery disease presenting with an
Primary Cough Headache exertional headache should get an exercise stress test or comparable
Cough headache is a headache of sudden onset that is precipitated by investigation.
a brief, nonsustained Valsalva maneuver such as coughing, laughing, Preventive treatment with a beta-blocker or indomethacin on a daily
sneezing, or bending over. The pain is typically bilateral, explosive, basis is effective in some primary exertional headache patients. Other
and lasts seconds to minutes (Chen et al., 2009; Pascual, 2009). As a migraine preventives may show benefit. Ergotamine or indomethacin
rule, the patient is free from pain between attacks. The mean age at preemptively before exercise may be effective. A prescribed warm-up
onset of primary cough headache is around 60 years. The proportion period can sometimes prevent exertional headache (Pascual, 2009).
of patients who have an underlying structural cause has varied between
11% and 59% in studies done in the MRI era. Chiari type I malforma- Primary Headache Associated With Sexual Activity
tion is the most common structural abnormality found on imaging, Headaches precipitated by sexual activity can occur as a dull bilateral
but other entities have been described, such as headache secondary to ache which gradually increases with sexual excitement (previously
spontaneous spine CSF leak, middle cranial or posterior fossa brain called preorgasmic headache) or an abrupt explosive headache at orgasm
tumors, brain metastases, pituitary tumors, posterior fossa arachnoid (previously called orgasmic headache), with some patients experiencing
cysts, basilar impression, sphenoid sinusitis, subdural hematoma, both (IHS, 2018). The pain is usually bilateral with a median duration
RCVS, and possibly unruptured intracranial aneurysm and carotid of 30 minutes (severe pain may last 1 minute to 24 hours). The mean
stenosis (Chen et al., 2009; Evans and Boes, 2005; Kato et al., 2018; age at onset ranges from the second to the fourth decade, and there is a
Pascual et al., 2008). As a spontaneous spine CSF leak can present as clear male predominance (Cutrer and DeLange, 2014). Three-quarters
cough headache without an orthostatic component, all patients pre- of patients have their headaches in bouts.
senting with cough headache should get an MRI with gadolinium to Symptomatic headaches precipitated by sexual activity share a sim-
look for pachymeningeal enhancement (Evans and Boes, 2005). In a ilar differential to secondary causes of exercise-induced headaches.
large series of spontaneous spinal CSF leaks secondary to CSF-venous With orgasmic headache in particular, it is mandatory to exclude such
fistulas headache occurred in isolation to Valsalva maneuvers in 12% conditions as subarachnoid hemorrhage, arterial dissection, pheo-
of patients; a finding that warrants considering this entity early in the chromocytoma, and RCVS. In patients with risk factors for coronary
differential diagnosis of Valsalva-induced (“cough”) headache (Duvall artery disease, the possibility of cardiac cephalalgia should also be
et al., 2019). Whether an unruptured intracranial aneurysm can pres- investigated.
ent with cough headache is unclear but given this possibility as well as Approximately 50% of patients can ease the headache by taking a
the possibility of reversible cerebral vasoconstriction, it would be rea- more passive role during sexual activity. Indomethacin (25–50 mg)
sonable to obtain an MRA of the intracranial circulation in most cases. given 30–60 minutes prior to sexual activity may prevent the head-
Typically cervical vessels do not need to be imaged unless symptoms of ache. For those intolerant of or unresponsive to indomethacin, an oral
cerebral ischemia are present. triptan can be tried 30–45 minutes before sexual activity (Frese et al.,
The treatment of choice is indomethacin, administered in a regi- 2006). For patients with frequent attacks, daily propranolol, metopro-
men similar to that described for PH. The response to indomethacin lol, or diltiazem may be effective.
does not confirm a benign etiology. Other reports suggest that primary
cough headache may respond to topiramate, acetazolamide, methy- Primary Thunderclap Headache
sergide, or LP (Chen et al., 2009; Medrano et al., 2005). Any chest dis- A “thunderclap headache” is a severe headache that reaches maxi-
ease that may be causing the cough should be identified and treated. mal intensity in less than 1 minute (IHS, 2018). It is the rapidity with
which the headache reaches maximum intensity that differentiates a
Primary Exercise Headache thunderclap headache from other severe headache types. As discussed
Primary exercise headache (previously called primary exertional head- previously, there are numerous potential causes of a thunderclap
ache) is a bilateral throbbing headache that is precipitated by prolonged headache, including but not limited to subarachnoid hemorrhage,
physical exercise. The ICHD-3 differentiates the exercise with this type spontaneous spine CSF leak, RCVS, cervical artery dissection, cerebral
of headache as more sustained strenuous effort rather than a short burst venous sinus thrombosis, pheochromocytoma, and hypertensive crisis
publication.
(see Subarachnoid Hemorrhage and Thunderclap Headache section). rounded or elliptical area of the head, typically 1–6 cm in diameter.
When no underlying cause for the thunderclap headache is identi- Pain is commonly described as pressure or stabbing, and is frequently
fied following a comprehensive evaluation, a diagnosis of “primary accompanied by hypesthesia, dysesthesia, paresthesia, allodynia, and/
thunderclap headache” is given. It is not clear if primary thunder- or tenderness (IHS, 2018).
clap headaches are a true entity or if they represent missed diagno- A minority of patients may develop trophic changes such as hair loss
ses of underlying causes for the thunderclap headache such as mild or a patch of skin depression. Hair heterochromia has been described
forms of the RCVS or RCVS with delayed angiographic appearance of in one patient (Dabscheck and Andrews, 2010). Similar headaches
vasoconstriction. have been related to structural lesions such as meningiomas, arach-
noid cysts, and fibrous dysplasia of the skull. It is therefore import-
Cold-Stimulus Headache ant to perform imaging with an MRI to rule out underlying structural
Cold-stimulus headache is a generalized headache that follows expo- etiologies. Local subcutaneous anesthetic injections are generally not
sure to a cold stimulus that is either applied externally, ingested, or felt to be helpful. Small series suggest that gabapentin (300–1800 mg
inhaled. For example, this might include exposure to cold weather, div- daily), tricyclic antidepressants, and onabotulinumtoxinA may be use-
ing into cold water, or passing a solid or liquid cold material over the ful (Cuadrado et al., 2018; Guerrero et al., 2012). Twenty-five units of
palate or posterior pharynx (previously known as ice cream headache) onabotulinumtoxinA divided among 10 injection sites in and around
(IHS, 2018). A lifetime prevalence of 15% was found in a cross-sec- the circumscribed affected areas of pain has been reported to help
tional epidemiological survey of a 25- to 64-year-old general popu- some (Mathew et al., 2008a), the procedure is repeated approximately
lation (Rasmussen and Olesen, 1992). Whether this disorder is more every 3 months if a favorable response is obtained. While one series
common in migraineurs is a matter of debate. The pathophysiology is also suggests local arterectomy may help in a select subset of patients
not completely understood. Clinically, after exposure to the cold stim- (Guyuron et al., 2018), this is not a treatment we recommend perform-
ulus, the pain begins within seconds, peaks over 20–60 seconds, and ing routinely at present.
then subsides within 10 minutes after removal of the stimulus (or up
to 30 minutes after removal of an external cold stimulus). The head- Hypnic Headache
ache location is most commonly midfrontal, followed by bitemporal or Hypnic headache is a primary headache disorder wherein the attacks
occipital. In patients with migraine, the pain might be referred to the of headache occur exclusively during sleep, often between 2 a.m. and
usual site of their migraine headaches. Cold-stimulus headache is best 4 a.m. (Holle et al., 2013). The mean age of onset is 63 years. The pain
prevented by avoiding the known stimulus. Cheshire and colleague is usually mild to moderate, but 20% of patients report severe pain.
suggest divers can prevent the headaches by using a Neoprene hood The pain is bilateral in about two-thirds of cases. The attack usually
when exposed to very cold waters (Cheshire and Ott, 2001). lasts from 15–180 minutes, but longer durations have been described.
In contrast to cluster headache, hypnic headache usually has no auto-
External-Pressure Headache nomic features.
External-pressure headache refers to headache which arises from com- Caffeine before bedtime (one strong cup of regular coffee or an
pression or traction on the scalp, without actual tissue damage. The espresso if available) is often helpful in preventing that night’s hypnic
headache should exclusively come on within an hour of stimulus expo- headache. Lithium, melatonin, and indomethacin can also be helpful
sure and remit within an hour of removal. Reported examples include in preventing hypnic headache. Patients responsive to gabapentin, pre-
headache from helmet wearing, swimming goggles, and traction from gabalin, verapamil, acetazolamide, onabotulinumtoxinA, topiramate,
a ponytail. and hypnotics have also been reported (Garza and Swanson, 2007).
Primary Stabbing Headache New Daily Persistent Headache

Patients with primary stabbing headache describe brief, extremely sharp New daily persistent headache (NDPH) is a daily headache that is unre-
jabs of pain that occur without warning and can be felt anywhere in the mitting from onset or very soon after onset (within 24 hours at most)
head, including the orbit. These recur with irregular frequency, one or (IHS, 2018). The vast majority of patients can pinpoint the exact date
many times per day. The pains are described as being like a spike driven their headache started. Infection, flu-like illness, surgery, and stress-
into the skull: hence, the previous term icepick headache. Similar pains ful life events may precede NDPH. How these may result in NDPH is
have been described under different terms by other investigators (e.g., unclear and more than half of patients do not recognize a triggering
jabs and jolts, ophthalmodynia periodica). There are no associated cra- or precipitating event (Rozen, 2016). Clinically, NDPH may have fea-
nial autonomic features and no trigeminal distribution trigger points tures suggestive of either migraine or tension-type headache. Secondary
(Pascual, 2009). Stabbing pains more commonly occur in patients headache disorders, particularly spontaneous spine CSF leaks and cere-
subject to migraine, cluster headache, or hemicrania continua. Icepick- bral venous sinus thrombosis, need to be ruled out. In general, if no
like head pain has also been described in patients with giant-cell arte- secondary headache cause is found, it is recommended to classify the
ritis. Because of the brevity of the pain, the sporadic nature of attacks, dominant headache phenotype, whether it is migraine or tension-type
and the common occurrence of spontaneous remissions, treatment is headache, and treat with preventives accordingly. Even with aggressive
not usually required and reassurance generally suffices. However, in treatment, however, unfortunately many patients do not improve and
patients with “icepick status,” in whom stabs of pain occur often, the become treatment refractory (Garza and Schwedt, 2010).
treatment of choice is indomethacin, administered in a regimen sim-
ilar to that described for PH. Cyclooxygenase-2 (COX-2) inhibitors, OTHER HEADACHES AND FACIAL PAINS
gabapentin, and melatonin (3–12 mg orally at night) have also been
reported to be useful (Ferrante et al., 2010; Franca et al., 2004). Neck-Tongue Syndrome
Neck-tongue syndrome describes paroxysmal sharp pain in the neck,
Nummular Headache occiput, or both, associated with ipsilateral sensory changes in the
Nummular headache, previously called coin-shaped headache, tongue, precipitated by neck movement. The pain lasts seconds to
describes a focal head pain felt in one small, fixed, well-defined minutes and may be associated with sensory changes over the neck and
publication.
occipital region. Though this syndrome may occur from early child- Painful Posttraumatic Trigeminal Neuropathy
hood to adulthood, the majority of reported cases in the literature have Painful posttraumatic trigeminal neuropathy, previously called anes-
had an onset of symptoms before age 21 (Gelfand et al., 2018). The thesia dolorosa, consists of persistent painful anesthesia or hypesthe-
exact mechanism remains speculative. Proprioceptive fibers from the sia in the distribution of the trigeminal nerve or one of its divisions
tongue travel in the lingual nerve, anastomose with the hypoglossal following traumatic injury. Often related to surgical trauma of the
nerve within the tongue, then travel via the ansa cervicalis to the ven- trigeminal nerve or ganglion, it most frequently occurs as a compli-
tral ramus of the C2 nerve root. Evidence supports that subluxation of cation of rhizotomy or thermocoagulation done to treat trigeminal
the atlantoaxial joint, among other conditions, may compromise the neuralgia. In different series of patients treated for trigeminal neural-
second cervical dorsal root during sudden neck rotation, resulting in gia, anesthesia dolorosa has developed in anywhere from 0% to 3%,
numbness, paresthesia, or a sense of involuntary movement in the ipsi- depending on the specific procedure performed (Barker et al., 1996;
lateral tongue (Orrell and Marsden, 1994). In general, the condition Maarbjerg et al., 2017). This painful numbness can be even more
is benign. In the absence of any structural abnormality, management unbearable than the pain from trigeminal neuralgia itself, warranting
is conservative and may include antiinflammatory agents, temporary careful decision making when considering surgical treatment for this
immobilization of the neck in a cervical collar, and possibly physical condition.
therapy exercises (Niethamer and Myers, 2016).
Persistent Idiopathic Facial Pain
Painful Trigeminal Neuropathy Previously known as atypical face pain, persistent idiopathic facial pain
Painful trigeminal neuropathy describes head and/or facial pain in the (PIFP) is essentially a facial pain of unknown cause with no associated
distribution of one or more branches of the trigeminal nerve and is neurological deficit. The diagnosis of PIFP should be considered only
associated with nerve damage. In contrast to the paroxysmal lancinat- when all facial pains due to disturbances of anatomy and pathophysiol-
ing pain of trigeminal neuralgia, painful trigeminal neuropathy tends ogy have been excluded, including trigeminal neuropathy. Exhaustive
to be a more persistent pain of highly variable character and intensity, radiographic and other imaging techniques may be necessary to
often associated with numbness, dysesthesia, or paresthesia. There is exclude conditions such as nasopharyngeal and sinus neoplasms, bony
a broad differential for neuropathy of the trigeminal nerve, including abnormalities of the base of the skull, and dental conditions such as
trauma, demyelination, infection, inflammation, and neoplasm (Smith cryptic mandibular and maxillary abscesses. Evaluation may also
and Cutrer, 2011). Unexplained neuropathy, especially with progres- require a chest roentgenogram or chest CT scan if referred pain from
sive worsening, warrants further investigation with MR imaging, with lung cancer is suggested by the history (smoker) or examination (dig-
special attention to the course of the trigeminal nerve. Isolated involve- ital clubbing).
ment of the mental nerve, with resultant chin numbness (i.e., numb Patients in whom PIFP is eventually diagnosed are usually mid-
chin syndrome), is a red flag for a potential metastatic lesion, and may dle-aged and predominantly female. A subset of patients may develop
require more detailed imaging of the mandible (Smith et al., 2015). PIFP after insignificant trauma to the face, teeth, or gums, suggest-
ing that PIFP and traumatic trigeminal neuropathy may repre-
Painful Trigeminal Neuropathy Attributed to Herpes Zoster sent extremes on a continuum of injury-induced neuropathic pain
Painful trigeminal neuropathy may occur acutely during herpes (Benoliel and Gaul, 2017). Pain is commonly felt in the nasolabial fold
zoster infection, and in some patients may persist for longer than or on one side of the chin but can spread to wider areas of the face and
3 months (referred to as postherpetic neuralgia, though technically neck. Patients complain of deep, poorly localized pain. Generally uni-
a neuropathy/neuronopathy). Pain may be burning, stabbing, itch- lateral, but occasionally bilateral, the pain may be described in graphic
ing, or aching, often with sensory abnormalities and allodynia. The terms such as tearing, ripping, or crushing, or often as aching and bor-
diagnosis is suggested if there is a history of a vesicular rash in the ing. The pain is usually present all day and every day, and gradually
distribution of pain (or pale purple scars present as sequelae of her- worsens with time. It is not influenced by factors such as alcohol con-
petic eruption). In rare cases where there is no rash present, the sumption, heat, or cold or by factors that trigger trigeminal neuralgia.
diagnosis can be confirmed by varicella zoster viral DNA in the CSF Local anesthetic blocks of the trigeminal nerve do not relieve the pain.
(IHS, 2018). Many patients have already undergone extensive dental, nasal, or sinus
Pain during the acute phase of herpes zoster trigeminal neuropathy operations to no avail. Pain may be associated with other comorbid
is severe and may require opioid analgesics. Antiviral drugs and pred- pain conditions such as chronic widespread pain and irritable bowel
nisone can decrease the pain during this stage. Once developed, pos- syndrome (IHS, 2018).
therpetic neuralgia may persist indefinitely, although with time it may When no symptomatic etiology is identified, tricyclic antidepres-
become less severe. Many elderly patients with this distressing pain sants such as amitriptyline are considered first line. Medications used
become depressed, lose weight, and become withdrawn. Treatment of to treat central neuropathic pain, such as gabapentin, pregabalin, or
established postherpetic neuralgia is difficult and in many instances duloxetine, may also be tried.
ineffective. Tricyclic antidepressants, gabapentin, pregabalin, opioids,
and lidocaine patches may all be helpful in select patients (Dubinsky Cranial and Facial Neuralgias
et al., 2004).The use of topical capsaicin is not practical in this disorder. Trigeminal Neuralgia
Procedures to denervate the affected area of skin, trigeminal destruc- Clinical symptoms. Trigeminal neuralgia describes paroxysmal
tive procedures, and trigeminal tractotomy have been used for control pain felt within the distribution of one or more divisions of the
of pain, but they are rarely used at present. trigeminal nerve. The pain is often triggered by a sensory stimulus to
When the herpes zoster infection affects the ophthalmic division of the skin, mucosa, or teeth within the area innervated by the ipsilateral
the trigeminal nerve (i.e., herpes zoster ophthalmicus), it can affect the trigeminal nerve. The trigger zone most commonly occurs near the
eye and vision, sometimes leading to a keratitis that can permanently nasolabial fold and may be remote from the site of pain. Chewing, teeth
scar the cornea. For this reason, aggressive management with systemic brushing, talking, and even cool breeze striking the face are commonly
antivirals is recommended (Schuster et al., 2016). reported triggers. The pain is described as electric shock-like, shooting,
publication.
or lancinating. Each attack lasts only seconds, but the pain may be nerve is surgical exploration and decompression of the nerve.
repetitive at short intervals, so that the individual attacks blur into Management of classical trigeminal neuralgia can be either medical or
one another. After many attacks within a few hours, the patient may surgical.
describe a residual lingering facial pain. Attacks of trigeminal neuralgia Sodium channel blockers, such as carbamazepine or oxcarbaze-
are most common in the second and third divisions of the nerve. Pain pine, are considered the drugs of choice for treatment of trigeminal
confined to the ophthalmic division is extremely rare. Attacks of pain neuralgia, with a highly favorable response in a majority of patients.
during sleep are uncommon but do occur. Frequent attacks may be Administration of carbamazepine must be initiated with small doses
associated with weight loss, dehydration, or depression. of 50–100 mg and increased slowly as tolerated. Vertigo, drowsiness,
In the current ICHD-3 classification, classical trigeminal neuralgia and ataxia are common side effects if the preparation is introduced
refers to trigeminal neuralgia with evidence of vascular compression too quickly, especially in elderly patients. Therapeutic doses generally
of the trigeminal nerve (by MRI or surgery), with associated nerve range from 600 to 1200 mg/day in divided dosing. The appropriate
root atrophy or displacement. Secondary trigeminal neuralgia is due to dose is the lowest dose needed to control the pain. Once the pain is
an underlying disease such as multiple sclerosis or a space-occupying controlled completely, the dose can be tapered every few weeks to
lesion, and may present as both paroxysmal pain and a concomitant determine whether a remission has developed. Oxcarbazepine may
continuous or near-continuous pain. If evaluation shows no under- be better tolerated, but may be associated with sometimes prominent
lying etiology and no clear morphological change (atrophy or dis- hyponatremia. When starting these medicines, regular blood counts
placement) in the nerve root related to blood vessel contact, the term (monitoring for agranulocytosis), liver function tests, and serum
idiopathic trigeminal neuralgia is preferred (IHS, 2018). sodium should be performed for the first few months and once a year
Physical findings. In classical trigeminal neuralgia, there is no thereafter.
sensory impairment, and the motor division of the nerve is intact. The Second-line options for the management of trigeminal neuralgia
presence of physical signs such as sensory loss or masticatory muscle include gabapentin, pregabalin, phenytoin, and baclofen. Other drugs
weakness suggests a secondary cause for trigeminal neuralgia, though a that have been used include lamotrigine, valproate, clonazepam, and
more accurate description in this case would be trigeminal neuropathy. topiramate (Cheshire, 2007; Maarbjerg et al., 2017). Second-line drugs
This could be secondary to a lesion or mass affecting the gasserian should be considered for trial, alone or in combination, when sodium
ganglion, main sensory root, or root entry zone in the pons. channel blockers are either unhelpful or not tolerated. Given the ben-
Laboratory and radiological findings. Idiopathic trigeminal neu- eficial effects of gabapentin in other neuropathic conditions and its
ralgia has no accompanying laboratory or radiographic abnormalities. benign side-effect profile, an initial trial with this drug may be an alter-
EMG and nerve stimulation (such as blink reflex studies) are normal. native option to carbamazepine/oxcarbazepine.
Imaging with MRI is done primarily to look for structural lesions such On occasion, one may encounter a patient in the midst of a severe
as a pontine lacunar infarct, demyelinating plaque, meningioma or attack. A useful technique in this situation is the administration of IV
schwannoma of the posterior fossa, or malignant infiltration of the fosphenytoin at a dose of 15–20 mg phenytoin sodium equivalents
skull base. High-resolution MRI and MRA may be able to identify vas- (PE)/kg. Anesthetizing the ipsilateral conjunctival sac with the local
cular compression in select cases. ophthalmic anesthetic proparacaine has also proved effective in pro-
Pathogenesis and etiology. Classical trigeminal neuralgia cases viding relief from pain for several hours to days.
are felt to be related to neurovascular compression of the trigeminal A patient who is refractory to medical therapy may be a candidate
nerve by neighboring vessels, including the superior cerebellar artery, for a surgical procedure. The most commonly performed surgical
anterior and posterior inferior cerebellar arteries, and superior procedures include percutaneous procedures on the trigeminal nerve
petrosal vein. Vascular compression is believed to increase with or gasserian ganglion (rhizotomy), Gamma Knife radiosurgery, and
age and contribute to focal demyelination of primary trigeminal microvascular decompression. Picking the best surgical option often
afferents near where the trigeminal nerve enters the pons (i.e., nerve involves a discussion with the patient about the potential risks of the
root entry zone). In pathology studies, vacuolated neurons, segmental procedure based on their age and comorbidities, as well as the risk of
demyelination, vascular changes, and other abnormalities were more pain recurrence.
common in gasserian ganglia from patients with a history of trigeminal The simplest nonmedical therapy is an alcohol block of the periph-
neuralgia than in control specimens. This focal demyelination of eral branch of the division of the trigeminal nerve that is painful.
axons in the main sensory root is hypothesized to contribute to focal The mental or mandibular nerve can be blocked with 0.5–0.75 mL of
hyperexcitability, leading to ectopic and repetitive neuronal discharges. absolute alcohol to control mandibular division trigeminal neuralgia.
In secondary trigeminal neuralgia, structural lesions may contribute The infraorbital and supraorbital nerves can also be injected for pain
to pain through a similar pathophysiological mechanism (Maarbjerg involving the second and first divisions, respectively. Relief of pain
et al., 2017). occurs in a high proportion of patients so treated, but relapse is likely
Epidemiology. Trigeminal neuralgia begins after the age of 40 in most after 6–18 months. The procedure can be repeated once or
years in 90% of patients. It is slightly more common in women. The twice, but thereafter it is prudent to perform a more proximal and last-
incidence progressively increases with increasing age (Manzoni and ing procedure because the further injection of alcohol is likely to be
Torelli, 2005). Rare familial cases have been described, suggesting that ineffective. The advantages of a peripheral alcohol injection include
genetics may play a role in some families. low morbidity and the temporary nature of sensory loss. Preservation
Course and prognosis. Trigeminal neuralgia frequently has of corneal sensation is also an advantage.
an exacerbating and remitting course over many years. During For many patients, especially those who are elderly or have compli-
exacerbations, the painful attacks may occur many times a day for cating medical conditions, percutaneous radiofrequency thermocoag-
weeks or months at a time. A spontaneous remission may occur at any ulation of the trigeminal nerve sensory root as it leaves the gasserian
time and last for months or years. The reasons for these fluctuations ganglion is the procedure of choice. Investigators have reported pain
are unknown. relief in up to 93% of patients. Recurrence rates vary with the period
Treatment and management. Treatment of trigeminal neuralgia of follow-up. The procedure can be repeated when relapse occurs.
due to a focal lesion compressing the sensory root of the trigeminal Complications include damage to the carotid artery, adjacent cranial
publication.
nerves, and the trigeminal nerve motor root. Corneal sensory loss in lesions at the base of the skull. Therefore, presenting patients should
V1 lesions can lead to serious eye complications. Troublesome dyses- be evaluated with an MRI of the brain and soft tissues of the neck, with
thesias of the face are commonly encountered. Posttraumatic trigemi- specific attention to the glossopharyngeal nerve.
nal neuropathy (previously anesthesia dolorosa), a distressingly painful Carbamazepine and phenytoin have been administered with mixed
sensation in the numb area, occurs occasionally. success in glossopharyngeal neuralgia. Intracranial section of the glos-
Percutaneous balloon compression of the trigeminal ganglion has sopharyngeal and upper rootlets of the vagus nerve almost always
been shown to be an effective and technically simple treatment. The produces complete pain relief. A series of 47 patients treated with
early recurrence rate, however, is higher than that reported for radio microvascular decompression reported 98% found immediate relief
frequency thermocoagulation, with pain recurring 2–3 years later. after the procedure (Sampson et al., 2004).
Stereotactic radiosurgery with the Gamma Knife has also been shown
to be an effective therapy for trigeminal neuralgia and is a less inva- Nervus Intermedius Neuralgia (Geniculate Neuralgia, Hunt
sive surgical option. However, it is also associated with a relatively high Neuralgia)
recurrence rate, and patients who have previously undergone surgical This is a rare disorder characterized by brief paroxysms of pain felt
procedures may have an increased risk of facial dysesthesia following deeply in the auditory canal (IHS, 2018). The intermediate nerve of
Gamma Knife radiotherapy. Wrisberg (the nervus intermedius), a small sensory branch of the
In patients who are felt to be healthy enough for more invasive sur- facial nerve (cranial nerve VII), and/or the geniculate ganglion are
gery, the preferred procedure is microvascular decompression (MVD). believed to be the affected structures. The accurate incidence, prev-
This involves craniotomy and posterior fossa exploration to identify alence, and risk factors associated with this condition are unknown,
the area of neurovascular compression, dissection of the offending since it is so rare. Middle-aged women seem to be more frequently
vessel away from the trigeminal nerve, and placement of a synthetic affected. Clinically the pain is described as brief (seconds to min-
padding to prevent future compression. In Jannetta’s series of 1155 utes), severe, paroxysmal, and limited to the depths of the ear,
patients, 70% had excellent relief of pain continuing 10 years after the associated with a trigger zone in the posterior wall of the ear canal.
trigeminal nerve and the compressing vessel were separated. Relief of The pain can be sharp or burning and is not necessarily lancinat-
pain without the production of anesthesia is the major advantage of ing, as occurs in other cranial neuralgias. The diagnosis is made on
the procedure. Disadvantages include the need for a posterior fossa clinical grounds. Importantly, because of the complex ear sensory
exploration, with a reported mortality rate of 1% and a risk for injury innervation, other referred sources of ear pain should be consid-
to other cranial nerves, most commonly CN IV, VII, and VIII, depen- ered in the differential diagnosis when evaluating a neuralgic otalgia.
dent on the experience of the surgeon. Despite the inherent risks of a Nerves referring pain to the ear include branches of cranial nerves
retromastoid craniectomy, MVD is associated with the longest dura- V, VII, IX, and X, and upper cervical roots (De Lange et al., 2014;
tion of pain relief, preserves facial sensation, and remains the only Fig. 102.7).
surgical treatment that directly addresses the presumed mechanism. Nervus intermedius neuralgia can develop during an episode of
When no vascular loop is found at the time of operation, the options Ramsay-Hunt syndrome (herpes zoster virus involving the geniculate
include performing a partial or complete sensory root section or sub- ganglion/facial nerve, causing ipsilateral facial paralysis); therefore
sequently performing a radiofrequency procedure. patients with this deep stabbing ear pain should be checked for vesicles
For a young patient unresponsive to medical treatment, posterior in the external auditory canal, pinna, and tonsillar fossa. Because this
fossa MVD should be considered. For an elderly patient or a patient type of deep stabbing ear pain can be referred from the throat, imag-
with other medical complications, however, peripheral procedures ing of the soft tissues of the neck should be included in the evaluation
targeting the trigeminal ganglion, such as radiofrequency thermoco- (DeLange et al., 2014).
agulation or balloon compression, would be considered procedure of For treatment, a trial with carbamazepine is appropriate. If not
choice because of the ease of performance. Specific recommendations effective, other drugs used to treat cranial neuralgias and neuro-
relating to the various interventional or surgical procedures cannot be pathic pain (e.g., oxcarbazepine, gabapentin, phenytoin, lamotrigine,
made. Rather, the treatment must be individualized to the particular baclofen) can be tried. Neurosurgery is a last resort when pharmaco-
needs of the patient. therapy fails, and may involve excision of the nervus intermedius and
geniculate ganglion with or without exploration and/or section of CN
Glossopharyngeal Neuralgia V, IX, and X. Lovely and Jannetta (1997) reported good long-term
The pain associated with neuralgia of the ninth cranial nerve is simi- results in up to 90% of patients in a series using microvascular decom-
lar in quality and periodicity to that of trigeminal neuralgia. The pain pression of CN V, IX, and X, with or without section of the nervus
is lancinating and episodic and may be severe. It is felt in the distri- intermedius.
bution of the glossopharyngeal nerve and the sensory distribution
of the upper fibers of the vagus nerve. Pain in the throat, the ton- Occipital Neuralgia
sillar region, the posterior third of the tongue, the larynx, the naso- Occipital neuralgia can cause a headache in the occipital region. It is
pharynx, and deep in the ear is often described by patients with this a paroxysmal jabbing pain in the greater (C2), lesser (C2–C3), and/
rare neuralgia. The pain is usually triggered by swallowing, speaking, or third (C3) occipital nerve distribution, sometimes accompanied
laughing, or coughing and is unilateral in most patients. Bilateral by diminished sensation or dysesthesia in the affected area. The true
involvement does occur, but it is very rare. The age group involved incidence and prevalence of occipital neuralgia are not known, possi-
is generally older than 40 years. Bradycardia and syncope can occur bly because the diagnosis is frequently arbitrarily given to any pain in
when the painful attack strikes. the occipital region (Bogduk, 2004). Injuries to the C2–C3 nerve roots
Most glossopharyngeal neuralgia occurrences have been thought through different mechanisms (entrapment, trauma, inflammation,
to be idiopathic, but vascular compression of the ninth cranial nerve whiplash, etc.) might contribute to occipital neuralgia.
has been described. Secondary glossopharyngeal neuralgia may also be Clinically, the pain has a sudden onset and is described as a severe
due to oropharyngeal malignancies, peritonsillar infections, and other stabbing, electric shock-like, or sharp shooting pain that starts at
publication.
CN V
Auriculotemporal nerve
• Lateral surface of tympanic membrane
• External acoustic meatus
• Temporal scalp
• Pre-auricular area and tragus
• Temporomandibular joint
C2,C3
Lesser Occipital Nerve
• Posterolateral scalp
• Superior pinna
• Supra-auricular scalp
C2,C3
Great Auricular Nerve
• Angle of jaw
• Majority of pinna
• Lateral neck
• Skin over parotid gland
and mastoid process
CN Vll
Nervous Intermedius
• Concha
CN X
Branch of Vagus Nerve
• Pharynx and larynx
• Concha
CN IX
Branch of Glossopharyngeal Nerve
• Tonsils and pharynx
• Posterior tongue
• Middle ear
• Medial surface of tympanic membrane
• Mastoid air cells
Fig. 102.7 Sensory Innervation of the Ear and its Surrounding Structures. Boxes with their correspond-
ing colors illustrate each nerve’s distribution. Note that sensory distributions may overlap. (From DeLange,
J.M., Garza, I., Robertson, C.E. A 50-Year-Old Woman With Deep Stabbing Ear Pain. American Academy of
Neurology; 2014. Used with permission of Mayo Foundation for Medical Education and Research, all rights
reserved.)
the nuchal region and then immediately spreads toward the vertex. In the proper clinical scenario, the diagnosis is confirmed when the
Paroxysms can start spontaneously or, as in other neuralgias, be pro- pain is transiently relieved by a local occipital anesthetic block. A local
voked by specific maneuvers such as brushing the hair or moving the anesthetic block, however, is a nonspecific intervention, so symptom-
neck. Most often, occipital neuralgia is unilateral. Between attacks, atic relief does not indicate a specific etiology.
there may be a dull occipital discomfort as a background. On examina-
tion, pressure, palpation, or percussion over the occipital nerve trunks
HEADACHE IN CHILDREN AND ADOLESCENTS
may reveal local tenderness. These maneuvers may also trigger painful
paroxysms, exacerbate the background discomfort, or elicit paresthe- Headaches are very common in children, and more so in adolescents.
sias following the nerve’s distribution. Cervical range of motion may The prevalence of headache of any type is in the range of 37%–51%
be restricted, and local posterior neck muscle spasms may be found. in 7 year olds, increasing to 57%–82% in 15 year olds (Lewis et al.,
The neurological examination may find sensory deficits in the indi- 2002). Prepubertal boys are more often afflicted than girls, whereas,
vidual occipital nerve distribution but is usually otherwise unremark- after puberty, headaches occur more often in girls (Abu-Arafeh et al.,
able. An abnormal neurological examination should alert the clinician 2010; Lewis et al., 2002).
for potential alternative or underlying causes of the symptoms. Since Obtaining the child’s history of head pain can be challenging
structural and infiltrating lesions can cause occipital neuralgia, a cer- because most patients younger than 10 years old are unable to give
vical spine and brain MRI is commonly considered when evaluating clear details about the temporal profile of the headache, its frequency,
occipital neuralgia. and its characteristics. For this reason, the clinician must depend on
publication.
parental observations of the child’s behavior. Does the youngster con- adolescents (Abu-Arafeh et al., 2010; Slater et al., 2018). Although
tinue to play, want to go to bed, avoid light or sound, refuse food, migraine can manifest all the features seen in older patients, migraine
refuse to go to school, and then appear to recover? The neurological attacks in children are often shorter and occur less often than those in
examination in a child should evaluate the same factors as in an older adults. The description of headache tends to evolve as age increases. In
patient, including careful assessment of the optic fundus. In addition, younger children, migraine pain tends to be bilateral and non-throb-
head size should be measured, and developmental markers checked. bing, while unilateral pain and headache pulsation tend to become
Laboratory and other investigations are undertaken after a thor- more typical in adolescence (Virtanen et al., 2007). Migraine can be
ough history and physical examination. Neuroimaging is not done triggered by similar factors at all ages, including stress, fever, head
routinely. Features associated with the presence of a space-occupying trauma, and sleep and eating pattern changes. In girls, the onset of
lesion include (1) headache onset of less than 1 month, (2) absent fam- migraine may coincide with menarche.
ily history of migraine, (3) abnormal neurological findings on exam- In addition to headache, approximately 10% of migraine patients
ination (including gait abnormalities or papilledema), (4) the presence in a pediatric neurology practice present with recurrent discreet symp-
of seizures, and (5) progressive worsening of headaches. Headache in toms thought to be variants or precursors of migraine (Table 102.9). In
a child younger than 3 years old is uncommon and is a red flag for a the ICHD-3 classification, these are referred to as “episodic syndromes
secondary etiology for headache. Therefore, it would be reasonable to that may be associated with migraine,” and include recurrent attacks
perform neuroimaging for new headache in a child less than 6 years old of stereotyped symptoms such as abdominal pain or nausea/vomit-
(Gofshteyn and Stephenson, 2016). The child with a constant nonpro- ing, episodic attacks of dizziness, unsteadiness, or torticollis (Gelfand,
gressive headache may need a psychological evaluation, and the fam- 2015; IHS, 2018; Lagman-Bartolome and Lay, 2015).
ily dynamics may require full evaluation. Reports from teachers are of
value in assessing the child’s performance. The complete reference list is available online at https://expertconsult.
inkling.com/.
Migraine and Migraine Variants
Migraine is the most common cause of headaches in children referred
to a neurologist, and is estimated to affect 10%–12% of children and
TABLE 102.9 Episodic Syndromes That May Be Associated With Migraine

Typical Age of Onset Characteristics Associated Features
Infantile colic Peaks at 5–6 wk; typically Excessive frequent crying in an otherwise Crying tends to be late afternoon and evening hours
improves by 3–4 mo healthy, well-fed infant
Episodes last ≥3 h/day, ≥ 3 days/wk for ≥ 3 wk
Benign paroxysmal Typically 2–5 years old; may Brief spontaneous attacks of vertigo lasting Nystagmus, pallor, ataxia, vomiting, fearfulness
vertigo (BPV) resolve around age 5–6 minutes to hours Normal audiometric/vestibular testing between
attacks
Alternating hemiplegia Starts before 18 mo Recurrent attacks of hemiplegia alternating Should have one other paroxysmal symptom (tonic
of childhood between sides (occasionally quadriparesis) spells, dystonic posturing, choreoathetosis,
oculomotor abnormalities movements, autonomic
disturbance)
Abdominal migraine Around 4–7 yr Recurrent attacks of abdominal pain (dull, Anorexia, nausea/vomiting, pallor
moderate to severe, in the midline abdomen) Symptom free between attacks
lasting 2–72 h Exclude gastrointestinal/renal disease
Benign paroxysmal Starts around 5–6 mo, typically Recurrent episodes of head tilt to either side, Pallor, irritability, drowsiness, vomiting, ataxia
torticollis resolves by age 3–4 lasting minutes to days. May evolve into BPV or migraine with aura
Often in regular intervals (like monthly)
Cyclic vomiting Around 4–7 yr Episodic attacks of repeated vomiting (≥4/h) and Pallor, lethargy
syndrome severe nausea; attacks last hour to 10 days,
separated by at least 1 wk
publication.
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103
Cranial Neuropathies
Janet C. Rucker, Meagan D. Seay
OUTLINE
Olfactory Nerve (Cranial Nerve I), 1783 Anatomy, 1791
Optic Nerve (Cranial Nerve II), 1783 Clinical Lesions, 1792
Oculomotor Nerve (Cranial Nerve III), 1783 Vestibulocochlear Nerve (Cranial Nerve VIII), 1794
Anatomy, 1783 Glossopharyngeal Nerve (Cranial Nerve IX), 1794
Clinical Lesions, 1783 Anatomy, 1794
Trochlear Nerve (Cranial Nerve IV), 1787 Clinical Lesions, 1794
Anatomy, 1787 Vagus Nerve (Cranial Nerve X), 1795
Trigeminal Nerve (Cranial Nerve V), 1788 Clinical Lesions, 1795
Anatomy, 1788 Spinal Accessory Nerve (Cranial Nerve XI), 1796
Abducens Nerve (Cranial Nerve VI), 1790 Clinical Lesions, 1796
Anatomy, 1790 Hypoglossal Nerve (Cranial Nerve XII), 1796
Facial Nerve (Cranial Nerve VII), 1791 Clinical Lesions, 1796

OLFACTORY NERVE (CRANIAL NERVE I) communicating artery (PCOM) and is very near to this vessel at the
vessel’s junction with the intracranial internal carotid artery. In the
See Chapter 19. cavernous sinus, the third nerve is located within the dural sinus wall,
just lateral to the pituitary gland. From the cavernous sinus, the third
OPTIC NERVE (CRANIAL NERVE II) nerve enters the orbit via the superior orbital fissure. Just prior to entry,
the nerve anatomically divides into superior and inferior divisions in
See Chapters 16 and 43. the anterior cavernous sinus, although careful evaluation of brainstem
lesions and their corresponding patterns of pupil and muscle involve-
OCULOMOTOR NERVE (CRANIAL NERVE III) ment suggests that functional division occurs in the midbrain (Bhatti
et al., 2006; Vitosevic et al., 2013). Within the orbit, the superior divi-
Anatomy sion innervates the superior rectus and the levator palpebrae superio-
Paired oculomotor nuclei are located in the dorsal midbrain ventral to ris, and the inferior division innervates the inferior and medial recti,
the periaqueductal gray matter at the level of the superior colliculus. the inferior oblique, and the iris sphincter and ciliary muscles (Fig.
Each nucleus is composed of a superior rectus subnucleus providing 103.2). Prior to innervating the ciliary and sphincter muscles as the
innervation to the contralateral superior rectus; inferior rectus, medial short ciliary nerves, parasympathetic third nerve fibers synapse in the
rectus, and inferior oblique subnuclei providing ipsilateral innerva- ciliary ganglion within the orbit (see Fig. 103.2).
tion; and an Edinger-Westphal nucleus supplying preganglionic para-
sympathetic output to the iris sphincter and ciliary muscles (Che Ngwa Clinical Lesions
et al., 2014; eFig. 103.1). A single midline caudal central subnucleus Oculomotor Nucleus
provides innervation to both levator palpebrae superioris muscles. In addition to potentially causing ipsilateral weakness of the medial
A third nerve fascicle originates from the ventral surface of each rectus, inferior rectus, and inferior oblique muscles, an oculomo-
nucleus and traverses the midbrain, passing through or near to the tor nuclear lesion may result in bilateral superior rectus weakness.
red nucleus and in close proximity to the cerebral peduncles before Ipsilateral subnucleus involvement affects the contralateral superior
emerging ventrally as rootlets in the lateral interpeduncular fossa. In rectus because of the completely crossed nature of superior rectus
the interpeduncular fossa, the rootlets converge into a third nerve innervation (see eFig. 103.1). A unilateral oculomotor nuclear lesion
trunk that continues ventrally through the subarachnoid space toward may affect these unilateral originating fibers destined for decus-
the cavernous sinus, passing between the superior cerebellar artery sation, as well as those fibers that originated contralaterally and are
and the posterior cerebral artery. It travels parallel to the posterior already decussated. If the single midline levator palpebrae superioris
1783
CHAPTER 103 Cranial Neuropathies 1783.e1
Iris sphincter
and
cilary muscles
Levator palpebrae superioris
Superior rectus
Contralateral
Medial rectus
Inferior rectus
Inferior oblique
E-W
IR
SR
IO
CCN
MR
Superior colliculus
Paired Oculomotor Nuclei

eFig. 103.1 Schematic of the paired oculomotor nuclei with a single midline shared central caudal nucleus
(CCN). Each nucleus is composed of a superior rectus subnucleus (SR) providing innervation to the contra-
lateral superior rectus; inferior rectus (IR), medial rectus (MR), and inferior oblique subnuclei (IO) providing
ipsilateral innervation. The single midline caudal central subnucleus (CCN) provides innervation to both leva-
tor palpebrae superioris muscles. (Courtesy Marc Dinkin, MD.)
Long ciliary nerve Nasociliary

nerve
Anterior ethmoidal nerve
Ciliary Frontal
ganglion nerve Internal carotid
artery
Levator Lacrimal
palpebrae nerve
superioris Optic nerve
Superior
rectus
Oculomotor nerve
Lacrimal nerve Trochlear
nerve
Communication
between
lacrimal and
zygomatico-
temporal nerve
Mandibular
Inferior oblique
Maxillary nerve
Lateral nerve
rectus
Short Ophthalmic
ciliary Abducens nerve
nerves Infraorbital nerve
Inferior rectus nerve
Fig. 103.2 Oculomotor, Trochlear, Abducens, and Trigeminal Nerve Distributions in the Orbital Apex
and Orbit. (From Standring, G., 2005. Gray’s Anatomy, thirty-ninth ed. Churchill Livingstone, Philadelphia.)
subnucleus is involved in an oculomotor nuclear lesion, bilateral ptosis at the caudal end of the red nucleus or the pedunculopontine nucleus,
results. Isolated bilateral ptosis or isolated paresis of a single extraoc- a component of the mesencephalic locomotor region (Hathout and
ular muscle is also possible from a small focal nuclear lesion, given Bhidayasiri, 2005). Nothnagel syndrome is the combination of ipsilat-
the functional division of the subnuclei (Al-Sofiani and Kwen, 2015). eral oculomotor nerve palsy and ipsilateral hemiataxia from involve-
Involvement of the rostral and dorsally located Edinger-Westphal ment of the oculomotor fascicle and superior cerebellar peduncle or
nucleus will lead to pupil involvement. Common brainstem lesions pedunculopontine nucleus (see Table 103.1). Weber syndrome is the
include ischemia, hemorrhage, demyelination, infectious and nonin- combination of an ipsilateral fascicular oculomotor nerve palsy and
fectious inflammation, and neoplasm. contralateral hemiparesis from cerebral peduncle involvement (see
Table 103.1). Benedikt syndrome involves the oculomotor fascicle and
Oculomotor Palsy Appearance red nucleus, causing an ipsilateral oculomotor nerve palsy and con-
A complete oculomotor nerve palsy has the following ipsilateral exam- tralateral chorea or tremor (see Table 103.1). Common brainstem
ination features: eye deviation inferiorly and laterally (“down and out”); lesions include ischemia, hemorrhage, demyelination, infectious and
absence of ocular elevation, depression, and adduction; and complete noninfectious inflammation, and neoplasm (Kremer et al., 2013;
ptosis. A complete oculomotor palsy may be further described as com- Ogawa et al., 2016).
plete involving the pupil with an enlarged and nonreactive pupil or
as a pupil-sparing otherwise complete oculomotor palsy. A partial, or Interpeduncular Fossa and Subarachnoid Space
incomplete, third nerve palsy may present with any combination of The most common etiology of oculomotor dysfunction in this region
deficits of third nerve innervated structures. Great emphasis is often is compression by a PCOM aneurysm (Fang et al., 2017). Pupillary
placed on the presence of pupil involvement versus pupil sparing with fibers are located superomedially near the surface of the nerve and are
regard to probable lesion etiology; however, neither this, nor the pres- particularly prone to compression by a PCOM aneurysm. As a result,
ence or absence of pain or other demographic features can fully rule “rules” with regard to interpretation of pupillary involvement have been
out potential neurologically devastating emergent etiologies, such as a defined to guide diagnostic evaluation. These will be reviewed for com-
PCOM aneurysm or pituitary apoplexy (Newman and Biousse, 2017; pletion’s sake, though it is now fairly well accepted that all oculomotor
Tamhankar et al., 2013) (see section below on Interpeduncular Fossa palsies warrant imaging evaluation for a PCOM aneurysm (Newman
and Subarachnoid Space and section on Isolated Oculomotor Nerve and Biousse, 2017; Tamhankar et al., 2013; Trobe, 2009). Without con-
Palsy). troversy, any pupil-involving or pupil-sparing incomplete oculomotor
palsy requires immediate evaluation for a PCOM aneurysm, given the
Brainstem Fascicle high risk of subarachnoid hemorrhage and mortality if left undiagnosed
Claude syndrome is the combination of an ipsilateral oculomotor nerve and untreated (Connolly et al., 2012; Lv et al., 2016). Some patients with
palsy and contralateral hemiataxia (Table 103.1 and Videos 103.1 an aneurysmal incomplete oculomotor nerve palsy will lack pupillary
and 103.2; Liu et al., 1994). Although historically the syndrome was involvement at initial presentation, but the majority will progress to
described as involving the oculomotor fascicle and the red nucleus, the pupillary involvement within 1 week. Spontaneous improvement in
ataxia is likely due to involvement of the superior cerebellar peduncle oculomotor nerve function may occur with an aneurysm and should not
CHAPTER 103 Cranial Neuropathies 1785
TABLE 103.1 Named Cranial Nerve Syndromes

Syndrome* Symptoms and Signs Involved Structures
Claude Ipsilateral III III—brainstem fascicle
Contralateral ataxia Red nucleus/superior cerebellar peduncle
Nothnagel Ipsilateral III III—brainstem fascicle
Ipsilateral ataxia Superior cerebellar peduncle
Weber Ipsilateral III III—brainstem fascicle
Contralateral hemiparesis Cerebral peduncle
Benedikt Ipsilateral III III—brainstem fascicle
Contralateral chorea or tremor Red nucleus
Tolosa-Hunt Ipsilateral III, IV, VI Cavernous sinus
Ipsilateral first and second branches of V III, IV, VI, first and second branches of V
Ipsilateral Horner syndrome Sympathetic nerves
Wallenberg lateral medullary syndrome Ipsilateral facial numbness and ↓ pinprick Spinal trigeminal tract and nucleus
Contralateral hemibody ↓ pain and temperature Spinothalamic tract
Dysphagia and ↓ gag reflex Nucleus ambiguus
Limb ataxia Inferior cerebellar peduncle
Horner syndrome Sympathetic nerves
Vertigo Vestibular nuclei
Opalski syndrome Wallenberg in addition to ipsilateral hemiparesis Corticospinal fibers caudal to pyramidal decussation
Gradenigo Facial and mastoid area pain Petrous apex—temporal bone V, VI, VII
Ipsilateral 1st branch of V
Ipsilateral VI and VII
Foville Ipsilateral VI and VII VI and VII—brainstem
Contralateral ataxia Mid-cerebellar peduncle
Ipsilateral Horner syndrome Sympathetic nerves
Ipsilateral deafness Vestibulocochlear nerve/fascicle
Ipsilateral ↓ taste and facial sensation Spinal trigeminal tract/nucleus solitarius
Millard-Gubler Ipsilateral VI and VII VI and VII—brainstem
Contralateral hemiparesis Pyramidal tract
Raymond Ipsilateral VI VI—brainstem
Bell’s palsy VII VII—intratemporal nerve and geniculate ganglion
Ramsay Hunt VII VII
Vesicular otic or oral rash ± ↓ hearing ±VIII
Melkersson-Rosenthal VII VII—distal branches
Facial edema
Fissured tongue
Eagle IX XI—elongated styloid process or ossified stylohyoid
ligament
Vernet IX, X, XI Jugular foramen
Villaret IX, X, XI Jugular foramen
XII Hypoglossal canal
Horner syndrome Sympathetic nerves
Collet-Sicard IX, X, XI Jugular foramen
XII Hypoglossal canal
Avellis X X—brainstem or peripheral
Tapia X and XII X and XII—brainstem or peripheral
Dejerine medial medullary syndrome Ipsilateral XII XII—nuclei or fascicle
Contralateral hemisensory deficit Medial lemniscus
Babinski-Nageotte Combined symptoms and signs of Wallenberg and Hemi-medullary: lateral and medial medulla
Dejerine syndromes
*Descriptions of named syndromes vary slightly, depending on reference used.
↓, Decreased.
A B
E
Fig. 103.3 Traumatic left oculomotor palsy 3 months following a motor vehicle accident with closed head
injury and loss of consciousness. Patient initially had complete left ptosis and complete absence of adduc-
tion, elevation, and depression. Results of magnetic resonance imaging and magnetic resonance angiogra-
phy were normal. A, Central position with slight left ptosis, exotropia (outward deviation), and left pupillary
enlargement. B, Impaired adduction of left eye with right gaze. Note aberrant regeneration with anomalous
elevation of left lid upon adduction of left eye. C, Normal left gaze. D, Significant impaired elevation of left
eye with upgaze. E, Impaired depression of left eye with downgaze.
preclude diagnostic testing. A pupil-sparing otherwise complete oculo- Factors such as initial palsy severity and pretreatment palsy time may
motor palsy is exceedingly unlikely to result from PCOM aneurysmal also play a role in recovery potential (Zhong et al., 2019).
compression and the urgency of imaging in this setting is controversial In the subarachnoid space, the oculomotor nerve passes in close
(Miller 2017; Newman and Biousse, 2017). However, immediate imag- proximity to the medial temporal lobe. Herniation of the temporal
ing is favored to avoid errors in exam interpretation that increase the risk lobe uncus ipsilateral to a space-occupying supratentorial lesion sec-
of a missed diagnosis with high morbidity and mortality and because ondary to increased intracranial pressure may result in compression
both basilar aneurysm and pituitary apoplexy have been reported with of the oculomotor nerve, manifested clinically as sudden enlargement
pupil-sparing otherwise complete oculomotor palsy (Lustbader and and poor reactivity of the pupil ipsilateral to the lesion—the Hutchison
Miller, 1988; Tamhankar et al., 2013). Onset of oculomotor dysfunction pupil (Koehler and Wijdicks, 2015). Rarely, a unilateral enlarged and
following mild-moderate head trauma should also prompt investigation poorly reactive pupil may occur contralateral to the supratentorial
for an underlying aneurysm, though one may not always be found (Levy lesion (Chung and Chandran, 2007). Oculomotor nerve involvement
et al., 2005; Tajsic et al, 2017; Fig. 103.3). in the interpeduncular fossa and subarachnoid space may also occur
Magnetic resonance angiography (MRA) and computed tomo- secondary to inflammatory or neoplastic meningitis, in which case it
graphic angiography (CTA) are the preferred diagnostic tests for may be isolated or accompanied by signs of meningeal inflammation
aneurysm detection, but it is important to recognize that reliable such as meningismus or additional neurological signs. Enlargement
interpretation of these studies requires a high level of experience, and enhancement of the oculomotor nerve in the subarachnoid and
skill, and time (Chaudhary et al., 2009; Elmalem et al., 2011). The interpeduncular locations may be seen on magnetic resonance imaging
majority of PCOM aneurysms large enough to cause an oculomotor (MRI) in meningitis, with oculomotor nerve schwannomas, in associa-
palsy are at least 4 mm in size. For aneurysms larger than 5 mm, the tion with ganglioside antibodies such as GQ1b (with persistent or tran-
sensitivity of both MRA and CTA are higher than 95%; however, sient oculomotor palsy), and in so-called ophthalmoplegic migraine,
for aneurysms smaller than 5 mm, CTA sensitivity remains above a rare condition with recurrent oculomotor paresis and pain usually
90% when interpreted by a neuroradiology expert, but MRA sen- seen in children (see Chapter 102; Choi et al., 2019; Qureshi et al.,
sitivity in some studies is lower, leading some to advocate CTA as 2017; Shin, 2015; Wang et al., 2013; eFig. 103.4).
the initial diagnostic evaluation for PCOM aneurysms (Chaudhary
et al., 2009). Neither MRA nor CTA is 100% sensitive, and con- Cavernous Sinus
ventional angiogram is still warranted when strong clinical suspi- An oculomotor palsy in the cavernous sinus may occur in isolation or
cion for a PCOM aneurysm is present, and noninvasive studies are accompanied by dysfunction of other structures located in this space,
unrevealing. including the abducens and trochlear nerves, the first and second divi-
Surgical clipping for aneurysms causing oculomotor nerve palsies sions of the trigeminal nerve, and sympathetic fibers. Tolosa-Hunt
results in a higher rate of oculomotor recovery compared to endo- syndrome is a painful of idiopathic self-limited inflammation of the
vascular coiling in many (78% for surgery vs. 44% for endovascular cavernous sinus, typically responsive to corticosteroids (Mullen et al.,
coiling in a comparison review of retrospective studies) (Micieli et al., 2018; see Table 103.1 and Videos 103.3 and 103.4). Cavernous sinus
2017), but not all (Zhong et al., 2019) studies. Furthermore, surgery infiltration by metastatic disease may be clinically and radiographically
is associated with higher periprocedural morbidity and decisions identical to Tolosa-Hunt syndrome and should be suspected, espe-
regarding treatment must take into account patient status, aneurysmal cially in older patients. Cavernous sinus lymphoma is typically steroid
morphology, and treating physician experience (Micieli et al., 2017). responsive and should be considered, especially if disease recurs with
eFig. 103.4 Axial T1-weighted MRI with gadolinium at the level of the
midbrain demonstrates abnormal bilateral oculomotor nerve enhance-
ment (arrowheads).
corticosteroid taper. Inflammation associated with systemic rheuma- Elevation of the eyelid or constriction of the pupil upon adduction
tological disease or angioinvasive fungal infection, infiltration from or depression of the eye is indicative of aberrant regeneration (anoma-
adjacent nasopharyngeal neoplasm, carotid-cavernous fistulas, cavern- lous axon innervation). When aberrant regeneration develops follow-
ous sinus thrombosis (more common in the intensive care unit than ing an acute oculomotor palsy, a PCOM artery aneurysm or traumatic
the outpatient setting), and mass effect from an intracavernous inter- etiology is likely (see Fig. 103.3, B). When it develops spontaneously
nal artery aneurysm or meningioma may also cause a cavernous sinus without a pre-existing acute palsy, a cavernous sinus meningioma or
syndrome (Weerasinghe and Lueck, 2016). Pituitary apoplexy should internal carotid artery aneurysm is likely, although this may also rarely
be considered in the differential diagnosis for sudden-onset painful occur with an unruptured PCOM aneurysm. Aberrant regeneration
unilateral or bilateral oculomotor palsies, with or without accom- should not occur following a microvascular oculomotor palsy.
panying visual loss or other ocular motor cranial nerve involvement
(Hage et al., 2016). TROCHLEAR NERVE (CRANIAL NERVE IV)
Orbital Apex Anatomy
Oculomotor dysfunction in the orbital apex is typically accompanied Paired trochlear nuclei lie close to the dorsal surface of the midbrain
by dysfunction of neighboring structures including the abducens and just below the inferior colliculus. The fascicles emerge from the nuclei
trochlear nerves, the first division of the trigeminal nerve, and the optic and course dorsally only 3–9 mm before decussating in the anterior
nerve. Features of orbital disease such as proptosis, chemosis, and con- medullary velum, and exiting the brainstem. The trochlear nerves are
junctival injection may be present. Idiopathic inflammation (orbital the only cranial nerves to emerge from the dorsal brainstem surface.
inflammatory pseudotumor and immunoglobulin G4 [IgG4]-related After emergence, the nerves wrap around the surface of the midbrain
inflammation), infection (particularly aspergillosis and mucormy- to travel ventrally within the subarachnoid space toward the cavernous
cosis in diabetic or immunosuppressed patients), neoplastic infiltra- sinus. In the cavernous sinus, the trochlear nerve is located in the lat-
tion, and inflammation or compression from adjacent sphenoid sinus eral dural wall, inferior to the oculomotor nerve. From the cavernous
infection or mucocele should be considered (Kashi, 2014; Mombaerts sinus, the nerve passes into the superior orbital fissure and ultimately
et al., 2017). As in cavernous sinus idiopathic inflammation (Tolosa- innervates the superior oblique muscle contralateral to the nucleus of
Hunt syndrome) versus lymphoma, idiopathic orbital inflammatory origin (see eFig. 103.1). The superior oblique muscle is an intorter of
pseudotumor and lymphoma at the orbital apex are both likely to the eye, as well as a depressor of the adducted eye.
be steroid responsive, and lymphoma should be considered, espe-
cially if pain is absent and if disease recurs with corticosteroid taper. Clinical Lesions
Anatomical division of the oculomotor nerve into superior and infe- Trochlear Nucleus and Fascicle
rior branches occurs just before this location, and isolated involvement It is difficult to differentiate a trochlear nuclear lesion from a tegmental
of either branch is not uncommon. (ventral and dorsolateral to the periaqueductal gray matter) fascicular
lesion prior to the decussation of the fascicle. Both locations will result
Isolated Oculomotor Nerve Palsy in paresis of the contralesional superior oblique muscle. Brainstem
Isolated oculomotor dysfunction may occur from any lesion along lesions posterior to the cerebral aqueduct in the tectal (dorsomedial to
the course of the nerve. Microvascular ischemia, a common cause the periaqueductal gray matter) fascicle after its decussation may give
in older patients with vascular risk factors (Fang et al., 2017; Keane, rise to ipsilesional superior oblique paresis (Jeong et al., 2016). Isolated
2010), is typically pupil-sparing; however, relative pupil involvement nuclear or fascicular involvement occurs rarely; it may occur in isola-
with an average of 0.8 mm of anisocoria may be seen in up to one- tion or in association with other brainstem signs such as Horner syn-
third of patients with microvascular oculomotor nerve ischemia, but drome, internuclear ophthalmoplegia, or cerebellar ataxia. Brainstem
the pupil generally remains reactive (Jacobson, 1998). Confidence in lesions include ischemia, hemorrhage, demyelination, infectious
the absence of a PCOM aneurysm may only be present when all oculo- and noninfectious inflammation, and neoplasm (Jeong et al., 2016;
motor-innervated muscles other than the pupil are severely and com- Sudhakar and Bapuraj, 2010).
pletely impaired. In this era of modern noninvasive neuroimaging, it is
prudent to perform emergent noninvasive vascular neuroimaging for Trochlear Palsy Appearance
all oculomotor palsies to avoid missing a PCOM aneurysm or other Trochlear nerve dysfunction results in impaired intorsion of the eye,
emergent etiology (see above section on Interpeduncular Fossa and impaired depression of the adducted eye, elevation of the affected
Subarachnoid Space). The location of ischemia with a microvascular eye (hypertropia), and vertical or oblique diplopia. The diplopia and
palsy may be anywhere along the course of the nerve but is typically hypertropia are worse with downgaze when the eye is in an adducted
peripheral and often considered to be in the cavernous sinus, although position, as this is the direction of action of the superior oblique mus-
it is not visible with neuroimaging. Pain in the ipsilateral brow and eye cle. Impaired depression of the affected eye in the adducted position
is present in two-thirds of patients and may be severe (Wilker et al., may be seen but is often subtle (Fig. 103.5). A resting head tilt in the
2009); however, the presence and characteristics of pain do not dis- direction away from the paretic eye (e.g., right trochlear palsy, left head
tinguish microvascular from aneurysmal oculomotor palsies (Fang tilt) may be present and is considered a sign of chronicity. Because the
et al., 2017). Spontaneous resolution over 8–12 weeks is typical for a superior oblique is an intorter of the eye, diplopia is minimized when
microvascular etiology. An isolated oculomotor palsy may also arise a contralateral head tilt places the affected eye in an extorted position.
from temporal arteritis; thus, erythrocyte sedimentation rate (ESR), The Parks-Bielschowsky three-step test (see Chapter 18 for additional
C-reactive protein, and complete blood cell count (CBC) should be information) is an examination technique utilized to assess the dip-
obtained on all elderly patients with an isolated oculomotor palsy and lopia and hypertropia for conformation to the “pattern of a trochlear
neuroimaging should be considered (Chou et al., 2004; Tamhankar palsy” and consists of assessment of (1) which eye is hypertropic, (2)
et al., 2013; Thurtell and Longmuir, 2014). In the absence of complete whether the hypertropia is worse in right or left gaze, and (3) whether
spontaneous resolution with a suspected microvascular oculomotor the hypertropia is worse in right or left head tilt. The pattern of a fourth
palsy, neuroimaging is essential. is a hypertropia on the side of the trochlear palsy, worsening in the
associated with systemic rheumatological disease or angioinvasive

fungal infection, infiltration from adjacent nasopharyngeal neo-
plasm, carotid-cavernous fistulas, and mass effect from an intracav-
ernous internal artery aneurysm or meningioma are common causes.
Pituitary apoplexy very rarely, if ever, results in isolated trochlear
paresis (Hage et al., 2016).
Orbital Apex
See Orbital Apex section above under Oculomotor Nerve, Clinical
Lesions.
A
Isolated Trochlear Nerve Palsy
Congenital, traumatic, and microvascular ischemic trochlear pal-
sies are common causes of neurologically isolated trochlear paresis
(Dosunmu et al., 2018; Hata et al., 2013; Tamhankar et al., 2011).
Identification of a long-standing head tilt in old photographs of
the patient and increased vertical fusional amplitudes (a test of the
amount of image misalignment with which the individual can main-
tain binocular fusion—tends to be high with congenital lesions) can
help confirm the diagnosis of a congenital trochlear nerve palsy.
Overaction of the inferior oblique muscle, manifested by exces-
sive elevation upon adduction of the eye ipsilateral to the trochlear
B weakness, and hypertropia worsening in upgaze rather than down-
Fig. 103.5 Right Trochlear Palsy From a Large Right Petroclival gaze may also suggest a congenital etiology (Ivanir and Trobe, 2017;
Meningioma. Patient also had decreased hearing in right ear and Siatkowski, 2017).
cerebellar truncal ataxia. A, Note impaired depression of right eye in
adducted position. B, Preoperative T1-weighted coronal magnetic res-
onance imaging with gadolinium reveals an extensive mass in the pon-
TRIGEMINAL NERVE (CRANIAL NERVE V)
tine cistern, with significant brainstem compression. Anatomy
The trigeminal nerve consists of afferent sensory, efferent motor, and
contralateral gaze direction and upon ipsilateral head tilt (Muthusamy parasympathetic fibers. The ophthalmic (V1), maxillary (V2), and
et al., 2014). A fourth step is assessment of the hypertropia in the mandibular (V3) trigeminal sensory nerve branches emerge from the
upright versus supine position; reduction in size of the hypertropia anterior surface of the trigeminal (gasserian) ganglion in the Meckel
in the supine position suggests a skew deviation, given gravity depen- cave (a dural cavity overlying the apex of the petrous bone) and inner-
dence of the otolith vestibular organs (Hernowo and Eggenberger, vate the facial skin, mucous membranes of the nose and mouth, teeth,
2014; Wong, 2010). orbital contents, and supratentorial meninges (Fig. 103.7; also see eFig.
Evaluation for superior oblique paresis in the setting of oculomotor 103.1). The ophthalmic division courses in the lateral wall of the cav-
nerve dysfunction with impaired adduction from medial rectus paresis ernous sinus inferior to the trochlear nerve and exits the skull via the
is best assessed with the affected eye in an abducted position, where superior orbital fissure. It is the anatomical substrate for the afferent
intact intorsion during downgaze suggests intact trochlear function. limb of the corneal reflex. The maxillary division also courses in the
lateral wall of the cavernous sinus, exiting the skull via the foramen
Subarachnoid Space rotundum to enter the sphenopalatine (also called the pterygopal-
Within the subarachnoid space, the nerves are near the tentorium cer- atine) fossa and the inferior orbital fissure. The mandibular division
ebelli and are prone to unilateral or bilateral traumatic injury (Keane, exits the skull through the foramen ovale. Sensory input from these
2005). Unlike traumatic oculomotor palsy, which usually occurs three branches travels centrally from the trigeminal ganglion via the
following severe head trauma with loss of consciousness, the troch- trigeminal sensory root in the prepontine subarachnoid cistern to the
lear nerves are injured more easily by minor degrees of head trauma trigeminal sensory nucleus, which is composed of a mesencephalic
(Dhaliwal et al., 2006). subnucleus receiving proprioceptive input from V3, a principal (main)
Trochlear nerve involvement in isolation or accompanied by signs sensory subnucleus mediating tactile sensation, and descending spinal
of meningeal inflammation, such as meningismus, or additional subnuclei (oralis, interpolaris, and caudalis) that descend to the cervi-
cranial nerve palsies, may occur secondary to inflammatory or neo- cal spinal cord and mediate pain and temperature. Sensory informa-
plastic meningitis. Enhancement of the nerve as it travels around the tion ultimately ascends to the contralateral thalamus.
midbrain may be present on MRI. An increasingly recognized cause The motor efferents originate in the motor trigeminal nucleus in
of such enhancement in the setting of normal cerebrospinal fluid is the pons, medial to the principal sensory nucleus, emerge from the
trochlear nerve schwannoma (Elmalem et al., 2009; Torun et al., 2018; ventral pons as the motor root, travel inferior to the trigeminal gan-
eFig. 103.6). glion and then alongside the mandibular sensory division to inner-
vate the muscles of mastication (masseter, temporalis, pterygoids)
Cavernous Sinus and the mylohyoid, tensors tympani and palatini, and anterior belly
Trochlear palsy in the cavernous sinus is generally accompanied by of the digastric. Trigeminal nerve branches carry efferent postgangli-
dysfunction of other structures including the abducens and oculo- onic parasympathetic innervation from the pterygopalatine ganglia to
motor nerves, the first and second divisions of the trigeminal nerve, the lacrimal gland and from the submandibular ganglia to the salivary
and sympathetic fibers. Idiopathic inflammation, inflammation glands. Preganglionic parasympathetic fibers travel in the facial nerve.
eFig. 103.6 T1-weighted axial magnetic resonance imaging with gado-

linium at level of inferior colliculus shows enhancing lesion consistent
with a schwannoma (arrow) of right trochlear nerve as it courses ven-
trally around brainstem.
Nasociliary nerve
Frontal nerve
Lacrimal nerve Trigeminal ganglion
Ophthalmic
nerve Motor root
Supraorbital nerve Trigeminal nerve
Sensory root
Supratrochlear nerve
Chorda tympani nerve
Communication between
lacrimal and
zygomaticotemporal nerve Facial nerve
Maxillary nerve Tympanic membrane

Zygomatic nerve
Middle meningeal
Pterygopalatine ganglion artery
Infraorbital nerve Auriculotemporal

nerve
Middle superior
alveolar nerve Maxillary artery
Buccal nerve Styloid process

and stylohyoid
Lateral pterygoid
lower head (cut) Inferior alveolar nerve (cut)
Medial pterygoid
Nerve to mylohyoid
Lingual nerve
Submandibular ganglion
Facial artery
Mental foramen
and nerve Hyoglossus
Submandibular gland (cut)

Inferior alveolar nerve
Nerve to mylohyoid
supplying mylohyoid
and anterior belly
of digastric
Sublingual
Digastric (anterior belly) gland
Submandibular duct
Fig. 103.7 Trigeminal nerve ophthalmic (1), maxillary (2), and mandibular (3) branches emerging from the
semilunar (trigeminal or gasserian) ganglion. (From Standring, G., 2005. Gray’s Anatomy, thirty-ninth ed.
Churchill Livingstone, Philadelphia.)
Clinical Lesions have concomitant persistent pain (Maarbjerg et al., 2017). Pain is often
Trigeminal Nucleus elicited by sensory stimuli on the face, such as shaving or wind. There
The extension of the trigeminal nuclear complex throughout the entire is no accompanying sensory loss or motor weakness in the affected
brainstem renders it susceptible to involvement from any pathologi- distribution on examination. The second and third branches are most
cal brainstem process. Trigeminal lesions are particularly common with commonly affected, with less than 5% of patients experiencing involve-
demyelinating disease, may involve either the nuclei or sensory root, and ment of the ophthalmic division. Many cases are attributable to com-
may be clinically silent or symptomatic (Kremer et al., 2013; Zakrzewska pression of the sensory nerve root, typically at the transition between
et al., 2018). Ischemia, hemorrhage, infectious and noninfectious inflam- central and peripheral myelin, by a vascular structure, most often the
mation, and neoplasm are other causes of trigeminal brainstem involve- superior cerebellar artery or anterior inferior cerebellar arteries (Haller
ment (Kim et al., 2013). Additional brainstem signs are frequently present. et al., 2016). Evidence-based support for this vascular compressive etiol-
Wallenberg syndrome from lateral medullary ischemia typically causes ogy is provided by surgical outcome data showing that the pain is often
ipsilateral facial numbness and impaired pinprick sensation secondary to amenable to surgical decompression, especially in cases of classic pain
descending spinal tract and nucleus involvement (see Table 103.1). paroxysms (Barker et al., 1996; Sivakanthan et al., 2014). Because vas-
cular contact with the sensory or motor nerve roots is a relatively com-
Subarachnoid Space: Nerve Roots mon finding in cadavers and asymptomatic controls, vascular contact
Classic trigeminal neuralgia is characterized by seconds-long stereotyped alone may be insufficient to cause trigeminal neuralgia (Yousry et al.,
episodes of intensely painful electric-like shocks along one or more of 2004). Compression or indentation of the nerve root is likely neces-
the trigeminal nerve branches, though a large percentage of patients also sary, with resultant axonal loss and demyelination (Haller et al., 2016;
Miller et al., 2009). See Chapter 102 for additional discussion of trigem- or hematological malignancies (Assaf et al., 2014; Maeda et al., 2018;
inal neuralgia and other facial pain syndromes. eTable 103.2, available Sanchis et al., 2008), though it may also be a secondary effect of radi-
in the online version of this chapter at http://www.ExpertConsult.com, ation or pharmacological therapies (Fortunato et al., 2018). This syn-
outlines current treatments for facial palsy and trigeminal and glosso- drome may rarely be the presenting manifestation of malignancy but
pharyngeal neuralgia. more often represents recurrence or progression of known disease. The
Classic trigeminal neuralgia must be differentiated from symp- numb cheek syndrome occurs when branches of the maxillary division
tomatic trigeminal neuralgia secondary to an underlying neoplastic, are involved.
inflammatory, paraneoplastic, or meningitic cause, from which the
pain characteristics may be clinically indistinguishable (Gronseth ABDUCENS NERVE (CRANIAL NERVE VI)
et al., 2008; Kalanie et al., 2014; Maarbjerg et al., 2017; Wanibuchi
et al., 2012). It must also be carefully differentiated from trigeminal Anatomy
neuropathy with differing qualitative and temporal pain characteristics Paired abducens nuclei are located in the dorsal pons in the floor of
and sensory deficits on examination. Cerebellopontine angle acoustic the fourth ventricle in close proximity to the fascicle of the facial nerve.
schwannomas frequently involve the sensory nerve root, causing ipsi- Each nucleus contains abducens motoneurons that form the abducens
lateral facial sensory symptoms accompanied by ipsilateral tinnitus, nerve, and interneurons that decussate at the nuclear level and ascend
deafness, and vertigo from vestibulocochlear nerve involvement. in the medial longitudinal fasciculus (MLF) to the contralateral oculo-
motor medial rectus subnucleus to facilitate conjugate horizontal gaze
Trigeminal Ganglion in the direction ipsilateral to the abducens nuclear origin of the inter-
Middle cranial fossa malignant infiltration, compressive neoplastic neurons. The abducens fascicle exits the ventral surface of the nucleus,
lesions, and autoimmune inflammation are among the most common traverses the brainstem, emerges from the ventral pontomedullary
causes of trigeminal ganglion pathology. The trigeminal ganglion is sulcus at the caudal pontine surface, and travels in the subarachnoid
a location in which the varicella-zoster virus (VZV) often lies latent, space, where it ascends near the clivus. It pierces the dura and passes
sometimes reactivating along the course of the trigeminal ophthalmic under the petroclinoid (Gruber) ligament into the Dorello canal, then
branch later in life to cause herpes zoster ophthalmicus and a pain syn- travels through the body of the cavernous sinus lateral to the inter-
drome that may occur with or without an accompanying zoster rash nal carotid artery (unlike the oculomotor, trochlear, and trigeminal
(Birlea et al., 2014; Vrcek et al., 2017). Identification of skin lesions nerves, which are housed in the lateral dural wall), and ultimately into
along the side of the nose (Hutchinson sign) corresponding to the naso- the superior orbital fissure to innervate the ipsilateral lateral rectus
ciliary branch of the ophthalmic division strongly predicts subsequent muscle (see eFig. 103.1).
ocular complications (Nithyanandam et al., 2010).
Clinical Lesions
Trigeminal Nerve Branches Abducens Nucleus
Dysfunction of the ophthalmic branch results in numbness or pares- Because the abducens nucleus contains the interneurons destined
thesias in the anterior scalp, forehead, and supraorbital regions, and an to ascend in the contralateral MLF to the contralateral oculomotor
abnormal corneal reflex. A lesion of the maxillary branch affects the medial rectus subnucleus to permit conjugate horizontal gaze, abdu-
cheek, lower eyelid, and upper lip. A lesion of the mandibular branch cens nuclear lesions cause conjugate horizontal gaze palsy toward
affects the lower lip, chin, and lateral face anterior to the ear. Motor the side of the lesion. Isolated horizontal gaze palsy may occasion-
involvement in a trigeminal nerve lesion is often clinically undetect- ally occur but accompanying ipsilateral facial palsy with lower motor
able. Although it is tempting to localize a trigeminal nerve lesion based neuron facial weakness is typically present. Lesions involving both the
on symptom distribution, the complex branching pattern and orga- abducens nucleus and ipsilateral MLF cause the one-and-a-half syn-
nization of the trigeminal nuclei and ganglion prohibit such simple drome, with an ipsilateral conjugate gaze palsy and an ipsilateral inter-
localization. It is common for lesions proximal to the peripheral nerve nuclear ophthalmoplegia with impaired adduction of the ipsilesional
branches to evoke symptoms in a single trigeminal branch distribution. eye and abducting nystagmus of the contralateral eye (see Chapter 21).
Lesions of a single branch may result from inflammation, com- Common brainstem lesions include ischemia, hemorrhage, demye-
pression, or neoplasm (Briani et al., 2013; Perera et al., 2014). Damage lination, infectious and noninfectious inflammation, and neoplasm.
to small distal branches may occur after dental procedures. The oph- Periventricular necrosis from Wernicke encephalopathy also fre-
thalmic branch may be involved in Gradenigo syndrome in combina- quently results in horizontal gaze or abducens palsy from involvement
tion with the abducens and facial nerves from a lesion at the petrous of the abducens nucleus or fascicle, respectively.
apex, most common clinically as inflammation following otitis media
in children (Vitale et al., 2017; see Table 103.1). Both the ophthalmic Abducens Palsy Appearance
and maxillary branches may be affected by a cavernous sinus lesion, in Abducens nerve dysfunction results in impaired ipsilateral abduction
which setting dysfunction of the oculomotor, trochlear, and abducens of the eye and deviation of the eyes toward one another (esotropia)
nerves is often present. (Fig. 103.8 and Videos 103.5 and 103.6). Binocular horizontal diplopia
Two particularly ominous clinical scenarios are (1) insidious devel- and the esotropia are worse with gaze in the direction of the abduction
opment of facial numbness or paresthesias in a patient with a history deficit.
of facial skin malignancy, and (2) the “numb chin” or “numb cheek”
syndromes. In the first situation, perineural invasion of the trigemi- Brainstem Fascicle
nal branches is likely (Erkan et al., 2017; Warden et al., 2009). This is The original Foville syndrome was the combination of ipsilateral abdu-
most frequently seen with head and neck adenoid cystic carcinoma, cens palsy, ipsilateral lower motor neuron facial palsy, and contralateral
squamous cell carcinoma, and melanoma. The numb chin syndrome hemiparesis from corticospinal tract involvement (see Table 103.1).
results from involvement of the mental nerve branches of the mandib- It is now more commonly applied to the combination of ipsilateral
ular division and is most commonly due to focal metastatic nerve infil- abducens and facial palsies with contralateral ataxia, ipsilateral Horner
tration within the mandible, most often from breast, lung, prostate, syndrome, ipsilateral deafness, and ipsilateral loss of taste and facial
eTABLE 103.2 Facial Palsy and Trigeminal, and Glossopharyngeal Neuralgia Treatments
Condition Treatments Considerations
Facial palsy Lubrication and taping Corneal protection during temporary facial weakness with
minimal corneal risk
External upper eyelid weights, Botox, temporary tarsorrhaphy Corneal protection during temporary facial weakness with
corneal exposure
Permanent gold upper-eyelid weights or permanent tarsorrhaphy Corneal protection with permanent facial weakness
Facial physical therapy or neuromuscular facial retraining May be enhanced by electromyographic feedback; may be
helpful for synkinetic dysfunction
Brow elevation For visual dysfunction or discomfort from brow ptosis
Proximal facial nerve grafting with sural or greater auricular nerve; Facial mobilization procedures; most commonly used after
hypoglossal or spinal accessory to facial nerve anastomosis; permanent iatrogenic surgical facial nerve section or for
microneurovascular free muscle flap transfer (e.g., with tempo- neoplastic facial dysfunction
ralis or latissimus dorsi muscle)
Trigeminal and glossopharyngeal Pharmacological treatment with carbamazepine or oxcarbamaze- Prophylactic pain therapy; often the mainstay of therapy
neuralgia pine. Other options include baclofen, gabapentin, lamotrigine,
or topiramate
Microvascular decompression Typically, the preferred treatment for young patients with
medically refractory pain; low pain recurrence rate
Percutaneous radiofrequency thermocoagulation; glycerol rhizoly- May be the preferred treatment for older patients at high sur-
sis; balloon microcompression; peripheral branch neurectomy; gical risk with medically refractory pain; higher recurrence
nerve root Gamma Knife radiosurgery and complication rates than central surgical treatments
(Yuvaraj et al., 2019)
Petrous Apex
Abducens palsy is common in Gradenigo syndrome in combination
with trigeminal ophthalmic division and facial nerve involvement
from a lesion at the petrous apex (see Table 103.1). This is most com-
monly seen clinically as inflammation following otitis media in chil-
dren (Vitale et al., 2017).
A Cavernous Sinus
An abducens palsy in the cavernous sinus may occur in isolation or
accompanied by dysfunction of other structures including the oculo-
motor and trochlear nerves, the first and second divisions of the trigem-
inal nerve, and sympathetic fibers. The combination of abducens palsy
and ipsilateral Horner syndrome is highly suggestive of an ipsilateral
cavernous sinus lesion, because the sympathetic fibers travel along the
surface of the abducens nerve briefly in the posterior cavernous sinus
(Kang et al., 2011). Idiopathic inflammation, inflammation associated
B with systemic rheumatological disease or angioinvasive infection, infil-
tration from adjacent nasopharyngeal neoplasm, carotid-cavernous
Fig. 103.8 Right Microvascular Abducens Palsy. A, Right gaze with fistulas, and mass effect from an intracavernous internal carotid artery
impaired abduction of right eye. B, Normal left gaze. aneurysm or meningioma are common causes. The abducens nerves
are the most frequently involved ocular motor cranial nerves in pitu-
sensation. Millard-Gubler syndrome is the combination of ipsilateral itary apoplexy (Hage et al., 2016), though isolated involvement is rare
abducens and facial palsies with contralateral hemiparesis (see Table (Saffra et al., 2011).
103.1). Raymond syndrome is the combination of ipsilateral abducens
palsy and contralateral hemiparesis (see Table 103.1). Common brain- Orbital Apex
stem lesions include ischemia, hemorrhage, demyelination, infectious See Orbital Apex section above under Oculomotor Nerve, Clinical
and noninfectious inflammation, and neoplasm. Isolated abducens Lesions.
palsy from fascicular involvement is rarely the presenting manifesta-
tion of cavernoma, demyelination, metastatic disease, or paraneoplas- Isolated Abducens Palsy
tic brainstem encephalitis (Hammam et al., 2005; Mallery et al., 2012). Isolated painful abducens palsy often represents microvascular isch-
Quantitative assessment of the velocity of abducting saccades via emia, especially in older patients with vascular risk factors (see Fig.
eye movement recordings may help differentiate a central fascicu- 103.8). Spontaneous resolution over 8–12 weeks is typical. A small
lar abducens lesion from a peripheral abducens palsy. With an acute percentage of patients will have an underlying structural lesion or
abducens palsy (<1 month), saccadic velocities are reduced in both temporal arteritis; thus, ESR, C-reactive protein, and CBC should be
fascicular and peripheral lesion locations. However, after 2 months, obtained on all elderly patients with an isolated abducens palsy and
saccadic velocities return to normal with peripheral lesions and remain a low threshold for immediate neuroimaging is appropriate (Chou
impaired with fascicular lesions (Wong et al., 2006). et al., 2004; Elder et al., 2016; Tamhankar et al., 2013). In the absence
of complete spontaneous resolution, neuroimaging is essential. Head
Subarachnoid Space and Dorello Canal trauma, even if mild, is another cause of abducens palsy (Dhaliwal
Abducens palsy may occur in isolation or in combination with other et al., 2006). Impaired ability to abduct the eye past midline or bilateral
cranial nerve palsies from infectious, inflammatory, or neoplastic presentation predicts poor spontaneous recovery. The abducens nerve
meningitis, or in association with ganglioside antibodies such as is the ocular motor cranial nerve most commonly affected bilaterally
GQ1b (Choi et al., 2019). The abducens nerve is in close approx- in isolation. This occurs most often from trauma and increased intra-
imation with the clivus and the basilar and vertebral arteries in cranial pressure (Keane, 2005).
its subarachnoid segment and may be affected by a neoplastic or
inflammatory clivus or other skull-based process or compressed by FACIAL NERVE (CRANIAL NERVE VII)
an aneurysm, inferior petrosal sinus thrombosis, or dolichoectatic
artery (Mittal et al., 2017). Anatomy
The abducens nerves are particularly prone to dysfunction from The facial nerve comprises afferent gustatory, afferent sensory, efferent
alterations in intracranial pressure and from trauma. Unilateral or motor, and parasympathetic fibers. It innervates taste buds in the ante-
bilateral abducens palsies may be seen with spontaneous or post-lum- rior two-thirds of the tongue (Fig. 104.9). Unipolar neurons with cell
bar puncture intracranial hypotension and with intracranial hyper- bodies in the geniculate ganglion within the temporal bone carry taste
tension from any cause, the latter often accompanied by papilledema information from the taste buds via the chorda tympani facial nerve
(Porta-Etessam et al., 2011). It has been suggested historically that the branch, which is joined by the lingual branch of the trigeminal nerve.
abducens nerve is prone to such injury because of its long intracranial The chorda tympani nerve branch joins the main trunk of the facial
course; however, it has a shorter course than the trochlear nerve, which nerve just proximal to the stylomastoid foramen. From the geniculate
is not prone to injury from raised intracranial pressure. Rather, it is ganglion, taste information travels proximally to enter the solitary tract
likely tethering of the abducens nerve at the pontomedullary sulcus and ultimately the rostral solitary (or gustatory) nucleus in the rostral
and Dorello canal that predispose the abducens subarachnoid por- medulla via the nervus intermedius, which passes through the inter-
tion to stretch and distortion injury with alterations in intracranial nal auditory canal. Afferent sensory information from the soft palate,
pressure and with trauma (Dhaliwal et al., 2006; Hanson et al., 2004; middle ear, tympanic membrane, and external auditory canal travel in
Tubbs et al., 2012). the facial nerve.
The motor efferents originate in the motor facial nucleus in the lateral Clinical Lesions
tegmentum of the caudal pons. Supranuclear innervation is bilateral to Facial Palsy Appearance
the rostral portion of the nucleus, which innervates the upper facial mus- Facial nerve dysfunction results in unilateral upper and lower facial
cles, but unilateral to the caudal portion, which innervates the lower facial weakness manifested by flattening of the nasolabial fold, an asymmet-
muscles. Prior to exiting the brainstem, these motor efferent fibers ascend rical smile, poor eyebrow elevation, decreased forehead wrinkling, and
rostrally and wrap around the abducens nucleus as the genu of the facial weak eye closure (Fig. 103.10 and Video 103.7). The palpebral fissure
nerve fasciculus that protrudes into the floor of the fourth ventricle to is widened on the affected side, and deviation of the eye upward and
form the facial colliculus. Fascicular fibers then traverse the brainstem to laterally with attempted eye closure (Bell phenomenon) may become
exit the lateral pons. The motor fibers travel through the cerebellopontine visible with blinks or attempts at eyelid closure. Attention to ade-
angle to enter the petrous temporal bone via the internal auditory canal, quacy of corneal protection with provision of appropriate lubrication
travel through the geniculate ganglion without synapsing, and exit the sty- and protection will minimize the risk for permanent corneal damage
lomastoid foramen after a tortuous course through the temporal bone and from exposure due to incomplete eye closure. Lesions proximal to the
facial canal. Prior to exiting the skull via the stylomastoid foramen, a small greater superficial petrosal nerve increase the risk for corneal damage
branch is given off to the stapedius muscle (see Fig. 103.9). After exiting the by impairing lacrimal secretion (for treatments, see eTable 103.2, avail-
stylomastoid foramen, the motor nerve enters the substance of the parotid able in the online version of this chapter at http://www.ExpertConsult.
gland before branching into temporal, zygomatic, buccal, mandibular, com).
and cervical branches to innervate the muscles of facial expression, sty- Although it is theoretically possible to localize a facial nerve lesion
lohyoid, and posterior belly of the digastric. Muscles of facial expression to a specific nerve portion with specialized tests of tear production,
include the orbicularis oculi, orbicularis oris, buccinator, and platysma. stapedial muscle reflex, salivation, and taste, the primary clinical man-
Efferent motor fibers to the orbicularis oculi are the anatomical substrate ifestation of facial nerve dysfunction is facial weakness. This must be
for the efferent limb of the corneal reflex. distinguished from upper motor neuron facial weakness that causes
The facial nerve carries efferent preganglionic parasympathetic only lower facial weakness because of bilateral supranuclear innerva-
innervation for the lacrimal gland in the greater superficial petro- tion to the upper facial muscles. Upper motor neuron facial weakness
sal nerve, the first branch off of the peripheral facial nerve near the may also result in selective facial weakness for either volitional or emo-
geniculate ganglion (see Fig. 103.9). This is joined by the deep petro- tional facial movements, whereas lower motor neuron facial weakness
sal nerve carrying sympathetic fibers from the internal carotid artery from facial nerve palsy affects both equally.
plexus to form the nerve of the pterygoid canal (Vidian nerve) that
proceeds to the pterygopalatine ganglion. Preganglionic parasympa- Facial Nucleus and Fascicle
thetic innervation for the salivary glands originates in the brainstem Although isolated lower motor neuron weakness occasionally
superior salivatory nucleus and travels via the nervus intermedius occurs from a brainstem lesion, accompanying brainstem signs,
and chorda tympani to the submandibular ganglion (see Fig. 103.9). such as horizontal gaze palsy from abducens nuclear involve-
Postganglionic fibers are carried in trigeminal nerve branches. ment, are typically present. The original Foville syndrome was the
Internal
auditory
canal
Geniculate
ganglion
Greater
superficial
petrosal
Extracranial
Lacrimal gland
Tympanomastoid
Stapes
Sublingual gland
Stylomastoid
foramen Chorda tympani
Face
Facial movement
Tongue
Submandibular gland Taste
Salivation
Fig. 103.9 Facial Nerve Schematic Showing the Major Subdivisions and Their Principal Functions.
(Courtesy Patrick Sweeney, MD.)
schwannoma extends into the facial canal in the temporal bone (Jacob
et al., 2012; Mastronardi et al., 2018).
Intratemporal Facial Nerve and Geniculate Ganglion

Bell palsy, one of the most common causes of facial nerve palsy, is a
self-limited, typically monophasic facial nerve palsy of acute-subacute
onset (Hohman and Hadlock, 2013; Ozkale et al., 2014; see Fig. 103.10
and Table 103.1). Pain accompanies facial weakness in 60% of patients,
impaired lacrimation in 60%, taste changes in 30%–50%, and hypera-
cusis in 15%–30%. Ipsilateral facial sensory symptoms are not uncom-
mon and are hypothetically explained by extension of inflammation
from the facial nerve to the trigeminal nerve via the greater superficial
petrosal nerve. Internal auditory canal MRI often reveals enhance-
ment of the facial nerve, most commonly at the geniculate ganglion.
Eighty-five percent of patients spontaneously recover normal facial
Fig. 103.10 Right Facial Palsy. Upon attempting to smile, there is little function in 3 weeks. Bell palsy occurs with increased frequency during
right facial action, the right palpebral fissure remains widened, and the pregnancy, in which setting it is associated with a poorer recovery rate
right lower face fails to fully activate.
(Hussain et al., 2017). Residual abnormalities after acute Bell palsy
occur in 12% of patients and include persistent severe facial weak-
combination of ipsilateral abducens palsy, ipsilateral lower motor ness in 4% and synkinetic contraction and twitching of the upper and
neuron facial palsy, and contralateral hemiparesis from corticospi- lower facial muscles in 17% that can worsen for up to a year after the
nal tract involvement (see Table 103.1). It is now more commonly acute Bell palsy (Beurskens et al., 2010; Fujiwara et al., 2015; Kanaya
applied to ipsilateral abducens and facial palsies with contralateral et al., 2009; see Video 103.7). Acutely, the nasolabial fold is flattened
ataxia, ipsilateral Horner syndrome, ipsilateral deafness, and ipsi- and the palpebral fissure is widened on the affected side; however, with
lateral loss of taste and facial sensation. Millard-Gubler syndrome chronicity, the affected side often becomes hypercontracted, with a
is the combination of ipsilateral abducens and facial palsies with deepened and prominent nasolabial fold and a narrowed palpebral fis-
contralateral hemiparesis (see Table 103.1). Common brainstem sure. Aberrant regeneration involving the lacrimal gland may result in
lesions include ischemia, hemorrhage, demyelination, infectious tearing with facial muscle contraction (syndrome of “crocodile tears”),
and noninfectious inflammation, and neoplasm (Agarwal et al., particularly during eating. Electromyographic presence of sponta-
2011; Kremer et al., 2013). Continuous twitching of individual neous fibrillation in facial muscles 10–14 days after onset of facial
facial muscles, called facial myokymia, is most commonly seen with weakness is predictive of poor outcome in Bell palsy. Bell palsy may
demyelination and brainstem gliomas. be recurrent, but alternative causes such as Lyme disease or sarcoid-
osis must be considered. Bilateral facial weakness is also common with
Subarachnoid Space: Nerve Root acute inflammatory demyelinating polyneuropathy, Lyme disease,
Hemifacial spasm (HFS) is characterized by involuntary episodic con- sarcoidosis, and Epstein-Barr virus infection (Coddington et al., 2010;
tractions of the muscles innervated by the facial nerve (see Videos 103.7 Hansen et al., 2013).
and 103.8; Stamey and Jankovic, 2007; Yaltho and Jankovic, 2011). It is Although Bell palsy is considered idiopathic, herpes simplex virus
most often unilateral and may be caused by compression and indenta- and VZV reactivation in the geniculate ganglion have been implicated
tion of the facial motor nerve root at its brainstem exit by an aberrant in its pathogenesis. Evidence exists that Bell palsy treatment with oral
vascular loop or dolichoectatic artery (Choi et al., 2013). HFS infre- corticosteroids provides benefit in preventing unsatisfactory facial
quently results from neoplastic compression or inflammation of the recovery. Treatment with antiviral agents alone is not associated with
nerve root or from intrapontine lesions such as cavernoma, tumor, or a reduced risk of unsatisfactory recovery; however, co-administration
demyelination (Arita et al., 2012; Collazo et al., 2018). Features sugges- of corticosteroids and antiviral agents may provide added benefit over
tive of psychogenic (functional) HFS include bilateral asynchronous corticosteroids alone (Almeida et al., 2009; Fu et al., 2018; Gronseth
hemifacial involvement, isolated lower facial involvement, down- et al., 2012; Madhok et al., 2016; Thaera et al., 2010).
ward deviation of the mouth’s angle, lack of the “other Babinski sign” Ramsay Hunt syndrome consists of facial nerve palsy accompanied
(unilateral frontalis muscle contraction leading to eyebrow elevation by a vesicular otic or oral rash due to VZV, with or without vestib-
simultaneous with eye closure due to orbicularis oculi contraction) ulocochlear symptoms (see Table 103.1). The vesicular outbreak
(Stamey and Jankovic, 2007), ipsilateral downward movements of the may occur before, after, or simultaneous with the facial weakness.
eyebrow, and association with tremor or dystonia (Baizabal-Carvallo Diagnosis is confirmed by a rise in serological VZV titers or positive
and Jankovic, 2017). VZV polymerase chain reaction (PCR). Serological detection or pos-
Facial weakness in isolation or in combination with other cranial itive VZV PCR in facial palsy without a vesicular rash suggests zoster
nerve palsies may result from infectious, inflammatory, or neoplastic sine herpete. Facial weakness is more severe and spontaneous recovery
meningitis (Hiraumi et al., 2014). Cerebellopontine angle mass lesions, less common in Ramsey Hunt and zoster sine herpete than in idio-
such as meningioma, facial schwannoma, or acoustic schwannoma, pathic Bell palsy (Kim et al., 2019). Early diagnosis and initiation of
may cause facial nerve involvement (Leonetti et al., 2016). The facial corticosteroid and antiviral treatment significantly improve recovery.
nerve and vestibulocochlear nerves form a complex as they exit the Intratemporal facial nerve schwannomas within the facial canal,
brainstem, and sensorineural hearing loss is typically the primary fea- traumatic fractures, occult skull-based neoplasms of the temporal
ture of acoustic schwannomas. Acoustic schwannomas may be difficult bone, and complicated otitis media with mastoiditis may also affect
to differentiate from facial nerve schwannomas in the cerebellopon- the facial nerve (Leonetti et al., 2016). These entities should be consid-
tine angle, but the latter tend to have earlier clinical facial weakness ered when the onset of facial weakness is insidious and the course pro-
and the radiological appearance of a “labyrinthine tail,” as the facial gressive and accompanied by hearing loss, given the proximity of the
vestibulocochlear nerve. Gradenigo syndrome results from inflamma- petrosal nerve. Postganglionic fibers travel from the otic ganglion in
tion of the petrous apex and causes facial nerve palsy in combination the auriculotemporal nerve, a branch of the trigeminal nerve, to reach
with trigeminal and abducens nerve impairment (see Table 103.1). the parotid gland.
Traumatic temporal bone fractures may cause immediate or delayed
facial nerve palsy (Nash et al., 2010). Clinical Lesions
Glossopharyngeal Palsy Appearance
Facial Nerve Branches Glossopharyngeal dysfunction results in loss of the gag reflex ipsilateral
Parotid neoplasms, surgical procedures, and infiltration of facial skin to the lesion and poor pharyngeal elevation with speaking and swal-
cancers along facial motor nerve branches may result in weakness of lowing, which appears clinically as dysarthria and dysphagia. Taste in
individual facial nerve innervated muscles (Durstenfeld et al., 2014; the posterior tongue may be impaired, and patients may complain of a
Hohman et al., 2014; Leonetti et al., 2016). Taste changes and hypera- dry mouth from decreased salivary secretory functions.
cusis do not typically occur with these lesions, given their distal nature,
and either the upper or lower facial muscles may be affected in iso- Subarachnoid Space: Nerve Root
lation. This may lead to diagnostic confusion with an upper motor Glossopharyngeal neuralgia is characterized by paroxysmal severe
neuron lesion when only the lower facial musculature is involved. episodes of unilateral stabbing pain in the tongue base, tonsilar fossa,
Peripheral branches may also be affected by Lyme disease and sarcoid- pharynx, or middle ear. Pain is often triggered by oropharyngeal
osis in the absence of meningeal inflammation. Melkersson-Rosenthal movements such as chewing, swallowing, or yawning. It may rarely
syndrome is a rare granulomatous disease with a triad of facial nerve be associated with syncope when simultaneous vascular compression
palsy, facial edema, and tongue fissures (Elias et al., 2013; see Table of the glossopharyngeal and vagus nerve roots results in dysfunction
103.1). The complete triad occurs in only a quarter of patients. of the glossopharyngeal-vagal reflex arc, with precipitation of brady-
cardia or asystole. Glossopharyngeal neuralgia is much less common
VESTIBULOCOCHLEAR NERVE (CRANIAL NERVE VIII) than trigeminal neuralgia, but like trigeminal neuralgia, neurovascular
compression of the nerve root is likely a common etiology, and surgi-
See Chapters 21 and 22. cal neurovascular decompression or rhizotomy may result in symptom
relief (see Chapter 102) (Kandan et al., 2010; Rey-Dios and Cohen-
GLOSSOPHARYNGEAL NERVE (CRANIAL NERVE IX) Gadol, 2013) (for treatments, see Table 103.2).
Compressive lesions of the nerve root, such as cerebellopontine
Anatomy angle neoplasms or Chiari I malformations, may also cause glossopha-
The glossopharyngeal nerve contains afferent gustatory, afferent sen- ryngeal neuralgia. Brainstem pathology, such as tumor and demyelin-
sory, efferent motor, and parasympathetic fibers and innervates taste ation, is an infrequent cause. Eagle syndrome from compression of the
buds in the posterior one-third of the tongue. Unipolar glossopharyn- glossopharyngeal nerve by an elongated styloid process or ossified sty-
geal neurons with cell bodies in the superior and inferior (petrosal) lohyoid ligament may mimic glossopharyngeal neuralgia, but the pain
ganglia of the glossopharyngeal nerve at the jugular foramen in the tends to be more persistent and dull in nature and accompanied by a
base of the temporal bone carry taste information from the taste buds foreign body sensation in the throat and dysphagia (Badhey et al., 2017;
to the ganglia, and then proximally into the brainstem solitary tract and Ferreira et al., 2014; Ledesma-Montes et al., 2018; see Table 103.1).
rostral solitary (or gustatory) nucleus in the rostral medulla. Afferent
sensory information from the uvula, tonsil, pharynx, auditory canal, Petrosal Ganglion and Jugular Foramen
middle ear, and carotid sinus and bulb travels in the glossopharyngeal Neoplasia, blunt and penetrating trauma, inflammation, infection
nerve via the petrosal ganglion. This sensory information provides the (especially VZV), and internal carotid artery dissections may affect
afferent limb of the gag reflex, with the efferent limb provided by glos- glossopharyngeal function at the jugular foramen. Vernet syndrome
sopharyngeal and vagus motor fibers to the pharynx. Within the brain- is a pure jugular foramen syndrome with involvement of the glosso-
stem, sensory information is carried to the solitary nucleus and pain pharyngeal, vagus, and spinal accessory nerves (Ferreira et al., 2018;
information to the spinal nucleus of the trigeminal nerve. The carotid see Table 103.1). Since the jugular foramen is in close proximity to
sinus and carotid body are located at the bifurcation of the internal and the hypoglossal canal that houses the hypoglossal nerve, simultaneous
external carotid arteries. The carotid sinus is a baroreceptor involved involvement of cranial nerves IX through XII is not uncommon. When
in blood pressure maintenance; the carotid body is an oxygen sensor accompanied by Horner syndrome from sympathetic involvement,
or chemoreceptor, playing an important role in respiratory reflexes. the combination of cranial nerves IX through XII is called Villaret syn-
The nerve to the carotid sinus (nerve of Hering) has a connection to drome (posterior retropharyngeal syndrome) and is most commonly
the dorsal vagal nucleus that creates a pathway for glossopharyngeal due to internal carotid artery dissection or neoplasm (Okpala et al.,
detection of alterations in blood pressure and oxygen saturation, and 2014; see Table 103.1). In the absence of Horner syndrome, the combi-
vagal-mediated corrective responses. nation of cranial nerves IX through XII is called Collet-Sicard syndrome
The motor efferents originate in the rostral nucleus ambiguus in (see Table 103.1), which may occur with carotid dissection, jugular
the medulla, exit the brainstem dorsolateral to the inferior olive, and vein thrombosis, neoplasm, inflammation, or trauma (Handley et al.,
exit the skull via the jugular foramen in the temporal bone, while tra- 2010; Kohli and Gandotra, 2011; Lee et al., 2017).
versing the petrosal ganglion without synapsing. After exiting the jugu- Glomus jugulare tumors of the jugular bulb are the most common
lar foramen, glossopharyngeal branches innervate the stylopharyngeus tumors in the jugular foramen (Fayad et al., 2010). They are slow-grow-
muscle and the superior pharyngeal constrictors. ing, hypervascular, benign paragangliomas that present with a neck
The glossopharyngeal nerve carries efferent preganglionic fibers mass, pulsatile tinnitus, lower cranial nerve dysfunction, and hearing
from the brainstem inferior salivatory nucleus via the main glos- loss from extension into the middle ear (Carlson et al., 2015; Shapiro
sopharyngeal trunk. The tympanic nerve branch (Jacobson nerve) et al., 2018). Examination of the lower cranial nerves reveals the defi-
comes off of the main trunk at the jugular foramen and carries para- cits to be strictly unilateral, and skull-base imaging reveals the lesion.
sympathetic information to the otic ganglion via the lesser superficial Glomus tumors may also occur in the middle ear tympanic plexus, on
the vagus nerve, and in the carotid body. Schwannomas, meningiomas, Clinical Lesions
and metastases also occur in the jugular foramen. Glossopharyngeal Vagus Palsy Appearance
schwannomas more often present with vestibulocochlear dysfunction Vagus dysfunction results in unilateral loss of pharyngeal and laryn-
than glossopharyngeal involvement (Vorasubin et al., 2009). geal sensation, unilateral loss of sensation in the external ear, dys-
phagia, hoarseness of the voice, unilateral paralysis of the uvula and
Glossopharyngeal Nerve Branches soft palate, and deviation of the uvula contralateral to the lesion.
Direct pressure or stretch injury of the branches may occur from Otolaryngological examination reveals unilateral paralysis of the
surgical intervention, particularly with suspension laryngoscopy vocal cords.
and tonsillectomy (Ford and Cruz, 2004). Postoperative taste
changes and impaired swallowing are usually transient. Reflex Vagus Nucleus
otalgia, or referred middle ear pain, occurs with oropharyngeal Nuclear lesions may result from ischemia, hemorrhage, infectious and
neoplasms owing to the anatomical neural connections between noninfectious inflammation, neoplasm, and demyelination (Kremer
the oropharyngeal and tympanic branches. It is generally a poor et al., 2013; Oks et al., 2018). Wallenberg syndrome from lateral med-
prognostic sign that increases the likelihood of tumor recurrence ullary ischemia affects the nucleus ambiguus, causing dysphagia with
after treatment (Thoeny et al., 2004). Syncope in a patient with a bilateral impairment of pharyngeal and laryngeal function, possi-
history of head and neck cancer may be an ominous harbinger of bly explained by involvement of bilateral cortical prenuclear inputs
recurrent disease. Carotid hypersensitivity syndrome (syncope pro- into each nucleus (Oshima et al., 2013; see Table 103.1). Swallowing
voked by carotid massage), glossopharyngeal neuralgia with syncope, impairment is accompanied by hoarseness of the voice, decreased gag
and parapharyngeal space-lesion syncope syndrome (syncope in the reflex, ipsilateral facial sensory disturbances from trigeminal involve-
absence of neuralgia or carotid massage) are all occasionally seen ment, limb ataxia from cerebellar peduncle involvement, ipsilateral
from focal neoplastic infiltration of the glossopharyngeal nerve and Horner syndrome, contralateral body impaired pain and tempera-
the glossopharyngeal-vagal reflex arc. ture sensation from spinothalamic tract involvement, and vertigo
from vestibular involvement. Opalski syndrome is a variant of the lat-
VAGUS NERVE (CRANIAL NERVE X) eral medullary syndrome accompanied by ipsilateral hemiparesis due
to extension of the lesion into the cervical spinal cord, affecting corti-
Anatomy cospinal fibers caudal to the pyramidal decussation (Kk et al., 2014).
The vagus nerve contains afferent gustatory, afferent sensory, effer- Ipsilateral palatolaryngeal paresis in combination with contralateral
ent motor, and parasympathetic fibers. The vagus nerve innervates hemiparesis (Avellis syndrome) occurs most commonly from med-
taste buds in the epiglottis. Unipolar vagus neurons with cell bodies ullary pathology, although the initial description of the syndrome
in the inferior (nodose) ganglion of the vagus nerve, at the jugular was secondary to extramedullary vagus nerve involvement, presum-
foramen in the base of the temporal bone, carry taste information ably from a large lesion causing ventral brainstem compression with
from the taste buds to the ganglion, and then proximally into the hemiparesis (see Table 103.1). Nuclear involvement in multisystem
brainstem solitary tract and rostral solitary (or gustatory) nucleus in atrophy and Lewy body disease may explain the cardiovagal failure
the rostral medulla. Afferent sensory information from the larynx, and gastrointestinal symptoms in these diseases (Benarroch et al.,
trachea, bronchi, esophagus, stomach, intestines, colon, and aortic 2006). Evidence suggests the pathological hallmark of Parkinson dis-
sinus and bulb travels in the vagus nerve via the inferior (nodose) ease—Lewy bodies—initially develop in the enteric nervous system
ganglion. Within the brainstem, the sensory information is carried to and propagate in a retrograde fashion to the central nervous system
the solitary nucleus. Afferent sensory information from the external via the dorsal motor nucleus of the vagus nerve (Uemura et al., 2018).
ear and meatus travels in the vagus nerve via the superior (jugular) Motor neurons in the nucleus ambiguus are preferentially affected in
ganglion of the vagus nerve and proximally into the brainstem caudal amyotrophic lateral sclerosis.
spinal trigeminal nucleus.
The motor efferents originate in the nucleus ambiguus and dorsal Nodose Ganglion and Jugular Foramen
motor nucleus in the medulla, exit the brainstem laterally, and exit the Neoplasm, blunt and penetrating trauma, inflammation, infec-
skull via the jugular foramen in the temporal bone while traversing the tion (especially VZV), and internal carotid artery dissection may
nodose ganglion without synapsing. After exiting the jugular foramen, affect vagus function at the jugular foramen. Vernet syndrome is a
branches innervate the palatal constrictors and intrinsic laryngeal mus- pure jugular foramen syndrome with involvement of the glosso-
cles. Pharyngeal innervation by the vagal and glossopharyngeal nerves pharyngeal, vagus, and spinal accessory nerves (Ferreira et al., 2018)
provides the efferent limb of the gag reflex, with the afferent limb pro- (see Table 103.1). Simultaneous involvement of cranial nerves IX
vided by glossopharyngeal sensory fibers to the pharynx. The superior through XII is common because of the proximity of the jugular fora-
laryngeal branch exits the main vagus trunk just inferior to the nodose men and hypoglossal canal. As noted earlier, when accompanied by
ganglion, and the inferior laryngeal branch (recurrent laryngeal nerve) Horner syndrome, the combination of cranial nerves IX through XII
exits the main trunk in the thorax. The course of the left and right is called Villaret syndrome (posterior retropharyngeal syndrome). In
recurrent laryngeal nerves differs, with the right nerve crossing under the absence of Horner syndrome, the combination of cranial nerves
the right subclavian artery and ascending in the neck and the left nerve IX through XII is called Collet-Sicard syndrome. The combination of
wrapping under the aorta to ascend more vertically. Both nerves enter vagus and hypoglossal nerve lesions is called Tapia syndrome (see Table
the larynx. 103.1), although the original description was of a patient with a brain-
The vagus nerve carries efferent preganglionic fibers from the stem lesion and contralateral hemiparesis. Airway manipulation and
nucleus ambiguus and dorsal motor nucleus to the cardiac, pulmo- vertebral dissection may cause this syndrome (Al-Sihan et al., 2011;
nary, esophageal, gastric, mesenteric, and myenteric plexi. The para- Gevorgyan and Nedzelski, 2013).
sympathetic fibers descend in the neck, with motor and sensory fibers Glomus jugulare tumors of the jugular bulb were described ear-
in the main vagus trunk within the carotid sheath, which also contains lier in this chapter in the section on Glossopharyngeal Nerve (Cranial
the internal jugular vein and internal carotid artery. Nerve IX), Petrosal Ganglion and Jugular Foramen.
Vagus Nerve Branches foramen. These cranial accessory fibers then join the vagus nerve to
Direct pressure or stretch injury of the branches may occur from sur- innervate palatal and laryngeal muscles. Some anatomical studies call
gical intervention, particularly recurrent laryngeal nerve injury with into question the existence of this cranial branch, though a recent
thyroid or esophageal surgery, or vagus nerve stimulator placement cadaver study demonstrated the existence of the cranial branch in the
for the treatment of epilepsy or refractory depression. Peripheral majority of humans (Tubbs et al., 2014).
branches may be affected by herpes zoster, paragangliomas, thoracic Afferent proprioceptive sensory information from the sternoclei-
lymphadenopathy, and neoplasms. Referred ear pain may occur with domastoid and trapezius travels in the spinal accessory nerve branches
chest neoplasms, owing to direct infiltration or compression of nerve via unipolar neurons with cell bodies in the cervical dorsal root ganglia.
branches connected via the trigeminal nuclear system to sensory vagus
nerve branches to the ear. Peripheral branch involvement in Parkinson Clinical Lesions
disease, especially of the superior laryngeal nerve, may explain the dys- Spinal Accessory Palsy Appearance
phagia often experienced by these patients (Mu et al., 2013). Spinal accessory nerve dysfunction results in weakness of contralat-
eral head turning and ipsilateral shoulder elevation. Unilateral atrophy
SPINAL ACCESSORY NERVE (CRANIAL NERVE XI) of the sternocleidomastoid and trapezius occurs with chronic lesions
(eFig. 103.12). Scapular winging with active external shoulder rotation
Anatomy may be seen (Chan and Hems, 2006). Pain in the neck or shoulder is
The spinal accessory nucleus is located in the dorsolateral ventral common.
horn of the cervical spinal cord. Motor neurons from this nucleus exit
the cervical cord as distinct nerve rootlets that converge and ascend Spinal Accessory Nucleus
through the foramen magnum to form the main trunk of the spinal Amyotrophic lateral sclerosis preferentially involves the spinal acces-
accessory nerve, which exits the cranium via the jugular foramen with sory and other motor neurons in the ventral horns of the spinal cord.
the glossopharyngeal and vagus nerves (Fig. 103.11). After exiting the Intrinsic spinal cord pathology such as neoplasm or syrinx may affect
jugular foramen, nerve branches innervate the ipsilateral sternoclei- these motor neurons in combination with other spinal tracts.
domastoid and trapezius muscles. Contralateral epileptic head turn-
ing and sternocleidomastoid function following hemispheric strokes Jugular Foramen
indicate that each cerebral hemisphere innervates the ipsilateral ster- Vernet, Villaret, and Collet-Sicard syndromes are described earlier and
nocleidomastoid muscle, seemingly after a double decussation in the in Table 103.1.
brainstem.
According to classic anatomical teaching, fibers originating in the Spinal Accessory Nerve Branches
caudal nucleus ambiguus travel through a cranial accessory branch Iatrogenic injury during lymph node biopsy or dissection for head
to join the spinal accessory branch as it travels through the jugular and neck cancers is the most common cause of spinal accessory nerve
dysfunction (Camp and Birch, 2011). Variations in individual branch
anatomy make the nerve particularly prone to difficult identification
and traction or ischemic injury. Involvement of the dominant arm,
scapular winging, and limited arm elevation are poor prognostic indi-
Jugular foramen
cators. Spinal accessory branches may be intentionally injured in treat-
ment for cervical dystonia. Trauma and isolated peripheral neoplasms
occur rarely.
Nodose ganglion of
the vagus nerve (X)
HYPOGLOSSAL NERVE (CRANIAL NERVE XII)
Accessory nerve Anatomy
C2 The hypoglossal nucleus is located in the medial medulla. Supranuclear
inputs are generally considered to be bilateral and symmetrical, but
evaluation of tongue weakness in patients with hemispheric strokes
C3 Sternocleidomastoid suggests asymmetry with a greater contralateral innervation. Motor
muscle neurons emerge from the ventral surface of the nucleus, forming the
hypoglossal fasciculus that traverses the brainstem ventrolaterally, to
C4
exit as rootlets anterior to the inferior olive. The hypoglossal nerve
exits the skull via the hypoglossal canal in the occipital condyle of the
occipital bone. It then descends near the extracranial internal carotid
artery, ultimately branching to innervate the styloglossus, hypoglossus,
and intrinsic tongue muscles (Fig. 103.13). Fibers from cervical motor
nerve roots form the ansa cervicalis, which has multiple connections
with the hypoglossal nerve.
Clinical Lesions
Trapezius
muscle
Hypoglossal Palsy Appearance
Hypoglossal nerve dysfunction results in atrophy and fasciculation of
the ipsilateral tongue muscles and ipsilateral deviation of the tongue
upon protrusion from the mouth (Stino et al., 2016; Yu et al., 2016;
Fig. 103.11 Spinal Accessory Nerve Course. Fig. 103.14).
A B
eFig. 103.12 A, Normal left sternocleidomastoid muscle with forceful thrust of chin to the right. Note prom-
inent left sternocleidomastoid muscle. B, Same maneuver shown in A but to the left, showing loss of bulk
of right sternocleidomastoid muscle.
Hypoglossal
Superior cervical sympathetic ganglion
foramen
Nodose ganglion of vagus nerve (X)
Lingual nerve (V)
Intrinsic muscles of tongue
Nucleus
nerve (XII) Styloglossus muscle
C1
Genioglossus muscle
C2
Geniohyoid muscle
Hyoglossus muscle
Thyrohyoid muscle
Superior belly of omohyoid muscle
Sternohyoid muscle
Ansa
Sternothyroid muscle
hypoglossi
Inferior belly of omohyoid muscle

Fig. 103.13 Hypoglossal Nerve Course.
of swallowing impairment, hoarseness of the voice, decreased gag

reflex, facial pain, limb ataxia, Horner syndrome, contralateral hemi-
body impaired pain and temperature sensation, and vertigo (see Table
103.1). As with the other cranial nerves, there are multiple etiologies of
these brainstem syndromes. Although neurovascular compression as
the hypoglossal nerve roots exit the brainstem is not classically consid-
ered a cause of hypoglossal palsy, case reports suggest this as a diagnos-
tic possibility (Osburn et al., 2010; Straube and Linn, 2008).
Hypoglossal Canal
Neoplasm, blunt and penetrating trauma with occipital condyle frac-
tures, inflammation, and post-radiation injury may affect hypoglossal
function at the hypoglossal canal. Since the hypoglossal canal is in close
proximity to the jugular foramen, simultaneous involvement of cranial
nerves IX through XII is not uncommon. Villaret, Collet-Sicard, and
Tapia syndromes are described earlier and in Table 103.1.
Hypoglossal Peripheral Branches

Mechanisms of hypoglossal branch disease are similar to those in the
hypoglossal canal. Hypoglossal dysfunction is an ominous clinical
finding; 50% of cases are caused by neoplasm, typically malignant.
Nasopharyngeal carcinoma and skull-based metastatic disease are
Fig. 103.14 Axial Computed Tomography Scan Through Tongue in among the most common malignancies affecting the hypoglossal nerve.
Patient with Right Hypoglossal Palsy. Note tongue atrophy on right
The combination of hypoglossal dysfunction with abducens palsy is
side (black arrow). (Courtesy Miral Jhaveri, MD.)
highly suggestive of an aggressive clival malignancy. Retropharyngeal
mass lesions other than malignancy include granulomatous inflam-
Hypoglossal Nucleus and Fasciculus mation and abscess. Hypoglossal palsy may be the presenting man-
The medial medullary syndrome of Dejerine consists of ipsilateral tongue ifestation of carotid artery dissection or aneurysm and may occur
weakness, contralateral hemiplegia from pyramidal tract involvement, iatrogenically after carotid endarterectomy (Jurkiewicz et al., 2019).
and contralateral hemisensory loss from medial lemniscal involve-
ment (see Table 103.1). More common than isolated medial medul- The complete reference list is available online at https://expertconsult.
lary syndrome is the hemi-medullary syndrome of Babinski-Nageotte inkling.com/.
that combines the Dejerine and Wallenberg syndromes with deficits
Video 103.1 Large Left Hypertropia Secondary to Right Oculomotor Video 103.6 Esotropia. https://www.kollaborate.tv/player?id=870105
Nerve Palsy. https://www.kollaborate.tv/player?id=725741 Video 103.7 Facial Nerve Function in a Patient With a History of Right
Video 103.2 Left Appendicular Ataxia. https://www.kollaborate.tv/ Facial Palsy Two Years Ago and Current Left Facial Palsy.https://www.
player?id=870100 kollaborate.tv/player?id=870106
Video 103.3 Prominent Left Ptosis. https://www.kollaborate.tv/player? Video 103.8 Other Babinski Sign. https://www.kollaborate.tv/player?
id=870101 id=870107
Video 103.4 Cranial Neuropathies/Impaired Adduction, Elevation, (Clips 103.1–2 from Leigh R. J., Zee, D.S. The Neurology of Eye
and Depression With Intact Abduction of the Left Nerve.https://www. Movements, 5th Edition. 2015. © Oxford University Press; Clip
kollaborate.tv/player?id=870102 103.8 Courtesy of Joseph Jankovic, MD.)
Video 103.5 Bilateral Abduction Deficits Secondary to Demyelinating
Bilateral Abducens Palsies. https://www.kollaborate.tv/player?id=870104
1797.e1
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104
Disorders of Bones, Joints, Ligaments, and
Meninges
Christopher D. Geiger, Michael W. Devereaux, David Hart
OUTLINE
Heritable Disorders of Connective Tissue, 1798 Juvenile Kyphosis, 1813
Osteogenesis Imperfecta, 1799 Scoliosis, 1813
Ehlers-Danlos Syndrome, 1799 Diffuse Idiopathic Skeletal Hyperostosis, 1813
Chondrodysplasias, 1799 Ossification of the Posterior Longitudinal Ligament or
Marfan Syndrome, 1800 Ligamentum Flavum, 1813
Congenital and Inherited Craniospinal Malformations and Degenerative Disease of the Spine, 1814
Deformities, 1801 Spinal Osteoarthritis and Spondylosis, 1814
Craniosynostosis, 1801 Cervical Spondylosis, 1814
Occipitalization of the Atlas, 1801 Cervical Radiculopathy, 1814
Basilar Impression, 1801 Cervical Spondylotic Myelopathy, 1816
Klippel-Feil Anomaly, 1801 Vertebral Artery Stroke Caused by Cervical
Atlantoaxial Subluxation, 1801 Osteoarthritis, 1817
Chiari I Malformation, 1803 Thoracic Spondylosis, 1817
Spinal Dysraphism, 1806 Lumbar Spondylosis, 1818
Spina Bifida Occulta, 1806 Lumbar Radiculopathies, 1819
Myelomeningocele and Encephalocele, 1806 Monoradiculopathy, 1819
Dandy-Walker Syndrome, 1807 Lumbar Canal Stenosis, 1821
Tethered Cord Syndromes, 1807 Infectious Diseases of the Spine, 1821
Syringomyelia and Syringobulbia, 1808 Pyogenic Vertebral Osteomyelitis and Epidural Abscess, 1821
Clinical Presentation, 1809 Granulomatous Vertebral Osteomyelitis, 1823
Communicating and Noncommunicating Syringes, 1810 Inflammatory Joint Disease, 1823
Abnormalities of the Cervicomedullary Junction, 1810 Rheumatoid Arthritis, 1823
Syrinx Associated With Spinal Cord Tumors, 1810 Inflammatory Spondyloarthropathies, 1824
Syrinx Associated With Spinal Cord Trauma, 1810 Epidural Lipomatosis, 1825
Syrinx Associated With Other Focal Spinal Cord Pathologies, 1810 Chronic Meningitis, 1826
Spinal Deformities and Metabolic Bone Disease, 1811 Chronic Adhesive Arachnoiditis, 1826
Osteoporosis, 1811 Recurrent Meningitis, 1826
Osteomalacia and Rickets, 1811 Pachymeningitis, 1826
Osteopetrosis, 1812 Superficial Hemosiderosis, 1827
Paget Disease, 1812 Fibromyalgia, 1827

The bones, joints, ligaments, and meninges that support and protect the
tissues of the nervous system can give rise to numerous illnesses that affect
HERITABLE DISORDERS OF CONNECTIVE TISSUE
the nervous system. These disorders sometimes border on other medi- Heritable disorders involving the major connective tissues of the body
cal disciplines unfamiliar to the neurologist and hence can be enigmatic are among the most common human genetic diseases. The focus will
or difficult to diagnose. They may involve cognitive functions, disrupt be on those disorders that have neurological impact (Box 104.1). Many
cerebrospinal fluid (CSF) flow dynamics, or slowly compress and distort of these are being better understood at a molecular level: osteogenesis
central and peripheral neural structures. They have a mixture of genetic, imperfecta (OI), Ehlers-Danlos syndrome (EDS), chondrodysplasias,
developmental, traumatic, degenerative, infectious, and inflammatory and Marfan syndrome, to name a few.
mechanisms. For the clinical neurologist, awareness greatly strengthens Classifications of heritable disorders of connective tissue can rely on
diagnostic skill, therefore this chapter reviews many of these disorders. pattern of inheritance, clinical features, anatomical pattern, or known
Chapters of overlapping interest include Chapters 27, 33, 58, 85, 89. molecular defects. To date, genetic or molecular classification is not
For an expanded version of this chapter that includes figures and always helpful clinically because there are significant genotype-to-phe-
boxes that are only available online, please visit http://www.expert notype inconsistencies, testing is not widely available, and our under-
consult.com. standing of many disorders is incomplete. Connective tissues contain
1798
CHAPTER 104 Disorders of Bones, Joints, Ligaments, and Meninges 1799
and sensorineural hearing loss usually begins in the second decade and
BOX 104.1 Classification of Hereditary
affects more than half of patients by age 30 years. Joint laxity, indis-
Disorders of Connective Tissue tinguishable from that of EDS, can result in permanent dislocations.
Skeletal (Primarily Type I Collagen) Rarely, OI is complicated by cervical artery dissection resulting from
Osteogenesis imperfecta fragility of large blood vessels (Grond-Ginsbach and Debette, 2009).
Aortic regurgitation, floppy mitral valves, and mitral incompetence
Dermis, Tendons, and Ligaments (Primarily Type I Collagen) can lead to cerebrovascular complications. For unknown reasons, some
Hypermobile Ehlers-Danlos syndrome (type III) patients develop a hypermetabolic state with elevated serum thyroxine
Classic Ehlers-Danlos syndrome (type I) levels, hyperthermia, and excessive sweating. Wide phenotypic varia-
Vascular Ehlers-Danlos syndrome tion is characteristic and appears to be related to the abundance of over
900 unique mutations in the type I procollagen COL1A1 and COL1A2
Cartilage (Primarily Fibrils of Type II Collagen, Proteoglycans) genes, combined with undefined chance events during embryonic and
Chondrodysplasias fetal development (Prockop and Czarny-Ratajczak, 2008).
Achondroplasia Treatment is symptomatic and tailored to the severity of symptoms,
Pseudoachondroplasia though women require special attention during pregnancy and after
Stickler syndrome menopause when the risk of fractures increases. More severely affected
Craniosynostosis (syndromic) children require more comprehensive physical therapy and orthope-
dic management. For severe hearing loss, stapedectomy or cochlear
Skeletal, Cardiovascular, and Eye (Type I and Type III implant may prove helpful. Neurological complications relating to
Collagen, Fibrillin, Elastin) potential brainstem and spinal compression require appropriate atten-
Marfan syndrome tion. Oral or intravenous bisphosphonates are commonly prescribed
MASS phenotype (mitral valve prolapse, aortic dilation, skin, and skeletal to individuals with OI. Although studies demonstrate increased bone
features) mineral density as a result, it is unclear whether bisphosphonates
Loeys-Dietz syndrome improve clinical status (Dwan et al., 2016).
Beals syndrome (congenital contractual arachnodactyly)
Dermal/epidermal (keratin, laminin, type VII collagen, plectin, integrin) Ehlers-Danlos Syndrome
Epidermolysis bullosa The EDSs are a rare group of disorders with an overall frequency of
Basal lamina (type IV collagen, laminin, nidogen) 1:5000. They are a clinically and genetically heterogeneous group of
Alport syndrome inherited connective tissue disorders characterized by joint hyper-
mobility, skin hyperextensibility and tissue fragility. The Villefranche
nosology in 1998 identified 6 EDS subtypes based on clinical features,
a wide range of complex macromolecules assembled in the extracel- mode of inheritance, and biochemical and genetic findings (Malfait
lular matrix. There are at least 28 different types of collagen in bone, et al., 2017). In 2017 the EDS Consortium revised the classification to
skin cartilage, tendons, and ligaments. Other molecules including now include 13 subtypes. However, given the vast genetic heterogene-
fibrillin, elastin, proteoglycans, fibronectin, hyaluronate, osteonectin, ity and phenotypic variability of the subtypes and the clinical overlap
and osteocalcin contribute to tensile strength and elasticity. Forces between the subtypes, a definitive diagnosis of all EDS subtypes (except
that control the three-dimensional organization of these components for the hypermobile subtype) relies on identification of the causative
remain largely unknown. In growth and development, collagen fibrils genetic variant (Malfait et al., 2017).
in all these supporting tissues undergo repeated synthesis, degradation, Of importance is that many of these subtypes can include neuro-
and resynthesis. Nutrition, gravitational forces, trauma, other physical logical features that may lead a patient to a neurologist for evaluation
stresses, endocrine factors (such as glucocorticoids), and inflammation before a diagnosis of EDS has been established. Neurological fea-
all modify these tissues (Prockop and Czarny-Ratajczak, 2008). tures include a number of neuromuscular symptoms such as weak-
ness, hypotonia, myalgia, and paresthesia (Voermans et al., 2009).
Osteogenesis Imperfecta Uncommon neuromuscular disorders include axonal polyneuropathy
The various types of OI or “brittle bone disease” (incidence ≈1:20,000 and compression neuropathies. In addition, skeletal disorders include
births) are inherited, predominantly autosomal-dominant connective cranial cervical instability and scoliosis. Postural orthostatic hypoten-
tissue disorders caused by gene mutations that affect type 1 collagen. sion (POTS) may occur. Any of the above symptoms/signs coupled
Rare recessive inheritance has been reported (Pyott et al., 2013). This with joint hypermobility, a feature present to a greater or lesser degree
disorder is characterized by brittle osteopenic bones and recurrent in most subtypes, and skin changes as noted above, should raise the
fractures (Basel and Steiner, 2009). As many as nine types are known, suspicion for EDS. The Beighton joint flexibility score is a useful
with wide variations in severity and associated findings such as short screening tool for the degree of joint mobility (Table 104.1)
stature, blue sclera, progressive hearing loss, poor dentition, scoliosis, The differential diagnosis includes Marfan syndrome and OI. If
and skeletal abnormalities (osteopenia, irregular ossification, multiple EDS is suspected, referral to a clinical geneticist is essential.
fractures). Laboratory studies show a molecular defect in type I procol-
lagen in two-thirds of patients. Chondrodysplasias
Potential neurological complications of OI include communicating Chondrodysplasias, also referred to as skeletal dysplasias, are herita-
hydrocephalus, basilar invagination, macrocephaly, kyphoscoliosis, ble skeletal disorders characterized by dwarfism and abnormal body
skull fractures, subdural hematomas, and epilepsy. The basilar invagi- proportions. These are the most common cause of abnormally short
nation can lead to brainstem compression (Menezes, 2008). Spinal cord stature. This category also includes some patients with craniosynos-
compression, syringomyelia, Chiari I malformation, Dandy-Walker tosis (see later discussion) who have cranial and facial malformations
cysts, leptomeningeal cysts, microcephalus, or central nervous system associated with ocular change and cleft palate but normal stature
(CNS) tumors are rarer associations. Progressive, variably conductive and body proportions; this is more common in the more severe
TABLE 104.1 The Beighton Score BOX 104.2 Neurological Complications of

Thumb to forearm ■ Right ■ Left Achondroplasia
Bending little fingers back to 90 degrees or ■ Right ■ Left
Macrocrania, with or without hydrocephalus
more
Foramen magnum abnormalities with cervicomedullary compression
Elbows hyperextend to 10 degrees or more ■ Right ■ Left
Respiratory disturbances, including sleep apnea and sudden infant death syn-
(i.e., bend backwards 10 degrees or more
drome
in the wrong direction)
Syringomyelia, diastematomyelia
Knees hyperextend to 10 degrees or more ■ Right ■ Left
Spinal stenosis with spinal cord or nerve root compression
(i.e., bend backwards 10 degrees or more
Infantile hypotonia
in the wrong direction)
Cortical atrophy
Palms flat to floor with legs straight ■ Able or ■ By history
Atlantoaxial subluxation
Total score
Psychomotor delay (most have normal intelligence)
Score 1 point for each positive indicator of hypermobility. Maximum
Adapted with permission from Ruiz-Garcia, M., Tovar-Baudin, A., Del
score is 9 points; a score of 4 or more is indicative of hypermobility.
Castillo-Ruiz, V., et al., 1997. Early detection of neurological manifesta-
Adapted from Beighton, P.H., Horan, F., 1969. Orthopedic aspects of
tions in achondroplasia. Childs Nerv. Syst. 13, 208–213.
the Ehlers-Danlos syndrome. J Bone Joint Surg. Br. 51, 444–453.
chondrodysplasias. Many patients develop premature degenerative expression; its most prominent features affect the skeleton, heart,
joint disease. Mild chondrodysplasias in adults may be difficult to dif- great vessels, and eye. More than 90% of patients have a mutation
ferentiate from primary generalized osteoarthritis. in the fibrillin-1 gene. Fibrillin-1 is an important matrix component
They encompass over 400 disorders, which vary from mild dis- of both elastic and nonelastic tissues. The classic patient is tall with
tortions of cartilaginous structures and the eye to severe malforma- inordinately long limbs and digits. Other skeletal changes are ante-
tions that are fatal in early life (Bonafe, 2015). A number are unique rior chest deformity, scoliosis, thoracic lordosis, high arched palate
and identified by eponyms based on isolated case reports. Among with crowded teeth, and some ligamentous laxity. Ocular prob-
the features of these syndromes are high forehead, hypoplastic facies, lems include myopia, flat corneas, and ectopia lentis. The major
cleft palate, short extremities (with gross distortions of the epiphyses, life-threatening problem is aortic aneurysm or dissection; aortic
metaphyses, and joint surfaces), cataracts, degeneration of the vitre- and mitral valves can also be affected. Case reports link Marfan syn-
ous, and retinal detachment. We will highlight those types most prone drome to intracranial vascular abnormalities such as arterial dissec-
to neurological complications. tions, giant aneurysms, or hemifacial spasm associated with vascular
compression of the facial nerve. However, aneurysms or dissections
Achondroplasia are rare in patients with Marfan syndrome, and their highest risk of
Achondroplasia is an autosomal dominant disorder of endochondral stroke is from cardiogenic emboli, especially if they have prosthetic
bone formation. A specific mutation of a fibroblast growth factor recep- heart valves or atrial fibrillation (Wityk et al., 2002). Patients with
tor gene (FGFR3) is present in over 90% of patients. It is the most com- Marfan syndrome can have sleep apnea, possibly secondary to their
mon skeletal dysplasia in humans. Approximately three-fourths of cases skeletal deformities.
occur because of spontaneous new mutations. The syndrome is the most Dural ectasia, dilation of the caudal thecal sac, occurs in 90% of
common cause of short-limbed dwarfism accompanied by macrocephaly patients with Marfan syndrome and is a major diagnostic criterion.
and dysplasias of the metaphyses of long bones. The mutant genotype has Ectasia varies in severity, increases with age, and can cause lumbar
complete penetrance. The diagnosis can be confirmed by pathognomonic radiculopathy. Leakage from ectatic dura can cause intracranial hypo-
radiographic changes and/or by deoxyribonucleic acid (DNA) testing. tension. Case reports link Marfan syndrome to Chiari I malformation
Neurological complications associated with achondroplasia are common (CM-I). It is not clear whether these patients had classic CM-I or ton-
(Box 104.2). Young achondroplastic children should be observed for com- sillar herniation secondary to CSF hypotension. Patients can have axo-
plications such as hydrocephalus, compression at the foramen magnum, nal neuropathy or mild myopathy.
thoracolumbar kyphosis, and sleep apnea. Neurological complications of Many patients with Marfan-like features have neither Marfan syn-
spinal stenosis tend to occur later in life. drome nor any other currently identified mutations. These patients
are sometimes labeled as having MASS syndrome (mitral valve, aorta,
Pseudoachondroplasia skeletal, and skin involvement) and vary widely in severity of manifes-
Pseudoachondroplasia, another autosomal dominant cause of short tations (Loeys et al., 2010). A few examples of Marfan-like syndromes
stature, is due to gene mutations for the cartilage oligomeric matrix of neurological import are:
protein (COMP), a protein that interacts with both collagens and 1. Homocystinuria, a group of autosomal recessive disorders that can
proteoglycans in cartilage. Patients have leg deformities, short digits, cause marfanoid skeletal changes, myopia, and lens ectopia. It is
vertebral anomalies, and proclivity to develop severe osteoarthritis. important to distinguish homocystinuria from Marfan syndrome,
However, neurological complications are less common than in true since the former can cause mental retardation and hypercoagulabil-
achondroplasia. Nonetheless, patients are at risk for atlantoaxial (AA) ity leading to strokes and because it can be treated with vitamin B6,
dislocation. Children who carry both the achondroplasia and pseudo- folate, and vitamin B12.
achondroplasia mutations have been reported, with early onset of neu- 2. Loeys-Dietz aneurysm syndrome is similar to Marfan syndrome in
rological complications from lumbar or foramen magnum stenosis. skeletal and aortic manifestations but does not have lens ectopia
and is often associated with craniosynostosis. Neurological mani-
Marfan Syndrome festations can include Chiari I malformation, hydrocephalus, and
Marfan syndrome is an autosomal dominant disorder of fibrous con- developmental delay. It is usually due to mutations in either TGFB2
nective tissue with variable penetrance and variation of phenotypic or the closely related TGFB1 genes.
3. Shprintzen-Goldberg syndrome is also characterized by marfanoid digastric) (eFig. 104.3) and measurements can be used to make the
features, normal lenses, and craniosynostosis. Neurological issues diagnosis. Congenital basilar impression may occur in isolation or
can include hypotonia, Chiari I malformation, developmental may be associated with conditions such as achondroplasia, occipital
delay, mental retardation, and obstructive sleep apnea. dysplasia, Down syndrome, Hurler syndrome, Klippel-Feil anom-
4. Beals syndrome (congenital contractural arachnodactyly [CCA]) aly, and cleidocranial dysplasia. Some instances of basilar impres-
can cause marfanoid features, joint contracture, and some features sion are familial. The skeletal anomaly is often accompanied by
of OI. Like Marfan syndrome, it is autosomal dominant, but the anomalies of the neuraxis, including Chiari I or II malformation
mutated gene is for fibrillin-2 rather than fibrillin-1. and syringomyelia (Milhorat et al., 2007). Basilar impression can
cause compression of the brainstem (eFig. 104.4), the cerebellum,
CONGENITAL AND INHERITED CRANIOSPINAL or (rarely) the vertebral artery, leading to vertebrobasilar ischemia.
It is often asymptomatic, particularly when mild and unaccompa-
MALFORMATIONS AND DEFORMITIES nied by other anomalies.
Craniospinal malformations result from abnormalities of the bones Platybasia, or flattening of the skull, refers to straightening of
of the skull and spinal column, connecting ligaments, or other soft the angle between the clivus and the floor of the anterior fossa. It
tissues and may cause hydrocephalus, brain deformation, spinal cord infrequently accompanies basilar impression and can also occur as
compression, and syringobulbia or syringomyelia (Menezes, 1997). an isolated radiographic finding without any adverse neurological
Many of these are congenital. Magnetic resonance imaging (MRI) and consequences.
computed tomography (CT) scanning have improved the detection,
understanding, and treatment of these anomalies. Klippel-Feil Anomaly
Patients with the Klippel-Feil anomaly (congenital synostosis of the
Craniosynostosis cervical vertebrae) (eFig. 104.5) typically have short necks, low hair-
Craniosynostosis is among the most common and relatively benign lines, and limitation of cervical motion. The diagnosis is confirmed by
abnormalities, affecting about 1 in 2500 live births. It is caused by pre- radiographic demonstration of any two or more spontaneously fused
mature closure of one or more of the sutures of the skull bones. For cervical vertebrae. The condition is congenital, caused by failure of
babies who have abnormal skull shapes, CT scans can distinguish cra- normal segmentation of the cervical vertebrae between the third and
niosynostosis from results of fetal head position, birth trauma, or posi- eighth weeks of fetal development. Although familial instances occur,
tional plagiocephaly—flattened or misshapen areas on the head that most cases are isolated and idiopathic. The anomaly can cause direct
may develop due to sleeping position. Fig. 104.1 illustrates the various nerve root, cervical spinal cord, and vertebral or spinal artery compres-
types of craniosynostosis. sion. Patients may have cervical ribs, predisposing them to thoracic
Craniosynostosis often occurs alone, but about 20% of cases are outlet syndrome. Neck pain is common. Hearing loss is the most com-
associated with syndromes affecting other parts of the body; the most mon cranial nerve symptom. Klippel-Feil syndrome is the anomaly
common of these are Crouzon and Apert syndromes. However, there most likely to cause mirror movements (synkinesia), particularly of the
are over 150 syndromes associated with craniosynostosis, with con- hands. Patients with mirror movements can have abnormal clefts or
siderable overlap of symptoms between them. Clinical evaluation division of the spinal cord near the cervicomedullary junction, which
by a geneticist may be necessary to determine the most appropriate can be detected by MRI (Royal et al., 2002). Patients with Klippel-Feil
diagnosis. Most patients with syndromic craniosynostosis appear to anomaly can have a wide variety of associated abnormalities of brain,
have a mutation in the related FGFR2 gene. Genetic testing may be spinal cord, or skeletal development, especially congenital scoliosis or
necessary to confirm the diagnosis of a specific syndrome. A fam- Sprengel deformity with unilateral scapular elevation. Patients may
ily history of abnormal head shape can sometimes be found with develop hydrocephalus, syringomyelia, or syringobulbia. However,
genetic syndromes, though many syndromes are caused by de novo many patients with Klippel-Feil anomaly have no neurological symp-
mutations. toms or signs.
Occipitalization of the Atlas

Occipitalization or assimilation of the atlas refers to congenital partial or Atlantoaxial Subluxation
complete fusion of the atlas to the occiput (eFig. 104.2). The anterior Various congenital or acquired conditions can disrupt the integrity
arch of the atlas may fuse to the lower end of the clivus, or the posterior of the AA joint, leading to its dislocation (Box 104.3). In horizontal
arch of the atlas may fuse to the occiput. The anomaly is often asymp- subluxation, C1 usually moves anteriorly to C2. The movement can
tomatic until early adult life but may become symptomatic sooner after be assessed by measuring the separation between the dens and the
trauma. Unilateral occipitalization of the atlas is one cause of torticollis anterior arch of C1 on flexion, extension, and neutral radiographs; in
in young children. The loss of movement between the occiput and atlas adults, the separation should not exceed 3.5 mm. This measurement
increases the stresses at the AA joint, predisposing it to gradual degen- is known as the atlantodental interval (ADI). An alternative measure-
eration or traumatic dislocation. Patients with occipitalization of the ment is the PADI, or posterior atlantodental interval, which is mea-
atlas may have associated anomalies such as the Klippel-Feil anomaly, sured between the posterior border of the dens and the anterior surface
basilar impression, or Chiari malformation (Ghalue, 2007). of the posterior arch of C1. This measurement, therefore, represents
the “space available for the cord” and more accurately reflects the risk
of neurological compromise than the ADI. Patients with horizontal AA
Basilar Impression joint subluxation are likely to compress their spinal cords if the diame-
Basilar impression or invagination refers to caudal settling of the ter of the spinal canal at the level of the dens is less than 14 mm. This is
foramen magnum onto the cervical spine, generally with encroach- unlikely to occur if the diameter is more than 17 mm. The actual rela-
ment of the odontoid process into the foramen magnum, often tionship between the cord and the subluxing bones is best imaged with
resulting in brainstem and/or upper cervical spinal cord compres- MRI, which should include flexion and extension views if plain radio-
sion. Several radiological lines (Chamberlain, McGregor, McRae, graphs show significant subluxation on flexion/extension imaging.
CHAPTER 104 Disorders of Bones, Joints, Ligaments, and Meninges 1801.e1
eFig. 104.4 Magnetic Resonance Image of Patient With Basilar

Impression, Showing Brainstem Angulation.
eFig. 104.2 Occipitalization of the Atlas. Radiograph shows fusion of

lamina of atlas to occiput (open arrow). Lamina contains circular arcuate
foramina (arrow) through which vertebral arteries pass. Spinous pro-
cess of atlas (curved arrow) has fused with C2, making this a partial
incorporation of C1 into the skull base. A broad spectrum of variations
occur in this congenital anomaly. (Courtesy Erik Gaensler.)
eFig. 104.5 Patient With Klippel-Feil Syndrome, Showing Short

Neck.
eFig. 104.3 Chamberlain line (dashes) extends from roof of hard palate
to posterior lip of foramen magnum; McGregor line (solid) extends from
roof of hard palate to most caudal portion of occipital bone; McRae
line (dots) extends from anterior lip of foramen magnum to posterior
lip of foramen magnum. Tip of odontoid is normally not more than 5
mm above McGregor line and not above Chamberlain or McRae line.
(Modified with permission from Rosenbaum, R.B, Campbell, S.M.,
Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Diseases.
Butterworth-Heinemann, Boston.)
Metopic
Synostotic Trigonocephaly
Sagittal Lambdoid
Synostotic Scaphocephaly Synostotic Posterior Plagiocephaly
Frontal bone Metopic suture
Coronal suture
Anterior fontanelle
Parietal bone Sagittal suture
Posterior fontanelle Lambdoid suture

Occipital bone
Normal
Unicoronal (All Sutures Open)

Synostotic Anterior Plagiocephaly Deformational Posterior Plagiocephaly
Bicoronal
Synostotic Brachycephaly
Fig. 104.1 Craniosynostosis. (Courtesy Han Wang, MD.)
If MRI is contraindicated, then CT myelography is a consideration very adherent to the dura, making its resection potentially very haz-
(Manczak et al., 2017). AA subluxation is very frequently encountered ardous. The combination of AA subluxation and pannus formation
as part of the spectrum of cervical spine disease seen in rheumatoid can frequently result in significant myelopathy. Both conditions can be
arthritis (RA). The three cardinal cervical spine manifestations in RA treated with surgical fusion of C1 and C2, which corrects the sublux-
are AA subluxation, subaxial spondylolisthesis (often multiple levels), ation and also usually causes the pannus to resorb at least partially over
and formation of retro-odontoid pannus. The pannus is an inflamma- several weeks to months. In patients with rapidly progressive myelop-
tory mass of tissue that is often at least partially calcified, and can be athy it might not be safe to wait for this process to alleviate the spinal
cord compression, and direct resection of the pannus is required. This

BOX 104.3 Mechanisms of Atlantoaxial
is a difficult operation, usually performed via transoral approach. (See
Subluxation also section below on RA.) Patients with congenital AA dislocation
I. Congenital may have associated abnormalities such as Chiari I malformation or
A. Os odontoideum (failure of odontoid to fuse with body of diastematomyelia. They can develop secondary syringomyelia. AA
axis) subluxation in patients with long-standing RA is a prime example of
1. Isolated acquired abnormality of the AA joint and is discussed in more detail
2. With connective tissue dysplasias (e.g., Down syn- later in this chapter. Patients with AA subluxation may be asymptom-
drome, pseudoachondroplasia, multiple epiphyseal atic, particularly if their spinal canal diameter is generous. However,
dysplasia, spondyloepiphyseal dysplasia, Morquio dis- they are vulnerable to spinal cord trauma during intubation or other
ease, Klippel-Feil anomaly, Conradi syndrome) neck motion under anesthesia, or as a result of a whiplash injury.
B. Hypoplastic dens Patients at risk for AA dislocation, such as those with Down syndrome
1. With connective tissue dysplasia or chronic RA, should have lateral flexion and extension cervical spine
2. With incomplete segmentation (e.g., occipital assim- radiography performed before general anesthesia so the anesthesiolo-
ilation of atlas, basilar invagination, incomplete seg-
gist can plan appropriate care during intubation.
mentation of C2, C3, etc.)
C. Other anomalies of C2 (e.g., bifid dens, tripartite dens Chiari I Malformation
with os apicale, agenesis of all or part of dens)
John Cleland first described a series of structural defects in the skull
D. Laxity of transverse atlantal ligament (e.g., Down syn-
drome) base and cerebellum in 1883. Hans Chiari classified the malformations
II. Acquired into four types in 1891. Julius Arnold further expanded the definition
A. Traumatic, acute or chronic un-united dens fracture of Chiari II malformations in 1894. In current usage, the terms Arnold-
B. Infectious Chiari and Chiari malformations are often used interchangeably for all
C. Neoplastic (e.g., neurofibroma) four types. Chiari malformations II, III, IV are discussed in the section
D. Arthritic (e.g., rheumatoid arthritis, ankylosing spondylitis, on Spinal Dysraphism. In addition to the four classic types of Chiari
renal amyloidosis) malformations, several subtypes not in common use have been added:
E. Bone disease (e.g., vitamin D-resistant rickets and others The Chiari 0 malformation and the Chiari 1.5 malformation (similar
associated with basilar invagination) to CM-II, but without a cervical syrinx) (Schijman, 2004; Tubbs et al.,
2001).
Chiari I malformation (CM-I) (Fig. 104.6), the most common type,
is characterized by abnormally shaped cerebellar tonsils with resultant
A B
C D
Fig. 104.6 A, Sagittal magnetic resonance imaging (MRI) scan of a patient with Arnold-Chiari type I malfor-
mation. Midline T1-weighted image demonstrates low cerebellar tonsils, 8 mm below foramen magnum. B,
MRI cerebrospinal fluid (CSF) flow study of same patient demonstrates diminished flow signal at cerebellar
tonsils, indicative of CSF flow propagation abnormality. Note normal CSF flow signal below tonsils and ante-
rior to brainstem. C, Sagittal MRI of a patient with low-lying cerebellar tonsils at 6 mm below foramen mag-
num. D, CSF flow study demonstrating normal flow signal at level of cerebellar tonsils, indicative of normal
propagation of CSF flow through foramen magnum.
TABLE 104.2 Summary of Posterior Cranial Fossa Morphology in Patients With Chiari
Malformations
Occipital Bone Size PCFV FM
CM-I/classic type Small Small Small
CM-I/craniosynostosis Small Small Small
CM-II/with myelodysplasia Small Small Large
CM-I/tethered cord syndrome Normal Normal Large
CM-I/cranial settling Normal Normal Normal
CM-I/intracranial space-occupying Normal Normal Normal
lesions
CM-I/lumboperitoneal shunt Normal Normal Normal
CM-I, Chiari malformation type I; CM-II, Chiari malformation type II; FM, foramen magnum; PCFV, posterior cranial fossa volume.
Adapted with permission from Milhorat, T.H., Nishikawa, M., Kula, R.W., et al., 2010. Mechanisms of cerebellar tonsil herniation in patients with
Chiari malformations as guide to clinical management. Acta Neurochir. (Wien) 152, 1117–1127.
A B C
D E F
Fig. 104.7 Morphometric Assessments of Foramen Magnum at Level of Superior Outlet Using Axial
Computed Tomography Images. A, Normal foramen magnum in 10-month-old male showing patent
basi-exoccipital (small arrows) and exosupraoccipital synchondroses (large arrows). B, Normal foramen mag-
num in 30-year-old female. C, Abnormally small foramen magnum in 28-year-old female with classical Chiari
I malformation (CM-I). D, Abnormally small foramen magnum in 25-year-old female with CM-I and craniosyn-
ostosis (Crouzon syndrome). E, Abnormally large foramen magnum in 27-year-old female with CM-I and teth-
ered cord syndrome. F, Abnormally large foramen magnum in 17-year-old male with CM-II. (From Milhorat,
T.H., Nishikawa, M., Kula, R.W., et al., 2010. Mechanisms of cerebellar tonsil herniation in patients with
Chiari malformations as guide to clinical management. Acta Neurochir. [Wien] 152, 1117–1127.)
tonsillar herniation through the foramen magnum (5 mm or more in fossa with clinical findings in 752 patients with Chiari malformations
young adults); this definition is anatomically precise, but can be con- (Milhorat et al., 2010; Table 104.2).
fusing because there are many causes of abnormal tonsillar herniation Patients with classic CM-I have a small posterior cranial fossa with
that are not Chiari malformations. Classic CM-I is a congenital meso- constriction increasing below the Twining’s line, which extends from
dermal malformation resulting in a hypoplastic posterior fossa, com- the anterior tuberculum sellae to the internal occipital protuberance.
pressing neural tissue and forcing the cerebellar tonsils down through The foramen magnum is constricted transversely and has reduced outlet
the foramen magnum. Distinguishing classic CM-I from other mech- area (Fig. 104.7). These findings suggest premature stenosis of the basi-
anisms of tonsillar herniation clarifies treatment despite overlapping exoccipital and exosupraoccipital synchondroses (see Fig. 104.7, A)
clinical features (Milhorat et al., 2010). Other potential disorders which, if normal, would permit lateral expansion of the foramen mag-
causing tonsillar herniation that are unrelated to skull-base hypopla- num during somatic growth. Failure of the foramen magnum to expand
sia include hydrocephalus, intracranial mass lesions, CSF leaks, pro- normally during development may explain the conical shape of the
longed lumboperitoneal shunting, hereditary disorders of connective posterior fossa in CM-I. Patients with achondroplasia can also have a
tissue associated with occipitoatlantoaxial joint instability and cra- stenosed foramen magnum and small posterior fossa, but the posterior
nial settling, tethered cord syndrome, and miscellaneous conditions fossa constriction is more generalized than in classic CM-I, suggesting an
such as craniosynostosis, acromegaly, and Paget disease. Milhorat additional pathogenic mechanism in achondroplasia. Crouzon syndrome
and colleagues have correlated measurements of the posterior cranial (see Fig. 104.7, D), Apert syndrome, nonsyndromic craniosynostosis,
TABLE 104.3 Mechanisms of Cerebellar Tonsil Herniation

Cranial Constriction Spinal Cord Tethering Cranial Settling Intracranial Intraspinal Hypotension
Hypertension
“Squeeze down” “Pull down” “Shake down” “Push down” “Suck down”
CM-I Tethered cord syndrome HDCT (e.g., EDS) Hydrocephalus Prolonged LPS
Craniosynostosis CM-II Posttraumatic CCI Posterior fossa cysts, tumors CSF leaks
Achondroplasia Osteogenesis imperfecta Subdural hematoma Dural ectasia
Acromegaly Intracranial mass lesions
Paget disease
CCI, Craniocervical instability; CM, Chiari malformation; CSF, cerebrospinal fluid; EDS, Ehlers-Danlos syndrome; HDCT, hereditary disorders of con-
nective tissue; LPS, lumbar peritoneal shunt.
Adapted with permission from Milhorat, T.H., Nishikawa, M., Kula, R.W., et al., 2010. Mechanisms of cerebellar tonsil herniation in patients with
Chiari malformations as guide to clinical management. Acta Neurochir. (Wien) 152, 1117–1127.
patients with hydrocephalus or intracranial mass lesions, raised intracra-

TABLE 104.4 Symptoms of Chiari I
nial pressure causes compartmental shifts that push the brain caudally.
Malformation In patients with occipitoatlantoaxial joint instability, cranial settling is
Symptom % of CM-I Patients (364) the main cause of the herniation. In patients undergoing prolonged lum-
Suboccipital headache (frequent retro- 81 boperitoneal shunting, overdrainage of CSF apparently creates a pres-
orbital component); exertional and sure differential between the cranial and spinal compartments, drawing
postural accentuation cerebellar tonsils downward. When the drainage is stopped, the pressure
Ocular disturbances: floaters, blurring, 78 gradient can resolve, and the herniation often reverses. Low spinal fluid
photophobia, diplopia pressure can also cause tonsillar herniation in patients with spinal CSF
Acoustic and vestibular complaints: dizzi- 74 leaks, dural ectasias, and myelodysplasia. Table 104.3 outlines five dis-
ness/dysequilibrium, tinnitus tinct mechanisms of cerebellar tonsil herniation; each mechanism has its
Dysesthesias: tenderness, numbness/tin- 59 own diagnostic and therapeutic implications.
gling, burning Measurements of the posterior cranial fossa enhance neuroradio-
Chronic fatigue 58 logical diagnosis of Chiari malformations. Computer analysis of stan-
Bulbar and coordinative problems: 52 dard MR and CT images is quick and easy. Diagnosis starts by assessing
• Dysphagia/dysarthria, sleep apnea the size of the posterior fossa; an abnormally small posterior fossa shows
• Palpitations (23 points with paroxysmal that the CM-I is likely due to cranial constriction. A normal-sized pos-
atrial tachycardia) terior fossa necessitates a search for alternative mechanisms of tonsillar
• Tremors, clumsiness herniation such as cranial settling, spinal cord tethering, raised intra-
Segmental pain 44 cranial pressure, or intraspinal hypotension. Measurement of the fora-
Impaired memory or concentration 39 men magnum helps in the differential diagnosis of tonsillar herniation
Cervical pain 34 because the foramen is enlarged in tethered cord syndrome and Chiari
Low back pain 24 malformation II but stenosed in classic CM-I, craniosynostosis, and
Urinary incontinence 17 miscellaneous disorders such as achondroplasia.
From Milhorat, T.M., Chou, M.W., Trinidad, E.M., et al., 1999. Chiari I Clinical Presentation
malformation redefined: clinical and radiographic findings in 364 symp- Tonsillar herniation, once considered rare, is now easily recognized on
tomatic patients. Neurosurgery 44, 1005–1017. sagittal brain MRI and has a prevalence of 0.1%–0.5% (Speer et al.,
2003). New genetic studies support a hereditary tendency, with a trans-
achondroplasia, acromegaly, and Paget disease are other causes of a small missibility rate approaching 12%. Women are affected three times
posterior fossa. In each of these conditions, the constricting small poste- more often than men.
rior fossa is the apparent cause of cerebellar tonsillar herniation. Patients with CM-I may experience no symptoms or first
Some patients have a small posterior fossa with the conical configu- have symptoms in adolescence or early adulthood (Meadows
ration typical of classic CM-I, but do not have tonsillar herniation; this et al., 2000; Table 104.4). At least a quarter of patients first have
has been called Chiari 0 malformation. This designation remains con- symptoms following relatively minor head or neck injury. Most
troversial. It is thought that these patients can have symptoms similar symptomatic patients have pressing occipital headache and neck
to CM-I secondary to abnormalities in the flow of CSF within the skull pain. Other manifestations can include visual disturbances, neuro-
and spinal canal (Schijman, 2004; Tubbs et al., 2001). otological complaints, cranial nerve dysfunction, cognitive dif-
When patients with CM-I have other abnormalities such as hydro- ficulties, and sleep-related breathing disorders (Milhorat et al.,
cephalus, basilar impression, occipitalization of the atlas, retroflexed 1999). Patients with CM-I often have associated syringomyelia
odontoid processes, elongated styloid processes, or C1-level spina bifida (discussed later), but motor, sensory, sphincter, and reflex distur-
occulta, the mechanism of the tonsillar herniation varies. In contrast to bances suggestive of myelopathy can occur whether or not a syrinx
CM-I, patients with tonsillar herniation due to hydrocephalus, intracra- is present. Clinical severity correlates generally but not perfectly
nial mass lesions, occipitoatlantoaxial joint instability, or prolonged lum- with the extent of tonsillar herniation and the degree of obstruc-
boperitoneal shunting have normal occipital bone size, posterior cranial tion to CSF flow. In more severe cases, the medulla descends below
fossa volume, and foramen magnum size; in these conditions, mecha- the foramen magnum; in which case brainstem dysfunction is
nisms other than a small posterior fossa cause the tonsillar herniation. In more likely to be among the clinical findings (Yamada et al., 2004).
TABLE 104.5 Suggested Upper Limits at the foramen magnum can be evaluated using phase-contrast MRI
and cardiac gating to acquire images throughout the cardiac cycle
of Normal for Position of Cerebellar Tonsils
(Clarke et al., 2013). Symptomatic Chiari I malformations can cause
Below Foramen Magnum an increase in peak systolic CSF flow velocity and decreased uniformity
Decade of Life Distance Below Foramen Magnum (mm) of flow.
First 6
Management
Second or third 5
Fourth to eighth 4
The severity and nature of symptoms of CM-I vary greatly, so natu-
Ninth 3
rally therapy should also vary from patient to patient. The minority of
patients require surgery. Headache symptoms sometimes respond to
Data used with permission from Mikulis, D.J., Diaz, O., Egglin, T.K., carbonic anhydrase inhibitors, simple approaches to associated para-
et al., 1992. Variance of the position of the cerebellar tonsils with age: cervical pain, or head elevation during sleep. Minor traumatic events
preliminary report. Radiology 183, 725–728. can aggravate symptoms, and patients should avoid activities that risk
head and neck injury.
Deciding whether common symptoms such as memory concerns, Management of labor and delivery in patients with CM-I is some-
back pain, or fatigue are caused by CM-I in an individual patient is a what controversial. Although avoiding epidural or spinal anesthesia
clinical challenge. Despite speculation and public interest, there is no has been recommended by some, there is a literature suggesting these
scientific confirmation of an association between CM-I and fibromyal- techniques can be employed safely in CM-I parturients for vaginal or
gia or chronic fatigue syndrome (Garland and Robertson, 2001). cesarean deliveries (Leffert et al., 2013). For women with syringomy-
Slight extension of the tonsils below the foramen is normal in child- elia, a cesarean section is advisable to avoid intrathoracic and abdom-
hood, and normal values decrease with increasing age (Table 104.5). inal pressure alterations associated with vaginal deliveries (Chntigian
When young children have symptoms, they can have oropharyngeal et al., 2002). Surgical decompression of the posterior fossa is appropri-
dysfunction and scoliosis. Children younger than age 3 can have vom- ate treatment for the minority of patients who have significant func-
iting and gastric reflux as the sole symptoms of CM-I. tional impairment due to persistent headache despite medical therapy
The posterior fossa or “Chiari” headache has diagnostically helpful or have progressive syringomyelia. It is not indicated for symptoms
characteristics: it is a suboccipital pressing head pain that is usually limited to chronic fatigue, musculoskeletal pain, or vertigo, or for
continuous, waxing and waning but not episodic, and radiating at prophylaxis against worsening of headache or of syringomyelia. Kula
times behind the eyes or to the vertex (Kula, 2006). The headache is (2006) discusses treatment in detail and provides a comprehensive
almost never hemicranial and is often exaggerated by physical activity management algorithm.
and Valsalva maneuvers including bearing down with bowel move-
ments, with laughter, crying, coughing, and sneezing. Exacerbations
SPINAL DYSRAPHISM
can be explosive rather than throbbing or pounding. There is no aura,
but visual sparkles and scotomas can punctuate the peaks of headache. Spinal dysraphism is congenital failure of the primitive neural tube to
Neck pain without radicular features is common. Patients may have close during fetal development and includes a number of disorders of
evanescent hand paresthesias and other generalized musculoskeletal fusion of dorsal midline structures of the spinal canal or skull (Copp
complaints. et al., 2013). Neural tube defects are one of the most common congenital
CM-I patients with “Chiari” headaches and little else may coinci- malformations, with 70,000–100,000 disabled individuals in the United
dently have migraine without aura, which can result in a diagnostic States alone (Blencowe, 2018). The neural tube normally closes during
dilemma. Both headaches occasionally can share some similar features the first 3 weeks following conception. There are genetic causes, but
such as occipital location and perimenstrual accentuation. “Chiari” environmental causes are important in most cases. The most extreme
headaches are not likely to respond to migraine abortive agents such as form is anencephaly, characterized by absence of the entire cranium at
the triptans or prophylactic agents including beta-blockers and sero- birth; the undeveloped brain lies at the base of the skull as a small vascu-
tonin reuptake inhibitors (SRIs). However, “Chiari” headaches like lar mass without recognizable nervous structures.
migraine may respond to topiramate, presumably because it is a car-
bonic anhydrase inhibitor and lowers CSF pressure. Patients may have Spina Bifida Occulta
tonsillar herniation on MRI and not yet have any CM-I–related symp- Spina bifida occulta is the most common and least symptomatic (usu-
toms. However, these patients can have migraine. It is therefore import- ally asymptomatic) form of dysraphism. In this anomaly, the vertebral
ant to first rule out migraine as a cause of headache before aggressively elements fail to fuse posteriorly, but the thecal and neural elements
treating a CM-I malformation. This is even more important in those remain within the spinal canal. It is most common at posterior ele-
patients diagnosed with Chiari 0. Neurological examination of patients ments of L5–S1 and is usually noted as an incidental finding on spi-
with CM-I may show subtle abnormalities but is often completely nor- nal plain radiography (eFig. 104.8). Cutaneous abnormalities may be
mal. The most typical finding is a vestibular-generated dysequilibrium associated (Box 104.4). Orthopedic foot deformities, urinary or rectal
and difficulty in tandem standing and walking. Nystagmus is difficult sphincter dysfunction, or focal neurological abnormalities can indicate
to appreciate even with Fresnel lens examination. Objective findings that the spina bifida occulta is associated with compression or malfor-
frequently elude sophisticated vestibular testing, which only occasion- mation of neural tissues or with spinal cord tethering.
ally reveals nystagmus of possible central or peripheral etiology. Classic
downbeat nystagmus is rarely seen even with tonsillar herniation as
striking as 20 mm. Myelomeningocele and Encephalocele
The malformation is best seen on a T2-weighted sagittal MRI scan In myelomeningocele (spina bifida) and meningocele (spina bifida
of the brain and cervical spine, which allows for assessment of the cystica), congenital defects of midline closure are accompanied by
shape of the posterior fossa and may detect an accompanying syrinx eventration of meninges and even of neural tissue. Spinal defects are
as well as the extent (if any) of brainstem compression. Flow of CSF often visible on examination of the back of the newborn (eFig. 104.9,
eFig. 104.9 Sagittal T1-weighted magnetic resonance image demon-

strates several findings: low-lying conus medullaris, lipomas of filum
terminale (bright signals within central canal), and spina bifida with pro-
truding lipomyelomeningocele through the defect (arrowheads).
eFig. 104.8 Lumbar Spine Radiograph Shows Spina Bifida Occulta.
BOX 104.4 Dorsal Midline Skin Findings

Associated With Spina Bifida Occulta
Asymmetrical gluteal fold
Dermal sinus or dimple
Hairy tuft
Cord
Hemangioma
Lipoma
Nevus
Pilonidal sinus
Rudimentary tail
Spinal aplasia cutis
Figs. 104.10 and 104.11). At times the skin and vertebral canal are
open, and a sac of meninges is directly visible. The defect is most
common in the lumbar region. If the sac contains nerve roots or spi-
nal cord, it is a myelomeningocele; if neural elements are absent from Roots
the sac, it is a meningocele. These brain and spinal cord malforma-
tions may be associated with CSF leakage into adjacent structures,
posing a risk of meningitis. Neurological deficits are directly related
to the anatomical extent of the malformation and vary from insignif-
icant to grave.
Either defect is often accompanied by hydrocephalus or by Chiari Fig. 104.10 Diagrammatical Representation of Myelomeningocele.
II malformation, in which the cerebellar vermis and caudal brainstem
descend through an enlarged foramen magnum (Stevenson, 2004;
Tubbs and Oakes, 2004). The extent of brainstem herniation is variable,
including portions of the medulla or even of the pons. Hydrocephalus
and syringomyelia are common accompanying features, and patients
often have various associated anomalies such as a small posterior fossa,
kink in the medulla, and polymicrogyria. These infants are at risk for
later development of tethered cord syndrome, spinal dermoid, and
epidermoid inclusion cysts. In Chiari III malformation, the displaced
cerebellar and brainstem tissue extends into an infratentorial menin-
goencephalocele. An important cause is maternal folate deficiency, and
most cases could be prevented if women with childbearing potential
routinely took folic acid daily. Other risk factors include family history
of neural closure defects and maternal treatment with some antiepilep-
tic drugs such as valproic acid and carbamazepine. Pregnant women
can be screened at 14–16 weeks for serum α-fetoprotein (AFP) levels,
which are elevated about 85% of the time when the fetus has neural
closure defects. The defects also can be detected by fetal ultrasonog-
raphy. Ultrasound detects greater than 90% of neural tube defects at
18–20 weeks (coupled with AFP >95%).
Planning treatment for affected infants, potentially including sur-
gery, is difficult. Initial surgical treatment in utero or in the neonatal
period can provide cosmetic repair and decrease the risk for meningi-
tis (Adzick, 2011). Also hydrocephalus can be shunted. Any existing
myelopathic or radiculopathic neurological deficit is likely to persist
after surgery. Some patients, especially infants with progressive brain- Fig. 104.11 Diagrammatical Representation of Meningocele.
stem dysfunction, are treated with decompression of the rostral spinal
canal. Less than 30% of such patients survive beyond the first year, and upward. The cerebellar vermis is aplastic, and the corpus callosum may
long-term problems including mental retardation and paraplegia are be deficient or absent. There is usually dilation of the aqueduct as well
often severe. Few patients with myelomeningocele are mentally nor- as the third and lateral ventricles. Chiari IV malformation is character-
mal, but most of those with lumbar meningocele are. ized by cerebellar and brainstem hypoplasia rather than displacement
and is probably a variant of the Dandy-Walker malformation.
Dandy-Walker Syndrome
Dandy-Walker syndrome results from the failure of development of Tethered Cord Syndromes
the midline portion of the cerebellum. A cyst-like structure associ- Congenital abnormalities of the spinal cord or cauda equina can result
ated with a greatly dilated fourth ventricle, expanding the midline, is in spinal cord tethering, in which stretching and tension develops within
often seen (Fig. 104.12). The malformation typically causes the occip- the cord tissue as the spinal column elongates during early life, result-
ital bone to bulge posteriorly and displaces the tentorium and torcula ing in the conus medullaris being found at an abnormally low vertebral
A B
Fig. 104.12 Dandy-Walker Malformation. A, T2-weighted magnetic resonance imaging (MRI). B,
T1-weighted MRI. (Courtesy Michael Coffee, MD.)
BOX 104.5 Causes of Tethered Spinal Cord medullaris appear normal on MRI. A few cases of cerebellar tonsillar her-
niation seem to be due to occult cord tethering; other features are syrinx
Primary Causes development below the T5 level and scoliosis (Milhorat et al., 2009). In
Dermal sinus tract contrast to patients with classic CM-I, patients with this variation of CM-I
Diastematomyelia with cord tethering have normal posterior fossa volume and an enlarged
Dural bands foramen magnum. Supporting the role of cord tethering as a cause of the
Intraspinal lipoma or tumor tonsillar descent are reports of increasing herniation of the cerebellar ton-
Meningocele, myelomeningocele, anterior sacral meningocele sils with somatic growth, cerebellar prolapse following Chiari decompres-
Neuroenteric cyst sion surgery, and anatomical improvements including ascent of the conus
Sacral agenesis medullaris, ascent of the cerebellar tonsils, and resolution of brainstem
Tight filum terminale elongation following section of the filum terminale.
Split spinal cord malformation (SSCM), formally termed diastem-
Secondary Causes atomyelia, is a congenital malformation of the spinal cord character-
Arachnoiditis ized by sagittal division of a portion of the cord into two hemicords.
Dermoid In most instances, the division is located in the lower thoracic or
Re-tethered spinal cord lumbar regions. SSCM is often accompanied by skin abnormalities
Suture granuloma such as a tuft of hair at the level of the lesion. Two types of SSCM are
Trauma described: type I, in which each hemicord has its own dural sheath, and
Adapted with permission from McLone, D.G., La Marca, F., 1997. The type II in which both hemicords are enclosed in a single dural sheath.
tethered spinal cord: diagnosis, significance, and management. Semin. Neurological deficits, scoliosis, and congenital foot deformities are
Pediatr. Neurol. 4, 192–208. more common in type I. Bony and cartilaginous spurs between the
hemicords are also more common with type I. Finally, surgical repair
level (Michelson and Ashwal, 2004; Box 104.5). Imaging studies, such as is more effective in type I and can be combined with distal untethering
spinal MRI, showing the conus medullaris caudad to the lower endplate if a tethered cord is present as well. The spur tethers the spinal cord,
of L2, can be evidence of tethering. A child or even an adult with these leading to progressive neurological dysfunction when the vertebral col-
abnormalities can develop progressive neurological dysfunction due to umn lengthens during growth. The diagnosis can often be suspected
traction on the cord or nerve roots. One presentation is lower motor neu- on plain radiography, which shows widening of the interpedicular
ron dysfunction in one or both lower extremities, but patients can also distance and a posterior bony bridge at the level of the lesion. MRI
have sensory loss, upper motor neuron signs, orthopedic foot deformi- or CT myelography can confirm the diagnosis (eFig. 104.13). Surgical
ties, and scoliosis. A tethered spinal cord can, in addition, cause isolated therapy consists of attempts to free all structures tethering the cord by
sphincter dysfunction as subtle as intermittent urinary incontinence. removing the spurs and dura in the cleft and cutting the filum termi-
The so-called occult tethered cord syndrome is an area of controversy nale if abnormally tethered.
(Drake, 2006; Selden, 2006). Uncontrolled surgical series suggest that chil-
dren with neurogenic voiding dysfunction and normal spinal MRI might
also have cord tethering. For some children, voiding dysfunction reportedly
SYRINGOMYELIA AND SYRINGOBULBIA
improved after lysis of the filum terminale, which microscopically can be Hydromyelia is an abnormal dilation of the central spinal canal with
abnormally thickened, fatty, and fibrous, even though the filum and conus “excess” CSF contained within the ependymal lining. When fluid
C
eFig. 104.13 Magnetic Resonance Images of Diastematomyelia. A,
Patient 1: Sagittal T1-weighted image shows severe scoliosis and divi-
sion of spinal cord into right (arrow) and left (curved arrow) hemicords.
Patient 2: Axial T1-weighted image (B) and axial T2-weighted image (C)
show two separate hemicords. (A, Courtesy Erik Gaensler.)
Fig. 104.14 Diagrammatic representation of persistent central canal

extending throughout length of spinal cord.
dissects into the surrounding white matter, forming a cystic cavity or

syrinx, the term syringomyelia is applied. A syrinx, then, is a cavity in
the spinal cord (syringomyelia) or brainstem (syringobulbia) (Figs.
104.14, 104.15, and 104.16). Hydromyelia and syringomyelia often
coexist, and many physicians use the terms interchangeably.
The widespread use of spinal MRI has greatly increased the detec- B
tion of cervical syringomyelia, which often produces nonspecific symp-
Fig. 104.15 A, Sagittal T2-weighted magnetic resonance imaging
toms such as neck pain and at times no symptoms at all. Estimated
demonstrates intramedullary signal abnormality posterior to T1–T3
prevalence in the United States is between 1:1300 and 1:1900.
level of spinal cord. Possible causes include edema, myelomalacia, or
The central canal of the spinal cord is normally wide open during syringomyelia. B, Axial computed tomographic myelogram performed
embryonic life and becomes atretic after birth. It is occasionally patent at a 3-hour delay demonstrates filling of area of signal abnormality with
in adults (see Fig. 104.14). Cervical or thoracic MRI in an adult will myelographic contrast that had been injected into lumbar subarachnoid
occasionally reveal an incidental asymptomatic hydromyelia, which is space. Filling of cavity with contrast is consistent with syringomyelia
typically linear or fusiform on sagittal images; extends over several lev- but would not be expected in cases of cord edema or myelomalacia.
els, sometimes discontinuously; and is round, central, and up to 4 mm
in diameter on axial images (Batzdorf, 2005). I malformation. Symptoms are more related to the pace of evolution of
the syrinx than to its absolute size. Otherwise healthy patients with slit-
Clinical Presentation like syrinx cavities may present with severe localized spinal and radicu-
The prototypical presentation of a symptomatic syrinx is the presence lar pain. Other patients with syrinx cavities displacing as much as 90%
of lower motor neuron signs at the level of the lesion, usually in the of the spinal cord mass may be virtually asymptomatic.
upper extremities, or in the case of syringobulbia, the lower cranial Pain is a prominent symptom in most patients with syringomyelia.
nerves. Furthermore, it can present as a myeloradiculopathy with lower Common complaints include neck ache, headache, back pain, radicular
motor neuron findings in the upper extremities and upper motor neu- pain, and areas of segmental dysesthesia. Painful dysesthesias are most
ron findings in the lower extremities. In addition, there is often a dis- likely to occur at or adjacent to the caudal extent of the syrinx cavity.
sociated, suspended sensory loss with impaired pain and temperature Some patients have trophic changes corresponding to segmental loss
sensation, but preserved dorsal column sensation (i.e., light touch). of pain sensation. Syringomyelia can cause neuropathic monoarthritis
However, few patients show this total picture. The clinical features (Charcot joint), most commonly in a shoulder or elbow.
vary with the size, location, and shape of the cavity; the rapidity of its Most syringes are in the cervical spinal cord. Those developing from
evolution; and any associated neurological conditions such as a Chiari hydromyelia are usually associated with Chiari I or II malformations,
In CM-I, the large majority (80%) occur within the cervical cord.
The thoracic cord can, however, be affected in isolation, and, more
rarely, a lumbosacral syrinx may appear associated with spinal cord
tethering secondary to a thickened and restrictive filum terminale.
Syrinx Associated With Spinal Cord Tumors

Syringes are associated with intramedullary tumors often enough
that any cystic process in the spinal cord should be considered
an intramedullary tumor until proven otherwise. Syringomyelia
accompanies 25%–60% of intramedullary spinal tumors; con-
versely, 8%–16% of syringes are caused by tumors (eFig. 104.17).
Intramedullary tumors in von Hippel-Lindau syndrome and
neurofibromatosis are particularly likely to be accompanied by
syringes. The syrinx extends from the tumor, more often rostrally
than caudally. Ependymomas, which represent up to 10% of child-
hood CNS tumors and affect adults as well, are particularly likely
to produce syringes because of their central location. Less than 2%
of extramedullary tumors in the spinal canal (e.g., meningiomas,
neuromas) are associated with syringes.
Fig. 104.16 Magnetic resonance image demonstrates a large syringo- Syrinx Associated With Spinal Cord Trauma
myelic cavity in the cervical cord.
Syringes can develop as a late effect of serious spinal cord trauma
(Carroll and Brackenridge, 2005). Estimates of the prevalence of
communicating hydrocephalus, or abnormalities at the cranioverte- syringes after trauma vary widely from 0.2% to 64%. However,
bral junction. Asymptomatic hydromyelia and syringomyelia may be delayed progressive intramedullary cystic lesions complicates 3%–4%
incidentally discovered by MRI while investigating unrelated cranial of dramatic spinal cord injuries. Symptoms of ascending long-tract
symptomatology, such as a Chiari malformation. A syrinx associated or segmental spinal cord dysfunction usually develop within 5 years
with a spinal cord tumor or trauma can occur at any level of the spinal after the acute traumatic myelopathy has stabilized, improved, or
cord. Although either CT or MRI can demonstrate a syrinx, MRI is even become asymptomatic. Pain or other sensory symptoms are
more sensitive for complete evaluation of the cord and surrounding often prominent. Findings usually evolve gradually but occasionally
soft tissues. In patients in whom MRI is contraindicated, CT myelogra- worsen suddenly after events such as a cough or Valsalva maneuver.
phy may be useful in discerning syringomyelia, which will commonly The cavities are typically eccentric and can be multiple, arising from
fill with contrast on delayed images due to communication with the areas of posttraumatic myelomalacia and then spreading rostrally or
CSF through the central canal of the spinal cord (see Fig. 104.15). caudally. Severe posttraumatic spinal deformity or arachnoid scarring
can also cause posttraumatic syringes.
Communicating and Noncommunicating Syringes
The terms communicating and noncommunicating syringes indicate Syrinx Associated With Other Focal Spinal Cord
whether the syrinx is in communication with the CSF pathways. Pathologies
However, it is often difficult to determine this, even at autopsy, so Any illness causing arachnoiditis can lead to formation of a noncom-
these terms are mainly of use in discussions of etiology. It is better to municating syrinx. Reported causes include meningitis, subarachnoid
classify syringomyelia according to its associations. hemorrhage, spinal trauma, epidural infections, epidural anesthesia,
and spinal surgery, but many cases of focal arachnoiditis are idiopathic.
Abnormalities of the Cervicomedullary Junction Syringes can develop as a complication of various intramedullary
Abnormalities of the cervicomedullary junction and posterior fossa, pathologies, including trauma and tumors (see previous discussion),
such as Chiari anomalies types I and II and the Dandy-Walker mal- spinal ischemic or hemorrhagic strokes, radiation necrosis, or trans-
formation, are the most common cause of nonidiopathic syringes. verse myelitis.
Up to 70% of nonidiopathic syringes are associated with CM-I.
The mechanism of formation of these syringes is controversial (Di Treatment
Lorenzo and Cacciola, 2005). Patients with cervical syringomyelia Indications for and approaches to surgical therapy for syringes are far
and no Chiari malformation often have a small posterior fossa or from standardized. In patients with Chiari I malformations, the syrinx
disturbed flow of CSF near the foramen magnum (Bogdanov et al., often improves after decompression of the malformation with various
2004). Syringes can extend beyond hydromyelia as an outpouch- combinations of suboccipital craniectomy, upper cervical laminec-
ing of the dilated central canal (see Figs. 104.15 and 104.16). One tomy, and/or dural grafting. The exact surgical technique is debated,
hypothesis is that the posterior fossa abnormalities interfere with and remains controversial, but it is agreed that the goal is adequate
the passage of CSF from the fourth ventricle through the foramina restoration of normal CSF flow and pressure across the craniocervical
of Luschka and Magendie into the subarachnoid space. The conse- junction. Two recent meta-analyses have both concluded that adding a
quence is transmission of bulk flow and the various pressure waves of duraplasty to posterior fossa decompression results in improvement in
the CSF (arterial, venous, respiratory) down the central canal of the syringomyelia, but is associated with higher rates of CSF leak and asep-
spinal cord, leading to dissection of a syrinx into the substance of the tic meningitis (Chai, 2018; Lin, 2018). Concerningly, another recent
spinal cord. Noncongenital abnormalities at the cervicomedullary study has concluded that 50% of patients treated with posterior fossa
junction that sometimes cause syringomyelia include arachnoiditis decompression will require an additional surgery for persistent, pro-
and meningiomas. gressive, and/or recurrent syringomyelia (Soleman et al., 2019). When
B
eFig. 104.17 Magnetic Resonance Image Demonstrates Syrinx
Associated With Spinal Cord Tumor (Hemangioblastoma). A,
T1-weighted image shows a nodule in upper cervical cord and a low-sig-
nal central mass suggestive of a cyst. B, Postgadolinium image shows
that nodule intensely enhances, which is classic for hemangioblastoma.
(Courtesy Erik Gaensler.)
the syrinx extends from an intramedullary tumor, resection of the

tumor usually leads to regression of the syrinx, so no specific surgical
drainage of the cavity is needed. When the syrinx extends from an area
of localized arachnoiditis or other obstruction of the subarachnoid
space, some patients benefit from resection of the arachnoiditis and
restoration of CSF flow patterns with an expansile duraplasty; shunt-
ing or entering the cavity (syringotomy) is a less desirable surgical
approach (Batzdorf, 2005). In patients with Chiari I malformation and
syrinx, pain and other sensory symptoms are more likely to improve
if the foramen magnum is decompressed within 2 years of onset of
the sensory symptoms (Attal et al., 2004). Among patients undergoing
surgery for syrinx in the absence of Chiari malformation, slightly more
than half improved or stabilized, but over a third required more than
one operation (Batzdorf, 2005).
Clinical Correlations
A single patient often has more than one of the conditions discussed
(Williams, 1991). Thus, a patient with one of the Chiari hindbrain mal-
formations also may have some combination of bony abnormalities of
the foramen magnum or cervical spine, syringomyelia, and myelome-
ningocele. The clinical manifestations of craniocervical deformities are
protean depending on which neural structures and associated anom-
Fig. 104.18 Spinal magnetic resonance image of a patient with ver-
alies are involved. When a patient has these problems, diagnosis and
tebral compression fracture secondary to osteoporosis. T1-weighted
treatment starts by analyzing each component. MRI and CT scans, images of lumbar spine show 70%–80% loss of height of midportion of
especially with measurements of the foramen magnum and poste- L1 vertebral body, with relative preservation of height of posterior por-
rior fossa, have greatly eased the analytical process. Many patients are tion of vertebral body. Bright appearance of vertebra indicates preserva-
asymptomatic or first present with neurological complaints in adult tion of fat within marrow compartment, which would be dark if replaced
life. Patients may have short necks or abnormal neck posture or move- by tumor. (Courtesy Erik Gaensler.)
ment, particularly if there is an element of skeletal deformity (e.g.,
Klippel-Feil anomaly, occipitalization of the atlas). Findings attribut- by loss of spinal range of motion. Pain increases with activity, decreases
able to the brainstem or cerebellum may occur with Chiari malforma- with bed rest, and resolves slowly, though sometimes incompletely.
tions, compression of the brainstem (e.g., basilar impression, vertical Patients with more disabling pain can be management challenges,
displacement of the dens), or syringobulbia. Uncommonly, AA dis- sometimes requiring hospitalization. Initial management includes
ease or basilar invagination can cause compromise of vertebrobasilar activity modification and pain control utilizing analgesics rang-
circulation, causing posterior circulation strokes or transient ischemic ing from nonsteroidal antiinflammatory drugs (NSAIDs) to opioids
attacks. Specific findings suggestive of disease at the foramen magnum depending on the severity of the pain. Bracing for a short period of
include downbeat nystagmus or the combination of long-tract signs time in the acute phase may prove helpful. For patients not respond-
with lower motor neuron dysfunction in the lower cervical spinal cord; ing to conservative treatments a vertebral augmentation procedure
lower motor neuron dysfunction has been attributed to impaired spi- (vertebroplasty or kyphoplasty) may be considered. While contro-
nal venous drainage at the foramen magnum. versy continues regarding the overall efficacy of these procedures for
Spinal cord syndromes can be caused by syringomyelia or by extra- pain management and which procedure should be utilized for a given
medullary cord compression (e.g., by the dens with AA dislocation, patient, there is some consensus that when administered to properly
by spinal stenosis in Klippel-Feil anomaly). Additional neurological selected patients with severe pain within a 6-week period of onset there
dysfunction can occur when the anomalies form part of more wide- can be some reduction in the severity of pain and a shortening of the
spread developmental failure (e.g., lumbar effects of myelomeningo- length of hospitalization (Rodriquez, 2017; Chandra, 2018). Once pain
cele in Chiari II malformation, accompanying cerebral malformations is controlled, an exercise program—including aquatic therapy, smok-
in Klippel-Feil anomaly). ing reduction, and, if indicated, reduced alcohol consumption—may
help reduce the risk of subsequent compression fractures.
SPINAL DEFORMITIES AND METABOLIC BONE Nonmetastatic compression fractures infrequently lead to spinal
DISEASE cord or nerve root compression. When a compression fracture accom-
panies a focal neurological compression syndrome, a metastatic verte-
Osteoporosis bral lesion should be considered. MRI features that favor a malignant
Osteoporotic vertebral compression fractures occur most commonly cause of the compression fracture include decreased T1-weighted and
in the thoracic and thoracolumbar spine, especially in postmenopausal increased T2-weighted signal in the vertebral body, with bulging of the
women (Fig. 104.18). By age 75 years, nearly a fourth of women have ver- posterior cortical wall, pedicle involvement, and associated epidural
tebral compression fractures. Although these fractures may lead to kypho- or paravertebral mass. Use of fluorodeoxyglucose positron emission
sis (“dowager hump”) and loss of body height, most are painless. The tomography (FDG-PET)/CT imaging can also be useful in this diagno-
presence of a vertebral fracture in a postmenopausal woman or older man sis (Cho and Chang, 2011).
is a very strong predictor of subsequent fracture risk and an indication for
pharmacological treatment of osteoporosis. In younger men and women, Osteomalacia and Rickets
acute traumatic compression fractures are more likely to be painful. The Osteomalacia and rickets are conditions of deficient bone mineraliza-
pain usually is centered at the level of the compression and accompanied tion. In adulthood, the most common mechanism for the development
of osteomalacia is vitamin D deficiency, either due to dietary restriction,

malabsorption, chronic kidney disease, or lack of sunlight exposure. The
most specific screening test in otherwise normal individuals is a serum
25-hydroxyvitamin D (25[OH]D) level, though additional biochemical
findings may include: low serum calcium, low serum phosphate, elevated
serum alkaline phosphatase, and elevated parathyroid hormone (Kennel
et al., 2010). A technetium (Tc-99m) bone scan can show increased
activity as a result of widespread osteoblast activation. Radiographs may
reveal pseudofractures, bands of decreased bone density along the corti-
cal surface. Long bones are typically more involved than the spine. Spinal
pain, kyphosis, and compression fractures can occur in osteomalacia,
but compression of spinal cord or nerve roots is rare. Basilar impression
can occur in patients with osteomalacia.
Osteomalacia can result in bone pain, fractures, impaired gait,
and muscle cramps. A painful proximal muscle weakness, especially
in the hip girdle, can also occur. The mechanism of this myopathy is
thought to be related to the aforementioned hyperparathyroidism. The
physical examination reveals diminished muscle power, hypotonia, Fig. 104.20 Radiograph of a patient with Paget disease of the skull.
atrophy, and a “waddling” quality in the gait. When there is second- Note thickening of calvaria (white arrows) and bony sclerosis with a
ary hyperparathyroidism with hypercalcemia, tendon reflexes may be cotton-wool appearance (black arrows). Patient has basilar invagination;
brisk. Needle electromyography (EMG) may show small-amplitude, note high position of dens with respect to clivus. (Courtesy Erik Gaens-
short-duration, polyphasic motor units, without electrophysiological ler.)
evidence of active denervation. Muscle biopsy may show type II atro-
phy. Strength can improve after adequate vitamin D replacement. A few families have an autosomal dominant illness, which has now
been characterized as valosin-containing protein (VCP) disease, and
Osteopetrosis includes the triad of inclusion body myositis, frontotemporal demen-
The osteopetroses are a group of rare inherited diseases characterized tia, and Paget disease of bone (Mehta et al., 2013).
by increased bone density due to impaired bone resorption (Jenkins
et al., 2013; eFig. 104.19). Varied genetic defects can cause osteope- Diagnosis
trosis, resulting in three clinical variants: infantile severe autosomal Paget disease usually can be diagnosed by characteristic radio-
recessive, intermediate autosomal recessive, and autosomal dominant. graphic findings of mixed osteolytic and osteoblastic lesions (see
Osteopetrosis of the skull can cause cranial neuropathies (most often Fig. 104.20). Osteolytic activity can cause well-demarcated round
optic neuropathy), basilar impression, hydrocephalus, or syringo- patches of low bone density in the skull (osteogenesis circumscripta).
myelia. Osteopetrosis of the spine can contribute to spinal canal ste- Osteoblastic activity leads to thickening of cortical bone and then to
nosis with secondary compressive myelopathy. Other complications a general increase in bone density, often with distortion of normal
include thrombocytopenia, anemia, osteomyelitis, and fractures. organization.
Some patients can be treated by hematopoietic stem cell transplanta- Although most patients with Paget disease have elevation of serum
tion. Other rare sclerosing bone disorders like progressive diaphyseal bone alkaline phosphatase and markers of bone resorption, focal skel-
dysplasia (Camurati-Engelmann disease) or endosteal hyperostosis etal disease with neurological complications may occur in patients
occasionally have neurological complications (Grond-Ginsbach and without laboratory abnormalities. Alkaline phosphatase levels, when
Debette, 2009). elevated, are helpful not only in making the diagnosis but also in follow-
Very rarely, infants present with both osteopetrosis and infantile ing response to treatment. Evaluation of serum calcium and 25(OH)D
neuraxonal dystrophy and follow a course of neurodegeneration and levels should be completed to exclude other potential causes for the
death in infancy; neuropathology of these children includes neuronal alkaline phosphatase level. Biopsy is often not required but should be
ceroid lipofuscin and eosinophilic axonal spheroids. considered when radiographic findings are atypical. Potential mimics
include blastic lesions from metastatic disease or lytic lesions seen in
Paget Disease multiple myeloma.
Paget disease of the bone (osteitis deformans) is a focal metabolic bone
disease of excessive osteoclastic bony destruction coupled with reac- Cranial Neurological Complications
tive osteoblastic activity (Ralston et al., 2008) (Fig. 104.20). The inci- Neurological complications with cranial involvement are common in
dence increases with age and varies among ethnic groups, with a high Paget disease (Rubin and Levin, 2009). Paget disease of the skull can
incidence (nearly 5%) in elderly Caucasians of Northern European lead to head enlargement. Patients often complain of headache. The
descent. Men are slightly more commonly affected. Paget disease most common focal neurological manifestation is hearing loss. Paget
appears to be caused by a combination of genetic and environmental disease of the cribriform plate can disrupt olfaction. Other cranial
factors, including possible roles of calcium or vitamin D deficiency, mononeuropathies (e.g., optic neuropathy, trigeminal neuralgia, hemi-
toxins, and infections, especially with paramyxovirus. Paget disease is facial spasm) are much less frequent. Perhaps a third of patients with
usually asymptomatic and discovered only because of laboratory or Paget disease of the skull have some degree of basilar invagination, but
radiographic abnormalities. However, it may cause symptoms by bone symptomatic complications such as brainstem or cerebellar compres-
or joint distortion, fractures, compression of neurological tissue by sion, hydrocephalus, or syringomyelia are rare (Raubenheimer et al.,
calcification, hemorrhage, or focal ischemia due to a vascular steal by 2002). Patients with Paget disease of the skull occasionally develop
the metabolically hyperactive bony tissue. Uncommonly, neoplasms, seizures. The pagetic skull is more vulnerable to bleeding from minor
especially osteogenic sarcoma, can develop in pagetic bone. trauma, which can lead to epidural hematoma.
eFig. 104.19 Radiograph of a Patient With Osteopetrosis; Skull Is

Extremely Dense. Radiograph is slightly overexposed; note darkness
of the central areas (arrow). Bone of petrous apex (curved arrow) is
particularly dense. (Courtesy Erik Gaensler.)
Spinal Neurological Complications each patient presenting with scoliosis and myelopathy, an important
Symptomatic Paget disease of the spine occurs most often in the lum- consideration is whether the myelopathy caused, rather than resulted
bar region, where it can cause back pain, monoradiculopathies, or from, the scoliosis.
cauda equina syndrome. The disease may involve adjacent vertebral Patients with congenital scoliosis, unlike those with idiopathic
bodies and the intervening disk space or may cause root compression childhood scoliosis, usually have anomalous vertebrae and may have
by extension from a single vertebral body. The differential diagnosis other associated developmental problems such as Klippel-Feil anomaly
in patients with Paget disease and neurological dysfunction in a single or diastematomyelia. Scoliosis due to skeletal disease (e.g., achondro-
limb includes peripheral nerve entrapment by pagetic bone. plasia) is more likely than idiopathic scoliosis to lead to spinal cord
Paget disease of the spine leading to myelopathy is more often tho- compromise. Myelopathy can result from spinal cord distraction
racic than cervical. A variety of mechanisms are reported, including during treatment of scoliosis with traction or surgery.
extradural extension of pagetic bone, distortion of the spinal canal by Scoliosis can also be caused by various neurological diseases includ-
vertebral compression fractures, spinal epidural hematoma, or sarco- ing cerebral palsy, spinocerebellar degenerations (e.g., Friedreich
matous degeneration leading to epidural tumor. In a small number of ataxia), inherited neuropathies (e.g., Charcot-Marie-Tooth disease),
patients with myelopathy, imaging shows no evident spinal cord com- myelopathies (e.g., syringomyelia), paralytic poliomyelitis, spinal mus-
pression, thus suggesting a vascular steal phenomenon by hypermeta- cular atrophy, dysautonomia (e.g., Riley-Day syndrome), and myopa-
bolic bone in the vertebral body resulting in cord ischemia. In support thies (e.g., Duchenne disease) (Vialle et al., 2013). Excessive curvature
of this hypothesis, drug treatment of Paget disease in these patients can of the spine can also be due to various causes of axial extensor muscles
improve spinal cord function, sometimes within a few days. weakness (Mika et al., 2005) or due to overactivity of abdominal flex-
ors, as can be seen in stiff-person syndrome. Scoliosis is the most com-
Treatment mon skeletal complication of neurofibromatosis type 1. Scoliosis that
Potent nitrogen-containing bisphosphonates (e.g., zoledronic acid, develops in adulthood can often be traced to an underlying cause such
pamidronate, risedronate) are the drugs of choice for treatment of as trauma, osteoporotic fracture, degenerative spondylosis, or ankylos-
Paget disease. Bone resorption decreases within days. Within 1–2 weeks ing spondylitis; it can result in local back pain, nerve root compression,
of treatment, bone pain may improve. Osteoblastic bone formation or spinal canal stenosis.
and falling serum alkaline phosphatase levels occur after 1 or 2 months
of therapy. Some patients experience significant neurological improve- Diffuse Idiopathic Skeletal Hyperostosis
ment after treatment, but improvement is often delayed 1–3 months. Diffuse idiopathic skeletal hyperostosis (DISH) (Forestier disease,
In cases with severe cord compression, surgical decompression is indi- ankylosing hyperostosis) is a syndrome of excessive calcification that
cated, but drug treatment before surgery decreases the risk of operative develops with aging, more often in men than in women. The diagno-
bone hemorrhage. Calcitonin is an alternative treatment for patients sis is made by spinal radiographs that show “flowing” calcifications
unable to take bisphosphonates or who require more immediate sur- along the anterior and lateral portion of at least four contiguous ver-
gery (Wootton et al., 1978). Patients with cranial neuropathy have less tebral bodies, without loss of disk height and without typical radio-
impressive responses to drug therapy. Hydrocephalus can be treated graphic findings of ankylosing spondylitis (eFig. 104.21). Patients
successfully with ventriculoperitoneal shunting (Roohi et al., 2005). are often asymptomatic but may have spinal pain or limited spinal
Additional interventions such as hearing aids, analgesics, physical ther- motion. Large anterior cervical calcifications can contribute to dys-
apy, and orthotics are often required once the excessive bone turnover phagia, hoarseness, sleep apnea, or difficulty with intubation. A rare
has been addressed (Siris et al., 2006). complication is myelopathy due to spinal stenosis if the calcifications
are also present within the spinal canal. Like patients with anky-
Juvenile Kyphosis losing spondylitis, patients with DISH can develop spinal fractures
Juvenile kyphosis (Scheuermann disease) manifests as thoracic or tho- after relatively minor trauma. Treatment is focused on symptomatic
racolumbar kyphosis in adolescents. This is a self-limited disorder management.
which arises due to uneven vertebral bone growth with respect to the
sagittal plane. Spinal pain is more likely to accompany lumbar than Ossification of the Posterior Longitudinal Ligament or
thoracic disease. Spinal radiography shows anterior vertebral wedging, Ligamentum Flavum
increased Cobb angle, and elongated sagittal balance (horizontal dis- Ossification of the posterior longitudinal ligament anterior to the spinal
tance between the center of C7 and the superior-posterior border of canal (Fig. 104.22) and ossification of the ligamentum flavum poste-
the S1 endplate). Neurological abnormalities are uncommon, but spi- rior to the spinal canal are uncommon syndromes of acquired calcifi-
nal cord compression can occur from thoracic disk herniation or direct cation. The posterior longitudinal ligament extends the length of the
effects of severe kyphosis. spine, separating the posterior aspects of the disks and vertebral bodies
from the thecal sac. The ligamentum flavum is in the dorsal portion of
Scoliosis the spinal canal, attaching the laminae and extending to the capsules of
Scoliosis can be congenital, acquired secondary to an underlying dis- the facet joints and the posterior aspects of the neural foramina. Either
ease, or idiopathic. The most common form is idiopathic scoliosis, ligament can ossify in later life, apparently independently of the usual
with or without kyphosis, that usually develops painlessly in child- processes of spondylosis and degenerative arthritis. Ossification of the
hood and adolescence. A few cases of acquired scoliosis are associated posterior longitudinal ligament occurs more commonly in Asians than
with tumor, spondylolisthesis, or neurological pathology such as syr- in non-Asians and with a roughly 2:1 male:female ratio. It may be visi-
inx, myelomeningocele, or Chiari I malformation. Among patients ble on lateral spinal radiography but is usually asymptomatic. It is bet-
with acquired scoliosis, indications for spinal MRI include abnormal ter seen by CT scan, in which it is distinguished from osteophytes by
neurological examination or atypical curve features such as sudden favoring the middle of the vertebral bodies rather than concentrating
progression, left thoracic curvature, or absent apical segment lordosis at the endplates. Thickness of the calcification can range from 3 to 15
(Davids et al., 2004). Spinal cord compression is a rare complication of mm. Ossification of the posterior longitudinal ligament is most likely
idiopathic scoliosis and is particularly rare if no kyphosis is present. In to be symptomatic in the cervical spine, where it can contribute to cord
eFig. 104.21 Lateral Thoracic Spinal Radiograph Shows Diffuse

Idiopathic Skeletal Hyperostosis. Note flowing calcification of anterior
osteophytes, with preservation of disk heights. (Reprinted with permis-
sion from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996.
Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann,
Boston.)
Fig. 104.22 Computed Tomographic Scan of a Patient With Posterior Longitudinal Ligament Ossifi-
cation. Note continuous bony ridge present at every level, not just at disk space. In contrast to calcified
degenerative spurs, these ligamentous calcifications are not connected to vertebral bodies. (Courtesy Erik
Gaensler.)
compression if it is thick or if the canal is further narrowed by congen- involved. Rarely, disk material breaks into the thecal sac or a frag-
ital and degenerative changes. ment ruptures into an epidural vein. Disk herniation is most likely
The ligamentum flavum can contribute by hypertrophy or ossifi- to occur in young adults.
cation to spinal stenosis, most often in the lower thoracic or lumbar By age 40 years, most adults have some disk degeneration with
spine, affecting the cord or cauda equina. Risk factors for development dehydration and shrinkage of the nucleus pulposus, necrosis and
of ossification of the ligamentum flavum include trauma, hemochro- fibrosis of the annulus fibrosus, and sclerosis and microfractures of
matosis, calcium pyrophosphate deposition disease, DISH spondylitis, the subchondral bone at the vertebral endplate. Compression of neu-
or ossification of the posterior longitudinal ligament. rological tissue can develop from a combination of disk herniation,
osteophyte formation, ligament hypertrophy, congenital stenosis of
DEGENERATIVE DISEASE OF THE SPINE the spinal canal, low-grade synovitis, and deformity and misalignment
of the spine.
Spinal Osteoarthritis and Spondylosis
Osteoarthritis of the spinal facet joints manifests radiographically as Cervical Spondylosis
joint narrowing, sclerosis, and osteophyte formation. Spondylosis refers Cervical osteoarthritis and spondylosis are ubiquitous with increasing
to degenerative disease of the intervertebral disks, visible on radiogra- age (eFig. 104.23). These disorders can rarely be attributed to specific
phy as disk-space narrowing, vertebral endplate sclerosis, and osteo- activities or injuries. An exception is patients with dystonia and other
phyte formation. Spinal osteoarthritis and spondylosis are inevitable cervical movement disorders, who seem predisposed to premature cer-
consequences of aging that are visible on routine spinal radiography vical spinal degeneration. Because cervical osteoarthritis and spondy-
in more than 90% of people by the age of 60 years. They are usually losis are so commonplace, it is usually difficult to ascertain their role
asymptomatic, but cause compression of the spinal cord or nerve roots in contributing to the pathogenesis of chronic neck pain or headache.
in a minority of people. Nonetheless, they are the most common cause Cervical spine surgery in the setting of degenerative pathology is rarely
of compressive myelopathy or radiculopathy, accounting for far more if ever indicated for treatment of headache or neck pain in the absence
neurological disease than all the other conditions discussed in this of cervical radiculopathy or myelopathy.
chapter combined.
In youth, the intervertebral disks consist of a gelatinous central Cervical Radiculopathy
nucleus pulposus and a firm collagenous annulus fibrosus. Disk Clinical Presentation
herniation syndromes occur when the nucleus pulposus bursts The symptoms of cervical radiculopathy often appear suddenly
through a tear in the annulus fibrosus. This herniation can com- (Carette and Fehlings, 2005). Although disk herniation or nerve
press the nerve roots or spinal cord, depending on the spinal level root contusion can be caused by acute trauma, most cases become
eFig. 104.23 Lateral Radiograph of Cervical Spine Shows Typical

Changes of Spondylosis and Osteoarthritis. (Reprinted with permis-
sion from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996.
Clinical Neurology of Rheumatic Disease, Butterworth-Heinemann,
Boston.)
symptomatic without an identifiable preceding traumatic event. Disk

herniation is more likely to be the cause in patients younger than 45
years; neuroforaminal stenosis by degenerative changes is more com-
mon than disk herniation and becomes more likely with increasing age.
Classic cervical radicular pain originates from the neck and radiates
down the arm with or without dysesthesias, paresthesias, numbness,
or even weakness. Subscapular or interscapular pain is common with
lower cervical radiculopathy (C7 especially, but also C6, C8, and/or
T1). Radiculopathic arm pain may increase with coughing or Valsalva
maneuver. Arm pain may increase with a combination of neck exten-
sion, rotation to the side of the pain, and downward axial compression
of the head (Spurling maneuver).
Spondylosis, osteophytes, and disk herniations at the C4–C5 level
can affect the C5 root, causing pain, paresthesias, and sometimes loss R L
of sensation over the shoulder, with weakness of the deltoid, biceps,
and brachioradialis muscles. The biceps and supinator reflexes may
be lost. Spread of the biceps reflex to the finger flexors, an increased
triceps reflex, or a paradoxical biceps reflex (absent or reduced biceps
reflex with reflex contraction of the finger flexors, or rarely the triceps)
suggest the presence of myelopathy. Pathology at the C5–C6 level can
affect the C6 root and cause sensory changes in the first two digits and/
Fig. 104.24 Computed Tomographic Scan of Cervical Spine With
or lateral distal forearm, with possible weakness in the brachioradia- Intrathecal Contrast Shows a Herniated Cervical Disk. Spinal cord
lis and wrist extensors. The biceps and brachioradialis reflexes may be (gray) and thecal sac (white) are distorted on the left by the disk.
diminished or inverted. Lesions at the C6–C7 level compressing the (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M.,
C7 root cause sensory changes in the index, middle, and/or ring fin- Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. But-
gers, and weakness in C7-innervated muscles such as the triceps, wrist terworth-Heinemann, Boston.)
flexors, and pronators. The triceps tendon reflex may be diminished.
The C5, C6, and C7 roots are the ones most commonly involved in effectively separates motor nerve fibers from their cell body, the ante-
cervical spondylosis because they are at the level of greatest mobility rior horn cell within the spinal cord. This same lesion usually affects
where disk degeneration is greatest in the cervical spine. The relative the root proximal to the dorsal root ganglion, allowing the sensory
frequency of root lesions in cervical spondylosis varies in different fibers to remain in continuity with their cell bodies. Needle EMG may
series. Clinically evident compression of the C8 root or of roots above reveal electrophysiological evidence of active denervation in the form
C5 is less common. of fibrillation potentials and/or positive sharp waves. Other sponta-
neous activity such as fasciculation potentials or complex repetitive
Diagnostic Testing discharges can suggest ongoing or remote motor neuron pathology,
Cervical plain-film radiography is of little value in diagnosing or respectively. With volitional activation of the tested muscle, motor
excluding cervical radiculopathy. MRI scanning of the cervical spine is units may be large in amplitude and/or long in duration, suggesting
usually helpful in identifying nerve root compression in patients with prior denervation with subsequent reinnervation.
cervical radiculopathy, as well as diagnosing causes of myelopathy, and There are several limitations to consider when interpreting electrodi-
is the imaging study of choice in most cases. Cervical myelography agnostic (EDX) testing for the diagnosis of radiculopathy. First, the study
followed by CT scanning is sometimes more sensitive than MRI (Fig. is of low diagnostic yield in the hyperacute period. The electrodiagnosis
104.24), and is particularly helpful in patients with MRI-incompatible of radiculopathy is insensitive in detecting radiculopathy in the absence
pacemakers, spinal cord stimulators, severe claustrophobia, and other of axonal loss. Therefore, one must allow for the completion of Wallerian
patients who cannot undergo MRI scanning. MRI images are often degeneration following an injury before the study is performed. This pro-
degraded by the presence of hardware from prior cervical spine fusion cess typically takes 5–6 days for motor fibers and 8–9 days for sensory
surgeries, making CT myelography particularly useful in these patients fibers. Needle EMG in isolation has been said to have moderate diagnos-
as well. However, MRI may show nerve root compression, particularly tic sensitivity, with different series citing 50%–71%. Root compression
in the neural foramina, which is invisible by CT myelography if the resulting in intermittent ischemia or mechanical deformation may result
site of compression is lateral to the subarachnoid space, thus not filled in isolated root demyelination without secondary axonal loss. In this sce-
with contrast agent. CT myelography is also better than MRI for dis- nario, a patient may experience classical radicular symptoms without any
tinguishing noncalcified disk herniation from osteophytes or calcified objective evidence of the disease. For these reasons it is important to have
disk herniations. All of that said, cervical MRI or CT myelography concordant clinical, radiographical, and electrophysiological data when
must be interpreted with caution because degenerative abnormalities making the diagnosis. A judicious approach helps to avoid unnecessary
are so commonly seen in the asymptomatic spine. and potentially harmful surgical procedures.
Needle EMG and nerve conduction studies (NCS) can be useful in
difficult diagnostic cases, both by identifying an affected motor nerve Treatment
root and myotome and by helping exclude other diagnoses such as bra- Most instances of cervical radiculopathy improve significantly over 4–8
chial plexopathy or peripheral neuropathy (Hakimi et al., 2013). NCS weeks regardless of treatment. Various treatments such as NSAIDs, tem-
yield a particular pattern in cervical radiculopathy: there may be loss of porary/situational use of a soft cervical collar, physical therapy, or cer-
amplitude in the affected compound muscle action potential (CMAP), vical traction give similar results. Other treatments such as chiropractic
but preservation of sensory nerve action potential (SNAP). This dis- manipulation, acupuncture, and epidural steroid injections remain in
crepancy occurs with intraspinal nerve root compression, which widespread use despite contradictory, conflicting, controversial, and/or
A B
Fig. 104.25 Cervical Spondylotic Myelopathy. A, Sagittal T2-weighted magnetic resonance imaging scan
shows maximal compression of thecal sac and spinal cord at C5–C6. B, Axial computed tomographic scan
with intrathecal contrast at this level shows a large osteophyte arising from posterior aspect of vertebral
body; spinal cord at this level is compressed, and thecal sac is so compressed that little of the white intrathe-
cal contrast is visible. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T.,
1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann, Boston.)
lacking scientific data. Patients with a typical clinical presentation and The anterior-posterior diameter of the cervical spinal cord is usu-
little or no neurological deficit usually can be managed with these nonin- ally 10 mm or less. Patients rarely develop cervical spondylotic myelop-
vasive approaches without imaging or EDX studies. When patients with athy (CSM) if the congenital diameter of their spinal canal exceeds
radiculopathy have marked and/or progressive weakness, intractable 16 mm. In congenitally narrow canals, disk protrusion, osteophytes,
pain, or have not improved with nonoperative therapy, surgical nerve hypertrophy of the ligamentum flavum, ossification of the posterior
root decompression is usually successful; however, there is little ran- longitudinal ligament, and vertebral body subluxations can combine
domized controlled comparison of nonoperative therapy and surgery to compress the spinal cord. MRI, CT, or myelography provide excel-
(Nikolaidis et al., 2010). Anterior cervical discectomy, with either fusion lent images of relation between the spinal canal and the spinal cord
or total disk arthroplasty, or posterior cervical laminoforaminotomy, (Fig. 104.25). MRI is the imaging study of choice in most cases, and
have all been shown to be effective surgical techniques. Selection of one provides detailed information about intramedullary pathology such as
technique versus another is a complex decision and is beyond the scope secondary cord edema or gliosis. CT provides better images of calcified
of this chapter. Such a determination depends on many factors, includ- tissues. Even with excellent cross-sectional imaging of the spinal canal,
ing sagittal alignment (kyphosis vs. lordosis), site of pathology (dorsal vs. the clinical correlation between neurological deficit and cord compres-
ventral vs. both), number of levels to be treated, and others. sion is imperfect; dynamic changes in cord compression and vascular
perfusion undoubtedly contribute to the pathogenesis of CSM.
Cervical Spondylotic Myelopathy The natural history of CSM is variable. Some patients have stable
Cervical myelopathy related to spondylosis and osteoarthritis usually neurological deficits for many years without specific therapy, whereas
develops insidiously, but it may be precipitated by trauma or prog- other patients have gradual or stepwise deterioration. Some patients
ress in stepwise fashion. Typical clinical findings include: leg spasticity; improve with treatments such as bed rest, soft collars, or immobilizing
upper-extremity weakness or clumsiness; and sensory changes in the collars, but these treatments have not been assessed in controlled trials.
arms, legs, or trunk. Either spinothalamic tract–mediated or posterior Many patients with CSM are treated by surgical decompression, with
column–mediated sensory modalities may be impaired. Sphincter dys- variable surgical results (Fig. 104.26). Surgical treatment tends to be
function, if it occurs, is often preceded by the motor and/or sensory highly effective at halting progressive loss of function, although recov-
deficits. Commonly, neck pain is not a prominent symptom, and neck ery of lost function is less reliable, and depends on the severity and
range of motion may or may not be impaired. Some patients experi- duration of symptoms prior to surgery, with better results when symp-
ence leg or trunk paresthesia induced by neck flexion (Lhermitte sign). toms are milder, have been present less than 12 months, and when
70
60 Laminectomy
60 Anterior surgery
52 No surgery
50
44
Percent of patients
40
34 33
30
24 23 23
20
10 6 A
0
Better No change Worse
Results of treatment
Fig. 104.26 Results of Treatment of Cervical Spondylotic Myelop-
athy. (Reprinted with permission from Rosenbaum, R.B., Campbell,
S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease,
Butterworth-Heinemann, Boston. [Data from Rowland, L.P., 1992. Sur-
gical treatment of cervical spondylotic myelopathy: time for a controlled
trial. Neurology 42, 5.])
the patient is younger than 70 years. Anterior cervical discectomy

and fusion, anterior cervical corpectomy and fusion, posterior lami-
nectomy, laminectomy with fusion, and laminoplasty are all potential
options. As is the case with choice of surgical options for cervical radic-
ulopathy, the choice of one technique over another is multifactorial
and must be tailored to each individual patient’s situation. Currently
available literature remains inconclusive regarding which surgical B
approach is best for CSM; a recent systematic review examined the lit-
erature for anterior versus posterior treatment of CSM and concluded Fig. 104.27 A, Left abdominal “pseudohernia” resulting from weak-
that both approaches are highly effective for improving CSM symp- ened abdominal wall musculature within a single thoracic myotome.
B, Left, lateral disk bulge compressing the exiting T8 root. (Courtesy
toms, that anterior approaches may have slightly higher quality of life
Bashar Katirji, MD.)
(QOL) outcomes, and that posterior approaches have higher direct
costs and slightly higher complication rates. However, the authors of
this study emphasize that the studies they reviewed were all level 2 and thus infrequency of spondylosis (Vanichkachorn and Vaccaro,
3 data, and that prospective randomized controlled trials will be neces- 2000). Thoracic osteophytes are more likely to develop on the
sary to settle this debate (Alvin et al., 2013). anterior or lateral aspects of the vertebral bodies and infrequently
cause clinical radiculopathy. Thoracic disk herniations are visible
Vertebral Artery Stroke Caused by Cervical on MRI in many asymptomatic individuals. Thoracic disk hernia-
Osteoarthritis tions occur most often in the lower thoracic spine. When a thoracic
Compression of a vertebral artery by an osteophyte is a rare cause of nerve root is impinged, the patient may note severe, sharp pain and
stroke in the vertebrobasilar distribution (Bulsara et al., 2006). The paresthesias involving the abdominal or chest wall. There can also
vertebral arteries pass through foramina in the transverse processes be associated abdominal muscle weakness resulting in a bulge or
from C6 to C2. Osteophytes from the uncovertebral joint can com- “pseudohernia” (Fig. 104.27). While pain may be significant and
press the arteries. The compression may occur with something as difficult to control in the acute phase, symptoms are often self-lim-
benign as head rotation. However, the rotation often leaves the con- ited (Chaudhuri et al., 1997).
tralateral vertebral artery uncompressed, so ischemic symptoms are Thoracic myelopathy due to disk herniation probably has an annual
usually limited to those patients who have both osteophytic arterial incidence of approximately 1 case per 1 million. Most cases occur
compression on one side and a contralateral hypoplastic, absent, or between ages 30 and 60 years. Symptoms often develop insidiously
occluded artery. Aggressive chiropractic neck manipulation should without identifiable preceding trauma. Back pain may or may not be
be discouraged since it can lead to vertebral artery dissection at the present. Patients have some combination of motor and sensory find-
AA loop with resultant vertebrobasilar distribution embolic strokes ings of myelopathy; sphincter dysfunction is present in more severe
(Devereaux, 2000). cases. Thoracic MRI, CT, or myelography can confirm the diagnosis
(Fig. 104.28). The treatment is surgical decompression when there is
Thoracic Spondylosis clear clinical and radiographic evidence of thoracic radiculopathy and/
Degenerative changes are less common in the thoracic than in the or myelopathy, but should be assiduously avoided when only axial back
lumbar or cervical spines given the relative lack of mobility and pain is present. Surgical options include transthoracic discectomy via
open thoracotomy, thoracoscopy or minimally invasive thoracotomy; presentation is a Brown-Séquard syndrome that can slowly evolve over a
if the pathology is located laterally enough, a posterolateral approach few years. Thoracic spine MRI shows the spinal cord ventrally deviated,
such as transpedicular discectomy, open or minimally invasive, could often with a kink at one level between T2 and T7, and with increased
also be considered (Fig. 104.29). dorsal subarachnoid space. CT myelography will show similar changes
Herniation of the thoracic spinal cord into the dura is a very rare and confirm that there is no subarachnoid space ventrally where the
cause of thoracic myelopathy (Sasani et al., 2009). The most common spinal cord is attached to the dura. This condition can be extremely dif-
ficult to differentiate radiographically from a dorsal thoracic arachnoid
cyst pushing the cord anteriorly, unless very blatant flattening of the
dorsal cord surface is present, suggesting pressure from a mass lesion
rather than anterior tethering alone. The adjacent vertebral body may
appear scalloped. Spinal cord herniation can be idiopathic, presumably
due to congenital defects in the dura, or occur after trauma or thoracic
spinal surgery. Rare instances are associated with thoracic disk hernia-
tion. Some patients improve after surgical reduction of the herniation,
but this is a highly technically challenging surgery.
Lumbar Spondylosis
Low Back Pain
Episodes of acute low back pain, which usually resolve within a few
days, are experienced by some 80% of persons. These episodes often
recur, and approximately 4% report chronic low back pain. Pain-
sensitive structures in the lumbar region include the nerve roots, zyga-
pophyseal joints, sacroiliac joints, intervertebral ligaments, muscles,
fascia, annulus fibrosis and circumferential portions of the disks, and
vertebral periosteum. Controlled local anesthetic injection studies sug-
gest that in some patients, the cause of low back pain can be localized
to specific zygapophyseal or sacroiliac joints. In other patients, injec-
tion of contrast media into lumbar disks reproduces pain, suggesting
that the lumbar disk is the source of pain. However, this localization
cannot be achieved reliably by history or physical examination, and,
when attempted, localization of the source of pain is often unsuccess-
Fig. 104.28 Thoracic Magnetic Resonance Images of a Patient With ful. Thus, in clinical practice, “nonspecific low back pain” is a com-
Thoracic Disk Herniation. This large acute disk herniation at T10–T11 monly made diagnosis.
consists of extrusion of most of the nucleus pulposus into the spinal The findings of osteoarthritis and lumbar spondylosis on radiog-
canal. There is secondary narrowing of the disk space and spinal cord
raphy (osteophytes, endplate sclerosis, disk-space narrowing) appear
edema (arrows) above and below the level of spinal cord compression.
(Courtesy Erik Gaensler.)
gradually with increasing age and are rarely absent by age 60 years (see
End plate
sclerosis
Anterior
Lateral
osteophyte
osteophytes
Narrow
Narrow
L5-S1
L5-S1
disk space
disk space
End plate
sclerosis
A B
Fig. 104.29 Lateral (A) and anteroposterior (B) radiographs of lumbar spine showing osteophytes, disk-space
narrowing, and sclerosis of vertebral body articular plates. (Reprinted with permission from Rosenbaum,
R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heine-
mann, Boston.)
convincing radicular symptoms, mild spondylolisthesis and no clear

BOX 104.6 Indications for Lumbar Spine
neuroforaminal stenosis by MRI, flexion and extension radiographs
Radiography in Patients With Acute Low can be considered. In some cases, imaging in a neutral position may
Back Pain fail to demonstrate significant foraminal compromise, but flexion/
extension films may reveal an unstable or “dynamic” spondylolisthesis
Red Flags for Trauma
(Even et al., 2014).
Major trauma (e.g., motor vehicle accident, fall from height)
Minor trauma or even strenuous lifting in older or potentially osteoporotic Lumbar Radiculopathies
patient
The back and leg neurological examination is central to decision
Prolonged corticosteroid use
making in patients with low back pain. Perhaps 1%–2% of patients
Osteoporosis
with acute low back pain have significant lumbar nerve root compres-
Age >70 years
sion. Three syndromes merit specific diagnostic consideration.
Red Flags for Tumor or Infection
Age >50 years or <20 years Monoradiculopathy
History of cancer Clinical Presentation
Constitutional symptoms (e.g., fever, chills, weight loss) Patients with an acute lower lumbar or lumbosacral monoradiculopa-
Risk factors for spinal infection (e.g., recent bacterial infection, intravenous thy due to nerve root compression typically present with unilateral leg
drug use, immunosuppression) pain (sciatica) radiating into the buttock, posterolateral thigh, and typ-
Pain that is worse when supine or is severe at night ically distally into the leg, foot and/or toe(s), sometimes with sensory
disturbance and/or weakness. Patients often also have localized, low
Adapted with permission from Agency for Health Care Policy and
back pain. Pain may increase with movement, coughing, sneezing, or
Research, 1994. Acute Low Back Problems in Adults. Assessment and
Treatment: Quick Reference Guide for Clinicians. US Department of
Valsalva maneuver and decrease with rest or recumbent positioning.
Health and Human Services, Rockville, MD. Pain often increases when the straightened ipsilateral leg is raised while
the patient is supine (straight leg-raising test, Lasègue sign) or when the
Fig. 104.29). The presence or absence of these findings does not cor- leg is straightened at the knee while the patient is seated (seated straight
relate with symptoms and demonstrating them is of no diagnostic or leg-raising). The most commonly compressed nerve roots are L5, usu-
therapeutic value. Therefore, radiography of the lumbar spine is indi- ally by L4–L5 disk herniation, or S1, usually by L5–S1 disk herniation.
cated only when alternative diagnoses such as compression fractures, These localizing guidelines are variable, in part due to different sites
neoplasia, or infections are being seriously considered. The Agency for of nerve root compression that are possible in the lumbar spine. For
Health Care Policy and Research has recommended that spinal radiog- example, a paracentral disk herniation at L4–L5 will usually compress
raphy be reserved for patients with “red flags,” which include history the traversing L5 nerve root, while a far lateral/intraforaminal disk
of and/or signs of trauma, tumor, or infection, or any neurological herniation at L4–L5 will compress the exiting L4 root. For L5 radicu-
deficit, but not pain alone (Box 104.6). Even limiting radiography to lopathy, the findings are typically anterior leg, dorsal foot, and hallux
patients meeting these guidelines results in many needless radiographs. pain, paresthesia (especially on the medial dorsal foot), and weakness
For example, back pain in a patient older than 50 years need not be an in the extensor hallucis longus muscle, ankle dorsiflexors, and pero-
indication for imaging studies unless other findings suggest a condi- neal muscles. L5 radiculopathy can be clinically similar to peroneal
tion more serious than nonspecific low back pain. mononeuropathy, but these can be differentiated by noting the pres-
There are many causes of lumbar disk disease, including body ence of weakness of foot inversion with L5 radiculopathy, which is
habitus, type and amount of physical activity, acute injury, history not seen with peroneal neuropathy (see Chapter 105). S1 nerve root
of tobacco abuse, and genetic predisposition, which is complex and compression can lead to plantar and lateral foot pain and paresthe-
polygenic with a number of known candidate genes (Kalichman and sia, depressed ankle jerk, and weakness of peroneal muscles and (less
Hunter, 2008). frequently) ankle plantar flexors. When the radiculopathy is mild, the
patient may have pain without obvious objective neurological deficits.
Spondylolysis and Spondylolisthesis
Spondylolisthesis is displacement of one lumbar vertebral body relative Diagnostic Studies
to an adjacent vertebral body. The most common type of spondylolis- Disk herniations, osteophytes, spondylolysis, spondylolisthesis, facet
thesis is degenerative, which usually results from deterioration of the joint hypertrophy, and hypertrophy or calcification of intraspinal liga-
facet joints, ligaments and disk. The increased laxity allows a certain ments can compress nerve roots of the cauda equina within the spinal
degree of anterolisthesis, but high-grade (beyond grade II) slippage is canal or in the lateral recesses and neural foramina through which the
rare with this type. This occurs most commonly in the lumbar spine at roots exit the spinal canal. The anatomical relations between the nerve
L4–L5. The second-most common cause is spondylolysis, a disconti- roots and the surrounding tissues are well visualized by lumbar MRI
nuity in the vertebral pars interarticularis, which disrupts the normal or CT myelography (Fig. 104.30, A, eFig 104.30, B). Each technique has
stabilizing effect of the facet joints. This is known as “isthmic” or “spon- high sensitivity for demonstrating causes of nerve root compression.
dylolytic” spondylolisthesis, can result in high-grade slippage, and is On occasion, when a patient has strong clinical evidence of lumbar
most common at L5–S1. Other causes of spondylolisthesis include radiculopathy, but initial imaging studies do not show the cause of
congenital vertebral anomalies and vertebral trauma. Spondylolysis the compression, a second complementary imaging study is indicated.
occurs in 5%–7% of the population and is usually asymptomatic. For example, imaging with a lumbar MRI usually is sufficient for most
Spondylolisthesis is often painless or may cause low back pain that clinical purposes, but occasionally a patient also needs CT myelogra-
sometimes radiates to the buttocks. Spondylolytic spondylolisthesis phy to clarify the anatomy. Unfortunately, all spinal imaging modal-
is a common cause of back pain in adolescents. Occasionally, spon- ities frequently show anatomical abnormalities that are not the cause
dylolisthesis can advance to the point of compressing nerve roots in of symptomatic nerve root dysfunction; all imaging results must be
the neural foramina or causing lumbar canal stenosis. In patients with interpreted carefully in clinical context.
B
eFig. 104.30 B, Axial T1-weighted MRI demonstrates an intraforaminal
focal disk protrusion (herniation) within the right neural foramen (arrow-
heads), well delineated owing to thin images angled to disk space and
the contrast of bright fat within neural foramen. Note nerve roots as
oval structures exiting each neural foramen.
judicious use of nonopioid medications, and behavioral therapies.

Prolonged immobilization is detrimental, and early mobilization
results in more rapid recovery. Many patients with acute low back pain
and sciatica can be managed initially based on clinical examination
without spinal imaging studies. Patients who have progressive weak-
ness or sensory loss or who have severe pain that fails to improve after
6 weeks of nonoperative therapy can be considered for surgical nerve
root decompression. Patients least likely to benefit from lumbar nerve
root surgery are those who lack radicular pain, objective neurological
signs of nerve root dysfunction, or corresponding imaging evidence of
nerve root compression.
Invasive techniques such as steroids and local anesthetics injected
epidurally or into facet joints are used for some patients with low back
pain or radiculopathy, but we still lack consistent proof of their long-
term efficacy or cost-effectiveness from randomized controlled trials
(Chou et al., 2009). Lumbar epidural steroid injections may result in
some improvement in radicular symptoms if pain is assessed 2–6 weeks
after injections, but the injections do not have proven longer-lasting
value (Armon et al., 2007).
A few patients develop a chronic low back pain syndrome or have
repeated exacerbations of acute low back pain. Back-strengthening
A exercises and the avoidance of maneuvers that put strain on the lower
back, together with the judicious use of NSAIDs, generally improve
Fig. 104.30 A, Lumbar magnetic resonance image of a patient with
such patients’ pain. Workers who are off work with low back pain for
lumbar disk herniation at L4–L5. Ventral dura is displaced (straight
arrows) posteriorly. Roots of cauda equina are compressed (curved longer than 6 months have a guarded prognosis for return to work.
arrows). (A, Courtesy Erik Gaensler.) Physicians caring for patients with low back pain lasting longer than 4
weeks need, whenever possible, to emphasize exercise, to avoid decon-
ditioning, and to enable early return to graded work.
As in cervical radiculopathy, EDX studies are usually performed When surgery is performed for lumbar nerve root compression, the
when confirmation of the clinical diagnosis of lumbosacral radiculop- surgical technique depends on the clinical details such as the cause of
athy is needed. This includes in patients whose history or examination compression and the number of nerve roots compressed. In patients
are limited; when a more distal lesion (e.g., lumbosacral plexopathy, with lumbar radiculopathy due to disk herniation, the most common
lower extremity mononeuropathy) needs to be excluded; or in patients surgical approach is microsurgical discectomy with minimal removal
in whom the clinical significance of an imaging abnormality is unclear. of the lamina. In controlled trials, this surgery provided better relief
In addition to confirming the presence of root compression, the EDX of symptoms than nonoperative therapy, based on results 2–3 months
study helps in the localization of the compression to either a single or after treatment; however, the advantage of surgery decreased with
to multiple roots; in defining the age and activity; and the severity of longer follow-up (Chou et al., 2009). Perhaps 90% of patients report
the lesion. excellent relief of neuropathic pain after surgery. Many are able to
Needle EMG remains by far the most sensitive EDX tool in patients return to physically strenuous work. However, a small proportion of
with suspected lumbosacral radiculopathy. The presence of fibrillation patients postoperatively present with severe chronic pain problems
potentials is the most objective EMG finding. The diagnosis is con- (failed back surgery syndrome), which particularly occurs when patients
firmed by the presence of denervation in a segmental myotomal dis- selected for surgery have neither clinical evidence of radiculopathy
tribution with or without denervation of the paraspinal muscles along nor corresponding neuroimaging evidence of nerve root compression.
with a normal SNAP in the corresponding dermatome. While chronic and ongoing pain after lumbar surgery is less common
EMG sensitivity is greater with a more severe or predominantly motor after simple discectomy than it is after multilevel laminectomy, or
radiculopathy. The needle EMG may be normal if only the dorsal root is particularly after lumbar fusion surgery, it does still occur. Recurrent
compressed and not the ventral root (such as in patients with only pain disk herniation, or incomplete discectomy, are both common causes of
and/or paresthesias); if the injured root lacks adequate myotomal rep- poor postoperative condition. Less common causes include excessive
resentation (such as L1, L2, and C4 roots); or, as previously mentioned, epidural scarring with compression and/or tethering of nerve roots,
the pathophysiology is entirely demyelinating. EMG and imaging studies arachnoiditis, hematoma, or postoperative spinal instability. Other
are often complementary in the diagnosis of lumbosacral radiculopathy. problems such as misdiagnosis prior to surgery, or even possible con-
EMG provides information about nerve root function, whereas imaging founding psychiatric and/or psychosocial issues, must be considered.
studies provide information about the anatomy of the nerve roots and
surrounding structures. The agreement between imaging and EMG is Acute Cauda Equina Syndrome
higher in patients with abnormal neurological examinations. Acute cauda equina syndrome presents as low back and bilateral leg
pain, motor weakness of the legs, and sphincter dysfunction caused
Treatment by compression of multiple lumbosacral nerve roots within the spi-
Most sufferers of acute low back pain and sciatica recover within 6 nal canal. Particularly worrisome findings are sacral sensory loss or
weeks using simple nonoperative therapies such as brief periods of bed impaired function of the rectal and urinary sphincters. Acute cauda
rest, activity limitations as required by pain, and simple nonopioid equina compression occurs in less than 1% of all patients who have
analgesics. Chronic lower back pain and sciatica are much more dif- lumbar or lumbosacral disk prolapses. The cause is usually a large
ficult to manage. Conservative measures can include physical therapy, midline disk herniation, most often at L4–L5 or L5–S1, but multiple
other causes can be seen, including fractures, fracture/dislocation, spi- Treatment. Patients who have neurogenic intermittent
nal tumors, lumbar epidural abscess, or rarely, very extreme cases of claudication may have stable symptoms for many years without
degenerative canal stenosis. When acute cauda equina compression developing progressive neurological deficit. Some even note regression
occurs, the patient needs urgent spinal imaging and decompressive of symptoms after months of recurrent claudication. These patients
surgery because the window of opportunity for restoration of neuro- may be managed with mild analgesics. Some describe decreased
logical function is limited to 24 hours, or perhaps 48 hours in some discomfort if they walk with a slight stoop or using a cane. Those
cases, with only partial recovery being the most likely outcome in patients with intractable leg pain or progressive neurological deficit
many cases. can be treated with wide laminectomy of the stenosed spinal canal,
which usually improves the symptoms of claudication and may help
Lumbar Canal Stenosis back pain (Chou et al., 2009; Weinstein et al., 2008). Laminectomy,
Lumbar canal stenosis results from subnormal cross-sectional area especially multilevel laminectomy, can potentially increase spinal
of the spinal canal due to varied anatomical changes, including con- instability, and if instability is present preoperatively or is expected
genitally small canal size, degenerative osteophytes, spondylolisthesis, to result from the decompression, the patient should be treated with
facet joint hypertrophy, thickening of the ligamentum flavum, disk- both laminectomy and fusion. For many decades, debate has persisted
space narrowing, and disk herniation (Katz and Harris, 2008). It usu- regarding the optimal surgical treatment strategy for patients with
ally develops insidiously with aging and rarely becomes symptomatic lumbar spinal stenosis with or without associated instability, usually
before age 40 years unless due to congenital stenosis or skeletal changes in the form of degenerative spondylolisthesis. Even in the presence of
like those of achondroplasia. Men are more often affected than women. spondylolisthesis, many authors have advocated for treatment with
Stenosis is often asymptomatic; however, patients can have low back laminectomy alone, while others have recommended supplemental
pain. A particularly characteristic pattern is back and lower extremity lumbar fusion. Many studies have addressed this question over the
pain that develops while standing but is absent while sitting or supine. years, with ultimately conflicting results. Two recent randomized
When ambulating, patients with lumbar canal stenosis may develop controlled trials were published in the same issue of the New England
neurogenic intermittent claudication. This manifests as progressive Journal of Medicine. Ghogawala et al. (2016) randomized 66 patients, all
lower extremity pain and/or paresthesia, which abates within minutes with lumbar stenosis and degenerative spondylolisthesis, to treatment
following flexion at the waist or sitting. Some patients are more com- with either laminectomy and fusion or laminectomy alone. At 4-year
fortable if they bend forward while they walk (the “shopping cart sign”) follow-up, they found slightly improved clinical outcome based on
or can bicycle without difficulty. They may develop leg symptoms with Short-Form 35 (SF-36) but not Oswestry Disability Index (ODI)
sustained erect posture or after lying with their back straight. In con- with laminectomy plus fusion, although this surgery was associated
trast, vasogenic intermittent claudication can be elicited by almost any with higher blood loss and longer hospital stay. They also found a
lower extremity exercise, but is not elicited or relieved by any specific significantly higher reoperation rate (34% vs. 14%) for laminectomy
postures. Vascular claudication does not induce paresthesia in the alone. The authors concluded that laminectomy plus fusion results in
lower extremities. Since both these conditions generally occur in older slightly greater, but clinically meaningful, improvement compared to
patients, they can occur together, which can be a diagnostic challenge. laminectomy alone. Conversely, Forsth et al. (2016) randomized 247
Physical examination signs of pallor, hair loss, delayed capillary refill, into four groups based on presence or absence of spondylolisthesis
and lack of palpable pulses in the feet should prompt attention toward and laminectomy alone versus laminectomy and fusion. They found
diagnostic vascular testing. A simple and inexpensive test for this is an no significant clinical differences between the treatment groups
ankle-brachial index (ABI). at 2 years or 5 years. When they analyzed only the subgroup with
Most patients with neurogenic intermittent claudication do not spondylolisthesis, again no clinical difference in outcomes was found,
have objective signs of nerve root dysfunction, likely as a result of even when this was applied to patients with anterolisthesis of 7.5 mm
intermittent nerve root ischemia without subsequent axonal loss. or greater. Reoperation rates were similar, as were complication rates.
Nerve stretch signs such as pain with straight leg raising are usually The authors of this study concluded that there was no benefit to adding
absent, but infrequently a patient has progressive neurological defi- fusion to the laminectomy, even in the presence of spondylolisthesis.
cits from chronic cauda equina compression. Some patients develop They also noted an increased cost of $6800 per surgery with the
leg weakness or other abnormal neurological signs following exercise; addition of fusion. Neither study can be said to be definitive, and larger
neurological examination before and after precipitation of the pain can studies will be needed to refine our understanding of this issue.
be a helpful part of the evaluation of neurogenic claudication. Patients Patients with 1- or 2-level stenosis can also be excellent candidates
with congenital lumbar canal stenosis often have accompanying con- for minimally invasive laminectomy. A less-invasive treatment option,
genital stenosis of the cervical canal and should be checked for signs of reserved for patients with classic neurogenic claudication relieved by sit-
a cervical myeloradiculopathy. ting and forward flexion, is placement of an interspinous process block-
Diagnostic studies. Spinal canal stenosis is generally evaluated ing device. This treatment is best for patients who are elderly, as it does
by MRI and less often CT (Fig. 104.31). MRI is best at demonstrating not stop progression of the underlying degenerative cascade, and, for
sagittal relationships such as the role of spondylolisthesis in narrowing that reason, may have limited longevity. It can be implanted under local
the canal. CT is best at studying calcified tissues and distinguishing disk anesthetic with or without light sedation, making it an appropriate alter-
from osteophyte, especially within the neural foramina. No imaging native for those who are too frail to be put under full general anesthesia.
modality quantifies the extent of nerve root compression, and clinical
correlations between symptoms and apparent reduction in size of the INFECTIOUS DISEASES OF THE SPINE
spinal canal are imperfect. In choosing which patients would benefit
from decompressive surgery, one should rely more heavily on clinical Pyogenic Vertebral Osteomyelitis and Epidural Abscess
findings than on the appearance of the canal in imaging studies. EMG Vertebral osteomyelitis and spinal epidural abscess (see Chapter 79)
is also a very useful tool in patient selection for decompressive surgery are uncommon conditions that present with focal spinal pain and ten-
by helping to establish/confirm the presence of radiculopathy/cauda derness (Curry et al., 2005; Zimmerli, 2010). Epidural abscesses in the
equina syndrome. anterior spinal canal are more likely than those in the posterior canal
A B
Fig. 104.31 Magnetic Resonance Image of Patient With Lumbar Spinal Stenosis. Midline (A) and
parasagittal (B) images of lumbar spine show narrow anteroposterior dimensions of spinal canal consistent
with spinal canal stenosis. (Courtesy Erik Gaensler.)
A B
Fig. 104.32 Magnetic Resonance Image of a Patient With Pyogenic Vertebral Osteomyelitis. A,
T1-weighted sagittal image shows replacement of normal marrow fat of C4 and C5 vertebrae with low signal
intensity edema, with narrowing of disk space (arrow) and thickening of epidural soft tissue (small arrows).
B, T2-weighted image shows mild spinal cord compression (arrow) and hyperintensity of anterior longitudinal
ligament, consistent with superior extension of infectious process (small arrows). (Courtesy Erik Gaensler.)
to be associated with osteomyelitis. In either location, they can cause and is particularly helpful to assess for epidural or paravertebral infec-
radiculopathic pain, compromise nerve root function, or lead to spinal tion. Spinal CT or radionuclide scanning are useful if MRI is unavail-
cord compression. Some patients with spinal epidural abscess or ver- able or contraindicated.
tebral osteomyelitis are afebrile at presentation, but most have an ele- Osteomyelitis may involve any vertebral body but is least common
vated erythrocyte sedimentation rate (ESR) and/or C-reactive protein in the cervical vertebrae. Often in pyogenic, but infrequently in gran-
(CRP). Early in the infection, routine spinal radiography may be nor- ulomatous osteomyelitis, the MRI shows involvement of the adjacent
mal. If the diagnosis is being considered, an MRI scan (Fig. 104.32) of disk space. Osteomyelitis and spinal epidural abscess usually occur
the involved area is sensitive for detecting vertebral body abnormalities by hematogenous spread and are more likely following septicemia.
The most common causative organism is Staphylococcus aureus, but a eponym Pott paraplegia. Cauda equina compression is uncommon
wide variety of other bacteria can be responsible. Polymicrobial infec- in TB. Treatment of vertebral TB requires long-term multiple-drug
tion is uncommon after hematogenous infection but can occur when anti-tuberculous therapy. Spinal surgery may be needed, depending
the source is open trauma or contiguous spread from other tissues. on the degree of spinal destruction or deformity, and is often required
Diabetes, infective endocarditis, alcoholism, acquired immunodefi- in cases of compression of neurological structures.
ciency syndrome (AIDS), and other forms of immunosuppression
increase the risk of its development. Other risk factors are intravenous INFLAMMATORY JOINT DISEASE
drug use and spinal trauma. Cases may be iatrogenic following spinal
surgery. Rheumatoid Arthritis
The annual incidence of hospitalization for vertebral osteomyelitis RA is a chronic, inflammatory, symmetrical, destructive, immune-me-
in the United States from 1998 to 2013 rose from 2.9 to 5.4 per 100,000 diated polyarthritis. In population studies, 0.2%–2% of the population
people. Reasons for this increase include the following (Berbari, 2015; is affected, women twice as often as men. Typically, patients may com-
Issa, 2018): plain of joint pain, swelling, and “morning stiffness.” Alternative sys-
• Increasing rates of bacteremia due to the greater utilization of intra- temic inflammatory conditions such as systemic lupus erythematosus,
vascular devices and various types of instrumentation psoriasis, and rheumatic disease must be ruled out. The exact cause of
• The increasing age of the population RA is unknown, but genetic factors are evident in familial cases, and
• The increasing number of patients receiving renal dialysis susceptibility is linked to certain human leukocyte antigen (HLA)-DR
• The increasing utilization of immunosuppressive therapies types (Okada, 2014). The most commonly affected regions are the small
Vertebral osteomyelitis and discitis are generally treated medically joints of the hands and feet. The diagnosis is based primarily on the
with long-term antibiotic therapy. CT-guided needle biopsy of the ver- patient’s history of polyarthritis of greater than 6 weeks, duration and
tebral body and/or disk space can provide a causative organism and the presence of characteristic clinical findings. The presence of anti-cy-
thus help tailor antibiotic therapy. In cases where extensive erosive and clic citrullinated peptide, rheumatoid factor, and acute phase reactants
destructive changes have caused spinal instability, bracing is suggested (e.g., ESR, CRP) may strengthen the clinical suspicion. That said, many
until the infection is cleared, at which point surgical stabilization can patients have seronegative RA, and conversely, there are numerous
be performed. Spinal epidural abscess, however, is almost always a other causes for elevation of rheumatoid factor. Radiography, sonog-
surgical emergency, particularly above the level of the cauda equina raphy, and MRI may reveal changes suggestive of synovitis; however,
(i.e., where spinal cord is present). This is because even in the absence these modalities do not have an established role in the diagnosis of RA
of marked neurological compression the abscess can trigger an acute as outlined by the American College of Rheumatology (Aletaha, 2010).
inflammatory thrombophlebitis, causing acute cord infarction and
irreversible neurological compromise. This can occur rapidly even in Pathogenesis
a patient who is neurologically normal at presentation. Many patients, The immunopathogenesis of RA is complex and includes T- and B-cell
however, develop an epidural phlegmon (“burned-out” post-infec- activation, angiogenesis and cellular proliferation in the synovium,
tious inflammatory tissue that enhances) without any free pus within it inflammation in soft tissue, and eventual destruction of cartilage and
(lack of rim enhancement on MRI) that is often misread as an abscess. bone matrix. Cytokine release, immune complex deposition, and vas-
The presence of phlegmon does not require surgical intervention culitis can all contribute to the inflammatory process. The inflamed
unless there is mass effect on the spinal cord. proliferative rheumatoid synovium is called pannus. In the spine, pan-
nus can disrupt stabilizing ligaments, particularly of the AA joint, and
Granulomatous Vertebral Osteomyelitis thick pannus can add to central canal stenosis with subsequent com-
Tuberculosis (TB) of the spine (Pott disease) is one of the more pression of nervous tissue. Rheumatoid inflammatory material can
common forms of nonpulmonary TB and by far the most common form nodules in soft tissue. On the rare occasions that these nodules
granulomatous spinal infection. The risk is highest in regions or pop- form in the dura, they can contribute to rheumatoid pachymeningitis.
ulations where TB is endemic. In the United States, high-risk factors
are immigration from an endemic area, AIDS, homelessness, and drug Neurological Manifestations
or alcohol abuse. Other organisms capable of causing granulomatous RA can result in complications of the CNS, peripheral nervous system,
osteomyelitis include brucellosis, a variety of fungi, Nocardia, and and muscle. Some of the most common neurological complications of
Actinomyces. Granulomatous spinal infection typically presents with RA are carpal tunnel syndrome and other nerve entrapments, periph-
insidious progression of back pain. The patient often has symptoms of eral neuropathy, and myopathy; these are discussed in Chapters 28,
systemic infection such as weight loss, fever, night sweats, or malaise. 105, and 106. RA can evolve to a rheumatoid vasculitis that, like other
Pott disease classically presents with destruction of vertebral bod- medium-sized vessel vasculitides, has the potential to cause ischemic
ies. Routine spine radiography results are usually abnormal by the mononeuritis, mononeuritis multiplex, or (rarely) stroke.
time the diagnosis is made, and spinal deformity (gibbus deformity, Headache and neckache are common in patients with RA. These
a form of structural kyphosis) is a common complication. MRI is the are often caused by rheumatoid disease of the cervical spine. Focal neu-
preferred imaging study to assess for contiguous abscess in the epidural rological dysfunction is a rare and later manifestation of spinal RA.
or paraspinal spaces and to evaluate possible nerve root or spinal cord Unsurprisingly, patients develop ubiquitous changes of spinal osteo-
compression when the spine is deformed (Fig. 104.33). Compression arthritis and spondylosis. In addition, early in RA, cervical radiogra-
of spinal cord or nerve roots can occur in vertebral TB by vertebral phy may show rheumatoid changes such as erosions and sclerosis at
deformity or collapse, epidural abscess, granulation tissue, or bony vertebral endplates and apophyseal joints. Patients may have cervical
sequestrum. Patients may develop delayed neurological complica- subluxations. Disk-space narrowing may occur at upper cervical disks,
tions after apparently successful treatment of the infection. This may without associated osteophytosis.
be due to infarction from endarteritis obliterans, delayed degenerative Patients with progressive RA can develop subluxation at the AA
bony changes, or reactivation of infection. Compression of nervous joint. Lateral AA joint subluxation rarely causes focal neurological
structures is most common with thoracic vertebral disease: hence the dysfunction but can contribute to neck ache and headache. Sagittal
Fig. 104.33 Magnetic Resonance Image of a Patient With Tuberculous Vertebral Osteomyelitis.
T2-weighted images show destruction of posterior inferior portion of T12 vertebra, with a soft-tissue mass
projecting posteriorly into spinal canal, compressing conus medullaris (black arrows). Note that T12 and L1
disks (white arrows) are relatively well preserved, a distinguishing feature of spinal tuberculosis. (Courtesy
Erik Gaensler.)
AA joint subluxation, often combined with adjoining soft-tissue Inflammatory Spondyloarthropathies

pannus, can cause myelopathy (eFig. 104.34). The earliest neurolog- Clinical Presentation
ical sign is usually hyperreflexia; assessment of gait and strength in The inflammatory spondyloarthropathies (SpA) include ankylosing
patients with advanced RA is often difficult because of their periph- spondylitis, reactive arthritis, psoriatic arthritis, and the arthritis of
eral joint pain and deformity. Vertical subluxation can lead to spinal inflammatory bowel disease. This is a group of heterogeneous disorders
cord or brainstem compression or rarely to vertebral artery compres- but share the common finding of inflammation in axial joints. Ankylosing
sion or injury. spondylitis is characterized by inflammatory low back pain, loss of spinal
Choosing which patients will benefit from surgical stabili- range of motion, sacroiliitis, and as it advances, radiographic evidence
zation of the subluxed joint is a clinical challenge. Findings of of sacroiliitis and spondylitis (eFig. 104.35). The clinical symptoms of
progressive myelopathy or brainstem dysfunction are usually inflammatory spine disease are the insidious onset of low back (and
indications for surgery if the general health of the patient per- sometimes buttock) pain lasting more than 3 months, prominent morn-
mits. Neurological dysfunction caused by AA subluxation usually ing stiffness, and improvement with activity. Nocturnal back pain may
occurs in patients who are already severely debilitated by their be present. Some patients with inflammatory back pain do not meet
disease. Many patients do not regain neurological function after diagnostic criteria for an inflammatory SpA (Heuft-Dorenbosch et al.,
surgical stabilization of the subluxation; goals are limited to pre- 2007). Most patients become symptomatic before age 40 years, and men
venting deterioration. The 5-year survival of patients at this late are affected more commonly than women. Other organ systems are
stage of RA is perhaps 50%. affected commonly in patients with inflammatory SpA; manifestations
A rare late manifestation of RA is rheumatoid pachymeningitis. include uveitis, mucocutaneous lesions, peripheral arthritis, gastrointes-
The dura may develop either focal rheumatoid nodules or diffuse infil- tinal disease, cardiac disease, and enthesopathy (inflammation at sites of
tration by inflammatory cells. In rare instances, focal dural disease can insertion of ligament or tendon to bone). The syndesmophytes that form
lead to compression of spinal cord, cauda equina, or cranial nerves. where spinal ligaments join vertebral bodies are one form of enthesop-
It may also result in focal cerebral complications such as seizures. athy. Examples of other sites of enthesopathy are the foot (Achilles ten-
Patients may experience encephalopathy, headaches, fever, cranial donitis, plantar fasciitis, heel pain), fingers or toes (dactylitis or sausage
nerve dysfunction, or weakness. MRI may reveal meningeal thickening digits), and symphysis pubis, clavicle, and ribs.
or enhancement. CSF analysis is typically bland, though protein may Reactive arthritis (formerly called Reiter syndrome) is classically
be elevated. In these cases, a course of glucocorticoids may improve preceded by venereal or gastrointestinal tract infection. The triad of
neurological symptoms (Ikeda, 2010). reactive arthritis is arthritis, conjunctivitis, and urethritis, but many
Entrapment neuropathies are present in up to 45% of patients with patients do not have all three manifestations. Inflammatory low
RA (Nadeau, 2002). Pure sensory, sensorimotor, and/or autonomic back pain is common in patients with reactive arthritis, and up to
neuropathies have been described in up to one-fifth of RA patients one-fourth of patients develop radiological evidence of sacroiliitis or
(Fleming, 1976). Muscle weakness can result from the primary affects spondylitis.
of RA in the form of overlap myositis or as an unintended consequence
of chronic steroid use. Furthermore, patients may develop generalized Pathogenesis
weakness from disuse or deconditioning on account of chronic joint The inflammatory SpAs are generated by a combination of genetic and
pain and immobility. environmental factors. In ankylosing spondylitis, the genetic factor is
eFig. 104.34 Lateral Radiographs of Flexed Neck of a Patient With eFig. 145.35 Anteroposterior radiograph of sacroiliac joint shows sac-
Rheumatoid Arthritis and Anterior Atlantoaxial Subluxation. Odon- roiliitis, with some preservation of left sacroiliac joint. (Reprinted with
toid and pedicle of C2 and elements of the ring of C1 are outlined. permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T.,
Atlantoaxial separation (double arrow) is also shown. (Reprinted with 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heine-
permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., mann, Boston.)
1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heine-
mann, Boston.)
TABLE 104.6 Spinal Complications BOX 104.7 Examples of Neurological

of Ankylosing Spondylitis Based on 105 Complications of Reactive Arthritis
Hospitalized Patients
Acute transverse myelitis
Anatomically Neurologically Brainstem dysfunction
Abnormal Abnormal Encephalitis
Spinal fracture 13 7 Neuralgic amyotrophy
Diskovertebral destruction 4 0 Personality change
Atlantoaxial subluxation 1 0 Seizures
Spinal canal stenosis 2 2 Unilateral ascending motor neuropathy
Data from Weinstein, P., Karpman, R.R., Gall, E.P., et al., 1982. Spinal Reprinted with permission from Rosenbaum, R.B., Campbell, S.M.,
injury, spinal fracture, and spinal stenosis in ankylosing spondylitis. J. Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease.
Neurosurg. 37, 609–616. Reprinted from Rosenbaum, R.B., Camp- Butterworth-Heinemann, Boston.
bell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic
Disease. Butterworth-Heinemann, Boston.
Cauda equina syndrome with insidious evolution of lower extrem-
ity pain, sensory loss, weakness, and sphincter dysfunction is a late
clearest, with perhaps 90% of patients expressing the gene for HLA- complication of inflammatory spondyloarthropathy. Imaging studies
B27, but only about 5% of people expressing this gene develop ankylos- (MRI, CT, myelography) show posterior lumbosacral arachnoid diver-
ing spondylitis. In the other SpA subtypes, the prevalence of HLA-B27 ticula (eFig. 104.37). Although arachnoiditis may play a role in devel-
positivity is lower. The exact mechanism by which HLA-B27 induces opment of this syndrome, the presence of the diverticula distinguishes
autoreactivity remains poorly understood. These diseases are largely it from most cases of chronic adhesive arachnoiditis.
mediated by cyclooxygenase (COX), tumor necrosis factor (TNF)-α, Other complications of spondyloarthropathy include lumbar
and interleukin (IL)-17A. All of these compounds play a role in induc- radiculopathy secondary to disk herniation or osteophytes, spinal
ing and organizing a host of pro-inflammatory mediators, resulting in canal stenosis, and from the era when spinal radiation was used to treat
autoimmunity (Veldhoen, 2017). The gut microbiome has also been spondylitis, radiation-induced cauda equina sarcoma.
implicated in stimulating a systemic immune response (Vieira-Sousa,
2015). In some patients a breakdown of the epithelial barrier in the gut Nonspinal Neurological Complications
allows the microbiome to infiltrate a host and set off an inflammatory Rare nonspinal complications of inflammatory SpA include brachial
cascade. plexopathy or entrapment neuropathies. Proximal weakness and
In reactive arthritis, the environmental factors are clearest, with atrophy, sometimes with mild elevations of serum creatine kinase
many patients experiencing a preceding gastrointestinal or genito- (CK) level, often occur in advanced cases of spondylitis, suggesting
urinary tract infection with organisms such as Shigella, Salmonella, an inflammatory myopathy. In patients with psoriatic arthritis, the
Yersinia, Campylobacter, or Chlamydia. Autoimmune T cells with tis- myopathy is occasionally painful. A number of case reports detail
sue specificity presumably mediate the inflammatory process at sites unusual neurological illnesses in patients with reactive arthritis
such as joints, entheses, and eyes. (Box 104.7).
Spinal Neurological Complications Laboratory Abnormalities

The neurological complications of the inflammatory SpA generally do Like RA, patients may have an elevated acute phase response. High
not occur until spinal disease is clinically advanced (e.g., loss of spinal ESR and/or CRP levels are seen in approximately 50%–70% of patients
range of motion, kyphosis) and radiologically evident (e.g., vertebral with active disease (Rudwaleit, 2009). Patients with inflammatory SpA
body squaring, syndesmophytes). Spinal complications include AA sometimes have mild elevations of CSF protein levels, with normal
joint subluxation, spinal fractures and pseudoarthrosis, diskovertebral glucose and cell counts. They can have unexplained abnormalities of
destruction, spinal canal stenosis, and cauda equina syndrome due to visual, auditory, and somatosensory evoked responses.
lumbar arachnoid diverticula (Table 104.6).
Subluxation of the AA joint is a late and uncommon complication
EPIDURAL LIPOMATOSIS
of inflammatory spondyloarthropathy. Diagnosis and management
issues are the same as those for patients who develop AA disease as part Epidural lipomatosis is a non-neoplastic accumulation of unencap-
of RA. The fused spondylitic spine is particularly susceptible to fracture, sulated adipose tissue within the thoracic or lumbar epidural space
especially in the midcervical region. The most common fracture site is which can lead to spinal canal stenosis and neural compromise. This
C6, followed by C5 and C7. After even minor trauma, the patient with phenomenon can occur idiopathically but is more commonly a com-
advanced spondylitis needs radiographic assessment of the cervical spine plication of chronic corticosteroid excess, obesity, or hypothyroidism
to detect fractures, if possible before myelopathic complications. Much (Fogel et al., 2005). This condition is very frequently underdiagnosed,
more rarely, patients with spondylitic rigid spines develop posttraumatic and often missed on imaging studies. On axial MRI there is often
myelopathy caused by epidural hematomas or cord contusions. encroachment on the dural sac posteriorly in a “Y”-shaped configura-
Destruction of a disk, particularly in the low lumbar or high tho- tion. Signal characteristics follow fat on all sequences (i.e., high on T1,
racic region, is a late complication of spondylitis (eFig. 104.36). The low on T1 fat suppression, high on T2). A typical patient has been on
adjacent vertebral bodies also may be involved. An initiating trauma is corticosteroids for more than 6 months and is obese and cushingoid;
not always identified. The destruction may be asymptomatic or pain- spinal radiography typically shows diffuse osteoporosis. Epidural lipo-
ful. The pain increases with movement and decreases at rest, in con- matosis is also a rare manifestation of the lipodystrophy that can com-
trast to typical inflammatory low back pain. An epidural inflammatory plicate highly active antiretroviral therapy in the treatment of human
response leading to cord compression can occur. immunodeficiency virus (HIV) infection. Symptomatic segmental
P A
eFig. 104.36 Magnetic resonance image shows diskovertebral destruction (arrows) in a patient with anky-
losing spondylitis. There is a chronic fracture in the lower thoracic spine, which is otherwise rigid because
of bony fusion. Chronic hypermobility at this single nonfused segment has occurred, leading to exuberant
fibrous tissue development. The fibrous tissue enhances on this post-gadolinium-enhanced T1-weighted
image. This appearance can be mistaken for infectious spondylitis (see Fig. 104.31) if the presence of a
bamboo spine on plain films is overlooked. (Courtesy Erik Gaensler.)
eFig. 104.37 Magnetic resonance image of lumbar spine shows a posterior lumbar arachnoid diverticulum in
a patient with ankylosing spondylitis. Spinal canal is expanded at T12–L1 by a mass that shows signal inten-
sity equivalent to cerebrospinal fluid (CSF) on these T1-weighted images. Isointensity to CSF suggests an
arachnoid cyst; small arrows outline cyst’s internal margins. Curved arrows show nerves of the cauda equina,
which have been displaced anteriorly. (Courtesy Erik Gaensler.)
spinal cord or nerve root compression is typically associated with no proof of their efficacy, and there are reports of arachnoiditis caused
epidural fat thickness of more than 7 mm in the region of compres- by their use. Therefore, most treatment is aimed at symptomatic man-
sion; however, the diameter of the spinal canal and other factors affect agement. Spinal cord stimulator implantation has been shown to have
the manifestations, so the epidural fat can be thickened asymptom- some clinical efficacy for reducing pain associated with arachnoiditis.
atically. Patients with epidural lipomatosis usually have a body mass Additional interventions include multimodal analgesics, physical ther-
index of more than 27.5 kg/m2 (eFig. 104.38). The compressive tissue apy, and psychotherapy.
can regress when corticosteroid doses are decreased and it responds
extremely well to aggressive weight loss in morbidly obese patients. Recurrent Meningitis
When neurological symptoms are severe, resulting in cauda equina Patients with recurrent attacks of acute bacterial meningitis need to
syndrome, decompressive laminectomy may be required and usually be screened for dural CSF leaks or fistulas, parameningeal infections,
has favorable outcomes (Bodelier et al., 2005). and immunodeficiency (see Chapter 78; Tebruegge and Curtis, 2008).
Recurrent meningitis can also be caused by chemical irritants leaked
from tumors like dermoids, epidermoids, or craniopharyngiomas.
CHRONIC MENINGITIS Drug-induced meningitis, most common as an idiosyncratic reaction
Most cases of chronic meningitis are due to infection (see Chapter 78), to NSAIDs, can recur with repeated drug exposures. Rarely, recurrent
neoplasia (see Chapter 76), or sarcoidosis (see Chapter 58). A com- meningitis can complicate systemic inflammatory diseases such as sys-
prehensive differential diagnosis includes Behçet syndrome, isolated temic lupus erythematosus, Sjögren syndrome, Behçet disease, Lyme
CNS angiitis (see Chapter 70), systemic lupus erythematosus, Sjögren disease, familial Mediterranean fever, or sarcoidosis.
syndrome, or granulomatosis with polyangiitis (formerly Wegener Recurrent benign lymphocytic meningitis, sometimes called Mollaret
granulomatosis). Some other chronic or recurring meningitic syn- meningitis, can cause multiple self-limited attacks with symptoms such
dromes merit discussion; however, a cause is not found in many cases as headache, fever, and meningismus. Each attack generally lasts a few
of chronic meningitis. days (Shalabi and Whitley, 2006). Transient neurological features that
may include seizures, hallucinations, diplopia, cranial nerve palsies,
Chronic Adhesive Arachnoiditis or altered consciousness can accompany the syndrome, implying that
Focal or diffuse inflammation of the spinal theca can cause neuro- some cases are actually meningoencephalitis. The spinal fluid shows
logical symptoms caused by inflammation, adhesion, and distortion a mixed pleocytosis, sometimes including large macrophage-like cells
of nerve roots or spinal cord. This condition is termed chronic spinal (Mollaret cells). Most cases are due to herpes virus infections, especially
arachnoiditis or chronic adhesive arachnoiditis. However, the process HSV2. In other cases, echovirus, coxsackie, and Epstein-Barr have been
usually involves all layers of the meninges and in its chronic stages may identified. Antiviral therapies (e.g., acyclovir, valacyclovir, famciclovir)
be fibrotic rather than inflammatory. Calcification of the meninges have been trialed in patients, though there is no controlled trial data to
(arachnoiditis ossificans) is an occasional late finding. Clinically, the support their efficacy in preventing disease recurrence (Pearce, 2008).
condition manifests as a gradually ascending, painful cauda equina Some argue that the eponym Mollaret meningitis should be reserved for
syndrome followed by a myelopathy as the arachnoiditis reaches the those cases without an identified causative organism: in other words,
spinal cord. Death may result in 3–10 years from decubiti, urosepsis, idiopathic recurrent aseptic meningitis.
and other complications of severe paraplegia. The uveomeningal syndromes are a group of disorders which com-
Adhesive arachnoiditis occasionally complicates a variety of surgical monly involve the uvea, retina, and meninges. The combination of
or medical violations of the thecal sac (eBox 104.8). Historically, severe chronic or recurrent meningitis and uveitis has a specific differential
cases of TB or syphilis invaded the spine and caused arachnoiditis. In diagnosis (Yeh et al., 2011; eBox 104.9). Specific entities include: gran-
recent years, fungal meningitis from tainted epidural steroid injections ulomatosis with polyangiitis, sarcoidosis, Behcet disease and acute pos-
has been a culprit. Arachnoiditis of the spinal cord is less common terior multifocal placoid pigment epitheliopathy (Brazis et al., 2004).
but can also occur after apparently successful treatment of epidural Often, ophthalmological characterization of the uveitis can refine the
or vertebral infection and can lead to myelopathy. Involvement at the differential diagnosis. For example, the uveitis of Vogt-Koyanagi-
craniocervical junction can be a cause of acquired syringomyelia. Focal Harada syndrome is bilateral and often causes retinal elevations and ret-
arachnoiditis is most common in the cauda equina following lumbar inal pigmentary changes. Vogt-Koyanagi-Harada syndrome also causes
disk surgery or myelography, particularly if oil-based contrast has skin and hair findings such as vitiligo, poliosis, and focal alopecia.
been used for the latter. Oil-based myelography dye has fallen out of
use for many years, but some patients can still be seen who had such Pachymeningitis
agents used when they were young. The symptoms of arachnoiditis Pachymeningitis is a rare condition, visible on MRI scans as thickened
can include local or radicular pain, radicular paresthesia, and less gadolinium-enhancing dura (Kupersmith et al., 2004; Fig. 104.39).
commonly more severe findings of polyradiculopathy such as motor The differential diagnosis is extensive (eBox 104.10). Low CSF pres-
loss or sphincter dysfunction. The diagnosis can usually be made by sure from causes such as post-lumbar puncture or idiopathic intra-
spinal MRI, which may show clumping of nerve roots, nodules in cranial hypotension can also cause apparent dural “enhancement”
the subarachnoid space, loculation of spinal fluid, and local areas of on MRI secondary to venous engorgement. The enhancement when
enhancement. The nerve roots may clump at the periphery of the the- the CSF pressure is low is usually diffuse and smooth, whereas pachy-
cal sac, usually adjacent to an area of previous surgery, or in the center meningitis can cause diffuse or localized irregular areas of enhance-
of the sac, usually in areas of spinal stenosis. The extent of the MRI ment. Idiopathic hypertrophic pachymeningitis refers to those cases for
findings correlates poorly with the severity of the clinical nerve root which cultures, serology, and dural biopsy fail to reveal a causative
dysfunction. Spinal fluid may show increased CSF protein levels and infection, tumor, or systemic inflammatory disease. These patients
mild to moderate mononuclear pleocytosis. Surgical debridement of can present with headache, cranial neuropathies, ataxia, or seizures.
the arachnoiditis is almost never attempted, is usually unsuccessful and Pachymeningitis in the spinal canal can cause radiculopathy or
may lead to increased scarring and progression of neurological deficits. myelopathy. CSF may show high protein or lymphocytic pleocytosis,
Epidural or intrathecal corticosteroids are sometimes tried, but there is but is sterile. Dural biopsy shows small mature lymphocytes, plasma
eFig. 104.38 Magnetic Resonance Image Shows Epidural Lipomatosis. T1-weighted axial images show
markedly increased fat (arrows) within spinal canal, compressing the thecal sac, which is quite small. Note
that the patient is quite obese, with large amounts of fat in the retroperitoneum and posterior paraspinous
tissues (open arrows). (Courtesy Erik Gaensler.)
eBOX 104.8 Causes of Adhesive eBOX 104.10 Causes of Thickened,

Arachnoiditis Abnormally Enhancing Dura Mater on
Myelography, especially with oil-based dyes
Gadolinium Magnetic Resonance Imaging
Spinal surgery Idiopathic cranial or spinal pachymeningitis
Ankylosing spondylitis Intracranial hypotension:
Intrathecal or epidural chemical exposure (e.g., spinal anesthesia, corticoste- Spontaneous
roids) Post spinal fluid drainage
Granulomatous infection (e.g., tuberculosis) Infections:
Ruptured dermoid or epidermoid cyst Lyme disease
Syphilis
Mycobacterium tuberculosis
Fungal infections
Cysticercosis
eBOX 104.9 Causes of Combined Uveitis Human T-cell lymphotrophic virus type 1 (HTLV-1)
and Meningitis Malignant external necrotizing otitis due to Pseudomonas
Acute multifocal placoid pigmentary epitheliopathy Systemic autoimmune/vasculitic disorders:
Acute retinal necrosis granulomatosis with polyangiitis
Behçet syndrome Rheumatoid arthritis
Human T-cell lymphotropic virus type 1 (HTLV-1) infection Sarcoidosis
Infection in immunocompromised host Behçet disease
Isolated central nervous system angiitis Sjögren syndrome
Lyme disease Temporal arteritis
Primary central nervous system lymphoma Malignancy:
Sarcoid Dural carcinomatosis
Syphilis Metastatic disease in adjacent skull bone
Systemic lupus erythematosus Lymphoma
Vogt-Koyanagi-Harada syndrome Meningioma
Trauma
Reprinted with permission from Rosenbaum, R.B., Campbell, S.M.,
Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease.
Butterworth-Heinemann, Boston.
A B
Fig. 104.39 Dural Enhancement. Axial (A) and coronal (B) T1-weighted images following gadolinium infu-
sion. In this case of pachymeningitis, the enhancement pattern is thin and diffuse; other cases show more
localized or irregular thickening.
cells, and epithelioid histiocytes. Immunoglobulin G4-related disease stereotyped episodes of weakness, sensory disturbance, or other focal
(IgG4-RD) is an increasingly recognized immune-mediated cause of deficits which spread over contiguous body parts (Charidimou et al.,
hypertrophic pachymeningitis. IgG4-RD has been previously described 2012) It is this gradual spread of symptoms which differentiate these
to cause autoimmune pancreatitis, sclerosing cholangitis and other spells from transient ischemic attacks. The underlying mechanism is
systemic disorders (Kamisawa et al., 2015). While rare, isolated CNS thought to be focal seizure activity or spreading cortical depression in
involvement has been described and it is an important entity to be response to small underlying hemorrhages. This theory has been sup-
aware of (Hayashi et al., 2018). Patients can improve after treatment ported by anecdotal evidence that anticonvulsant medications are effi-
with corticosteroids, sometimes supplemented with steroid-sparing cacious in alleviating these spells (Greenberg et al., 1993). In addition
immunosuppressants such as azathioprine and methotrexate. to supportive measures, treatment is focused on arresting the source
of bleeding once identified. In the case of cerebral amyloid angiopathy
Superficial Hemosiderosis there should be an attempt to medically optimize underlying vascular
Superficial hemosiderosis is a neurodegenerative disorder resulting risk factors (e.g., hypertension, hyperglycemia, dyslipidemia). Finally,
from recurrent leakage of blood into the subpial space. Analysis of CSF given the elevated hemorrhage risk, caution should be exercised when
often reveals xanthochromia, red blood cells, and/or elevated protein. placing this population on anticoagulants or antiplatelet agents.
Not all patients have an identifiable source of hemorrhage. Possible
sources include brain or spine trauma, neurosurgery, cerebral or spinal
FIBROMYALGIA
aneurysms or vascular malformations, cerebral amyloid angiopathy,
or spinal dural defects. Some patients with spinal dural leaks develop Fibromyalgia, a syndrome defined by chronic, diffuse musculoskeletal
both superficial hemosiderosis and intracranial hypotension (Kumar or soft-tissue pain and multiple tender points, is part of the differential
et al., 2007). Common neurological clinical manifestations include gait diagnosis of many patients with spinal pain. Patients may have numer-
ataxia and sensorineural deafness. These are sometimes accompanied ous other complaints across multiple organ systems, though their phys-
by other upper motor neuron exam findings: limb spasticity, brisk ical examinations are typically normal. The sheer volume of seemingly
reflexes, extensor plantar responses, bladder disturbance, or sensory unconnected symptoms and the lack of objective data to support those
signs (Kumar et al., 2006). Less common features include dementia, grievances are often a source of great frustration to healthcare providers.
anosmia, or anisocoria, and, more rarely, extraocular motor palsies, Similarly, patients may feel as though their ailment is not taken seriously
neck or backache, or radicular pain. While the clinical presentation or that there is some occult disease which has yet to be recognized. This
and examination are often nonspecific, the neuroradiological abnor- frustration on both sides is compounded by the general lack of under-
malities are striking. MRI shows a black rim around the posterior fossa standing regarding the disease itself. Although many mechanisms have
structures and spinal cord and less often the cerebral hemispheres on been proposed, no consensus has been reached as to the underlying
T2-weighted images (Fig. 104.40). These paramagnetic signal changes pathogenesis of the condition. That said, some believe the entity to be
represent encrustation of the brain surfaces with hemosiderin. The within the continuum of central sensitization syndromes, arising from
adjacent neural tissue atrophies, with accumulation of ferritin in dysfunction of central pain processing pathways (Clauw et al., 2011).
microglia and Bergmann cells in the cerebellum. The pattern of hemo- The American College of Rheumatology has proposed diagnostic
siderin deposition can sometimes be a clue to the underlying etiology. criteria for fibromyalgia and for the monitoring of symptom severity
Focal involvement is more likely the result of trauma or an underlying (SS). They suggest that a patient must have “widespread” pain and
vascular anomaly. Whereas disseminated superficial siderosis appears multiple somatic symptoms. The pain must persist for greater than 3
to be more specific for cerebral amyloid angiopathy (Charidimou months and must not otherwise be explained by a separate disorder.
et al., 2013). Another clinically important phenomenon related to A widespread pain index (WPI) is defined as the number of painful
cerebral amyloid angiopathy and secondary hemosiderosis is tran- areas out of 19 predetermined locations. Patients are also given an SS
sient neurological symptoms. Patients can experience recurrent, brief, score which describes the degree to which their condition impedes
Fig. 104.40 Axial T2-weighted magnetic resonance images demonstrate a thin ring of hypointensity sur-
rounding the medulla and midbrain, indicating hemosiderin deposition along the leptomeninges. (Courtesy
Jim Anderson, Oregon Health Sciences University, Portland, OR.)
their daily functioning. A score between 0 (no problems) and 3 (severe, syndrome. Neuroscientific research on the pathogenesis of fibromy-
pervasive problems) are assigned for three symptoms: fatigue, waking algia has examined muscle, sleep, neuroendocrine function, and cen-
unrefreshed, and cognitive symptoms. The number of somatic symp- tral pain processing, including studies using functional brain imaging
toms (e.g., headache, dizziness, cramps, paresthesias, chest pain, etc.) (Nebel and Gracely, 2009). Symptoms and signs of fibromyalgia can
are tallied from a review of systems. Somatic symptoms are also given occur in association with autoimmune diseases such as systemic lupus
a score between 0 (no symptoms) and 3 (a great deal of symptoms). erythematosus or other systemic illness such as hypothyroidism. Focal
The SS is calculated by combining the four values, with a maximum trauma can cause localized self-limited soft-tissue myofascial pain. The
score of 12. A patient satisfies the diagnostic criteria for fibromyalgia pathogenic role of trauma, on-the-job injury, or workplace stress is
when the WPI is ≥7 and SS is ≥5 or when the WPI is ≥3 and the SS is controversial. Treatment includes a supportive doctor–patient rela-
≥9 (Wolfe et al., 2011). tionship, aerobic exercise, and avoiding inactivity. Pregabalin, dulox-
Chronic pain syndromes, such as fibromyalgia, result in significant etine, and milnacipran are now approved by the US Food and Drug
psychosocial impairment, lost wages, and higher (often unnecessary) Administration (FDA) for treatment of fibromyalgic pain. Other drugs
healthcare utilization. A number of pharmacological and nonpharma- for chronic pain (e.g., tricyclic antidepressants) are sometimes tried
cological treatments have been explored. Current evidence suggests off-label. Small short-term controlled studies have suggested that some
that small doses of tricyclic antidepressants, cardiovascular exercise, patients benefit from acupuncture.
cognitive behavioral therapy, and patient education have utility, but
often provide incomplete or unsatisfactory results (Talotta, 2017). The complete reference list is available online at https://expertconsult.
The cause of most cases of fibromyalgia is unknown. Behavioral and inkling.com/.
biological factors both contribute to the clinical presentation of the
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105
Disorders of Nerve Roots and Plexuses
David A. Chad, Michael P. Bowley
OUTLINE
Disorders of Nerve Roots, 1829 Electrodiagnostic Studies, 1842
Anatomical Features, 1829 Radiological Studies, 1844
Traumatic Radiculopathies, 1830 Traumatic Plexopathy, 1844
Diabetic Polyradiculoneuropathy, 1835 Neurogenic Thoracic Outlet Syndrome, 1844
Neoplastic Polyradiculoneuropathy (Neoplastic Metastatic and Radiation-Induced Brachial Plexopathy in Patients
Meningitis), 1837 with Cancer, 1845
Infectious Radiculopathy, 1838 Idiopathic Brachial Plexopathy, 1846
Acquired Demyelinating Polyradiculoneuropathy, 1840 Disorders of the Lumbosacral Plexus, 1848
Acquired Disorders of the Dorsal Root Ganglia, 1841 Anatomical Features, 1848
Radiculopathies Simulating Motor Neuron Disease, 1841 Clinical Features, 1849
Disorders of the Brachial Plexus, 1842 Differential Diagnosis, 1849
Anatomical Features, 1842 Structural Lumbosacral Plexopathy, 1849
Clinical Features and Diagnosis, 1842 Nonstructural Lumbosacral Plexopathy, 1852
Neurological Examination, 1842 Idiopathic Lumbosacral Plexopathy, 1852

A disorder of the nerve roots is favored by abnormalities of the CSF

DISORDERS OF NERVE ROOTS (raised protein concentration and pleocytosis), paraspinal muscle nee-
The spinal nerve roots serve as the transition from the peripheral ner- dle electromyographic (EMG) examination (presence of positive sharp
vous system to the central nervous system (CNS). Each spinal nerve is waves and fibrillation potentials), and spinal cord magnetic resonance
derived from anterior (ventral) and posterior (dorsal) nerve roots; the imaging (MRI) (compromise or contrast enhancement of the nerve
anterior roots carrying efferent motor information from anterior horn roots per se).
cells of the spinal cord, and the posterior nerve roots carrying affer- The sections that follow cover some anatomical features relevant to
ent sensory information as the central axons of the pseudo-unipolar an understanding of the pathological conditions that affect the nerve
dorsal root ganglia cells. Both anterior and posterior nerve roots are roots, as well as specific nerve root disorders.
susceptible to diseases specific to their location and to many of the dis-
orders that affect peripheral nerves in general. Although surrounded Anatomical Features
by a rigid bony canal, they are delicate structures subject to compres- Each nerve root is attached to the spinal cord by four to eight root-
sion and stretching. Bathed by cerebrospinal fluid (CSF), they may lets that are splayed out in a longitudinal direction (Rankine, 2004).
be exposed to infectious, inflammatory, and neoplastic processes that The dorsal rootlets are attached to the spinal cord at a well-defined
involve the leptomeninges. Separated from the blood by an incomplete posterolateral sulcus, whereas the ventral rootlets are more widely sep-
blood–nerve barrier, the dorsal root ganglion (DRG) neurons may be arated and emerge over a greater area of the anterior surface of the
injured by circulating neurotoxins. spinal cord. For each spinal cord segment, a pair of dorsal and ven-
In the clinical sphere, it is usually not difficult to recognize symp- tral roots unite just beyond the DRG to form a short mixed spinal
toms or signs attributable to lesions of a single nerve root. Radicular nerve that divides into a thin dorsal ramus and a thicker ventral ramus
pain and paresthesias are accompanied by sensory loss in the der- (Fig. 105.1). The dorsal ramus innervates the deep posterior muscles
matome (the area of skin innervated by a nerve root), weakness in of the neck and trunk (the paraspinal muscles) and the skin overlying
the myotome (defined as muscles innervated by a spinal cord segment these areas. The ventral ramus, depending on its spinal segment, con-
and its nerve root), and diminished deep tendon reflex activity sub- tributes to an intercostal nerve, or to the cervical, brachial, or lumbosa-
served by the nerve root in question. However, when multiple roots are cral plexi and thereby supplies the trunk or limb muscles.
involved by a disease process (polyradiculopathy) the clinical picture Directly adjacent to the spinal cord, the nerve roots lie freely in the
may resemble a disorder of the peripheral nerves, as in a polyneurop- subarachnoid space, covered by a thin root sheath, composed of a layer
athy, or of the anterior horn cells, as in the progressive muscular atro- of flattened cells, that is continuous with the pial and arachnoidal cov-
phy form of amyotrophic lateral sclerosis (ALS). In these complicated erings of the spinal cord. Compared with spinal nerves, the roots have
clinical settings, clinicians may often turn to serological, radiological, fewer connective tissue cells in the endoneurium and considerably less
and electrodiagnostic studies to aid in diagnosis. collagen. Moreover, they lack an epineurium, as this dense connective
1829
CSF population of unmyelinated and thinly myelinated axons that come

Spinal cord from sensory and sympathetic ganglia (Hildebrand et al., 1997).
Dura
Dorsal nerve There are 31 pairs of spinal nerves that run through the interverte-
Arachnoid bral foramina of the vertebral column: 8 cervical, 12 thoracic, 5 lum-
rootlets
Pia Joint bar, 5 sacral, and 1 coccygeal (Fig. 105.2). Each cervical nerve root exits
Ligamentum above its corresponding vertebral segment, with the sole exception
dental Dural being the C8 nerve root, which exits below C7 and above T1. At tho-
septum racic, lumbar, and sacral levels, each root exits below its corresponding
Spinal vertebral level. An additional feature of clinical relevance is the pattern
ganglion formed by the lumbar and sacral roots as they leave the spinal cord and
make their way to their respective DRG to form spinal nerves. In the
Vertebral Dorsal
ramus
adult, the spinal cord is shorter than the spinal column, ending usually
artery between L1 and L2. Therefore, the lumbar and sacral roots descend
of nerve
Posterior Ventral ramus caudally from the spinal cord to reach the individual intervertebral
longitudinal of nerve foramina, forming the cauda equina. The concentration of so many
ligament nerve roots in a confined area makes this structure vulnerable to a
Ventral nerve
Anterior rootlets range of pathological processes.
longitudinal
Body of
ligament
vertebra Traumatic Radiculopathies
Fig. 105.1 Relations of Dura to Bone and Roots of Nerve Shown in Nerve Root Avulsion
an Oblique Transverse Section. On the right, the relations between As noted earlier, each spinal root is composed of lesser amounts of
the emergent nerve and the synovial joint are seen, but the joint collagen and is not supported by a dense epineural sheath compared to
between the vertebral bodies is not in the plane of the section. Dorsal the mixed spinal nerves they form. This lack of reinforcement results
and ventral roots meet at the dorsal root ganglion in the intervertebral in the spinal roots having approximately one-tenth the tensile strength
foramen to form the mixed spinal nerve. The small dorsal ramus is the of their corresponding peripheral nerves. Thus, the nerve root is the
most proximal branch of the mixed spinal nerve and serves the cervical weakest link in the nerve root–spinal nerve–plexus complex, leading to
paraspinal muscles (not shown). The dura becomes continuous with the root avulsion in the setting of traumatic traction injuries. Ventral roots
epineurium of the mixed spinal nerve at the intervertebral foramen. The
are more vulnerable to avulsion than dorsal roots, a consequence of
posterior longitudinal ligament helps contain the intervertebral disk (not
the dorsal roots having the interposed DRG and a thicker dural sheath.
shown), preventing protrusion into the spinal canal. CSF, Cerebrospi-
nal fluid. (Reprinted with permission from Wilkinson, M., 1971. Cervical In most cases, root avulsion occurs in the cervical region. Lumbosacral
Spondylosis: Its Early Diagnosis and Treatment. Saunders, Philadelphia.) nerve root avulsions are rare, and when they occur are generally associ-
ated with fractures of the sacroiliac joint with diastasis of the symphysis
pubis or fractures of the pubic rami (Chin and Chew, 1997).
tissue layer is contiguous with the dura mater. A capillary network Avulsion at the level of the cervical roots can be total or may
derived from the radicular arteries provides the blood supply to the result in two clinical syndromes of partial avulsion. One is Erb-
spinal nerve roots (Becske and Nelson, 2009). Duchenne palsy, in which the arm hangs at the side, internally
Where the nerve roots form the mixed spinal nerve, the pial cov- rotated, and extended at the elbow because of paralysis of C5- and
ering of the root becomes continuous with spinal nerve perineurium, C6-innervated muscles (the supraspinatus, infraspinatus, del-
and the nerve takes the dural nerve root sheath through the interverte- toid, and biceps). The second is Dejerine-Klumpke palsy, in which
bral foramen to become continuous with the epineurium of the mixed there is weakness and wasting of the intrinsic hand muscles, with
nerve. At the intervertebral foramen, the root–DRG–spinal nerve com- a characteristic claw-hand deformity due to paralysis of C8- and
plex is securely attached by a fibrous sheath to the transverse process of T1-innervated muscles. Injuries responsible for Erb-Duchenne
the vertebral body. At cervical and thoracic levels, the DRG is located palsy are those that cause a sudden and severe increase in the angle
in a protected position within the intervertebral foramina, but at the between the neck and shoulder, generating stresses that are readily
lumbar and sacral levels, the DRG may reside proximal to the neural transmitted in the direct line along the upper portion of the bra-
foramina in an intraspinal location (Levin, 2002) and therefore may be chial plexus to the C5 and C6 roots. Today, motorcycle accidents
vulnerable to direct compression as a result of disk herniation or from are the most common cause of this injury, but the classic para-
bony changes induced by osteoarthritis and lumbosacral spondylosis. digm is C5 and C6 root avulsions occurring in newborns during
Nerve fibers, together with their meningeal coverings, occupy obstetrical procedures. Brachial plexus injuries in the newborn are
35%–50% of the cross-sectional area of an intervertebral foramen. The discussed in Chapter 112. Dejerine-Klumpke palsy occurs when the
remaining space is occupied by loose areolar connective tissue, adi- limb is elevated beyond 90 degrees and tension falls directly on the
pose tissue (fat), and blood vessels. On computed tomographic (CT) lower trunk of the plexus, C8, and T1 roots. Such an injury may
and MRI scans, the fat acts as an excellent natural contrast agent that occur in a fall from a height in which the outstretched arm grasps
defines the thecal sac and nerve roots, allowing the detection of nerve an object to arrest the fall, or during obstetrical traction on the
root compression. extended arm when a newborn is delivered arm first.
The dorsal roots contain sensory fibers that are central processes Clinical features and diagnosis. At the onset of root avulsion,
of the DRG. On reaching the spinal cord, these fibers either synapse flaccid paralysis and complete anesthesia develop in the myotomes
with other neurons in the posterior horn or pass directly into the pos- and dermatomes served by the affected ventral and dorsal roots,
terior columns. In the ventral root, most fibers are essentially direct respectively. Clinical features supplemented by electrophysiological
extensions of anterior horn motor neurons or of neurons in the inter- and radiological studies help determine whether the cause of severe
mediolateral horn (preganglionic sympathetic neurons found in lower weakness and sensory loss is root avulsion or an extraspinal lesion of
cervical and thoracic segments). In addition, ventral roots contain a plexus or nerve.
CHAPTER 105 Disorders of Nerve Roots and Plexuses 1831
C1 For example: in the setting of a suspected C5 nerve root avulsion,

I C1 I
2 one would predict marked weakness of the rhomboids and spinati
II 2 II
3 muscles (innervated primarily by C5) and a lesser degree of weakness
III 3 III of those muscles of the upper trunk of the brachial plexus (deltoid,
4
IV 4 IV biceps, brachioradialis) which receive additional innervation from C6.
5 5
V 6 V A clinical sign of T1 root avulsion is an ipsilateral Horner syndrome
6 caused by damage to preganglionic sympathetic fibers as they traverse
VI 7 VI
VII
8 7 the ventral root to their destination in the superior cervical ganglion.
VII
T1 Electrophysiological tests that are valuable in differentiating a root
TI 8
2 TI avulsion from traumatic plexus or nerve injury include the measure-
II 3 T1 ment of a sensory nerve action potential (SNAP) and needle EMG
II
III 4 2 examination of the cervical paraspinal muscles. In the setting of a
III
IV 3
dorsal root avulsion, the patient may experience complete anesthesia
5
IV in the dermatome, yet the SNAP is preserved as the DRG cell bod-
V 6 4
V ies and the peripheral portions of their axons remain intact. Needle
7 5 EMG of the cervical paraspinal muscles permits separation of damage
VI VI
6 of the plexus and of ventral root fibers because the posterior primary
8 VII ramus, which arises just beyond the DRG and proximal to the plexus
VII
7 as the first branch of the spinal nerve, innervates these muscles (see
9 VIII
VIII 8 Fig. 105.1). Thus, cervical paraspinal fibrillation potentials support the
10 diagnosis of root avulsion.
IX
IX
11
9 In most cases, these tests are helpful in ascertaining whether root
X avulsion has occurred, but clinical assessment may be challenging, and
12 10
X testing results may be ambiguous. The physical examination may be
L1
XI
11 limited because of severe pain. An absent SNAP indicates sensory axon
2
XI
3 XII
loss distal to the DRG but does not exclude coexisting root avulsion.
4
12
Even when this test of sensory function points to avulsion of the dor-
XII 5
S1
sal component of the root, the status of the ventral root may remain
LI
2 uncertain if paraspinal fibrillation potentials are not found. Paraspinal
3 L1
LI
4 fibrillation potentials may be absent for two reasons. First, they do not
5 II
appear for 7–10 days after the onset of axonotmesis; and second, even if
II 2 the timing of the needle EMG is right, they may not be seen because of
III the innervation of paraspinal muscles from multiple segmental levels.
III
3 Paraspinal muscles have also been evaluated radiologically in the
setting of root avulsion. Contrast-enhanced MRI studies of the cervical
IV IV
paraspinal muscles showing severe atrophy were accurate in indicat-
4 ing root avulsion injuries, and abnormal enhancement in the multif-
V
V idus muscle was the most accurate among paraspinal muscle findings
(Hayashi et al., 2002). Intraspinal neuroimaging using postmyelo-
5 graphic CT or MRI usually demonstrates an outpouching of the dura
filled with contrast or CSF at the level of the avulsed root (Rankine,
S1
2004). This posttraumatic meningocele results from tears in the dura
2 and arachnoid sustained during root avulsion.
Treatment. Root avulsion produces a severe neurological deficit
3 that was once considered untreatable. In recent decades, microsurgical
4 techniques and intraoperative electrophysiological studies have
5 improved prospects for recovery for many patients with severe injury
Coc.1 to peripheral nerves. The procedures of neurolysis (freeing intact
nerve from scar tissue), nerve grafting (bridging ruptured nerves),
Fig. 105.2 Relationship of Spinal Segments and Nerve Roots to
Vertebral Bodies and Spinous Processes in the Adult. Cervical and neurotization, or nerve transfer (attaching a donor nerve to a
roots C1–C7 (i.e., all except C8) exit through foramina above the ver- ruptured distal stump), have all been employed in the management of
tebral body of the same number. The C8 root passes through the C7– root avulsion injuries (Rankine, 2004). After C5 and C6 root avulsion
T1 neural foramen, and all thoracic, lumbar, and sacral roots leave the injuries, for example, the plegic elbow flexors may be restored by several
spinal canal below the body of the vertebrae of the same number. procedures that provide for neurotization of the musculocutaneous
The spinal cord is shorter than the spinal column, ending between nerve, including reinnervating the biceps with nerve fascicles from an
vertebral bodies L1 and L2. Lumbar and sacral roots form the cauda unaffected donor nerve (Rankine, 2004; Samil et al., 2003; Sulaiman
equina and descend caudally, beside and below the spinal cord, to et al., 2009; Teboul et al., 2004). Carlstedt and colleagues (1995)
exit at the intervertebral foramina. (Reprinted with permission from
pioneered another approach—nerve root repair and reimplantation.
Haymaker, W., Woodhall, B., 1953. Peripheral Nerve Injuries, second
They reported on a patient who had an avulsion injury involving C6–
ed. Saunders, Philadelphia.)
T1 in whom they were able to successfully implant two ventral roots
(C6 directly and C7 via sural nerve grafts) into the spinal cord through
slits in the pia mater. The successful reimplantation of avulsed ventral
roots is time dependent, with better outcomes in motor strength seen strain or direct injury, in many instances there is no history of clinically
if repair is attempted within 4 weeks of injury (Carlstedt, 2009). The significant trauma preceding the onset of radiculopathy.
surgical treatment of patients with avulsion injuries is an area of active Reinforcing the annulus fibrosus posteriorly is the posterior lon-
ongoing investigation with the promise that if continuity between gitudinal ligament, which in the lumbar region is dense and strong
spinal cord and nerve roots can be restored, subsequent recovery of centrally, and less well developed in its lateral portion. Because of this
function may be possible. For example, measurement of power in anatomical feature, the direction of lumbar disk herniations tends to
upper extremity muscles years after cervical root reimplantation is be posterolateral, compressing the nerve roots in the lateral recess of
associated with a proximal to distal gradient of successful recovery the spinal canal. Less commonly, more lateral (foraminal) herniations
with shoulder girdle muscles (serratus anterior, pectoralis major and compress the nerve root against the vertebral pedicle in the interver-
minor, and supraspinatus) potentially achieving Medical Research tebral foramen (Fig. 105.3). On occasion, the degenerative process
Council (MRC) grade 4 or 5 strength, proximal upper extremity may be particularly severe. This leads to large rents in the annulus and
muscles (deltoid, biceps) achieving grade 3 or 4 strength and forearm posterior longitudinal ligament, thereby permitting disk material to
and hand muscles demonstrating little meaningful recovery (Carlstedt, herniate into the spinal canal as a free fragment with the potentially
2009). While functional motor recovery varies, the oft intractable damaging capacity to migrate superiorly or inferiorly and compress
pain of cervical root avulsion injuries is more responsive to surgical two or more nerve roots. Most cervical disk herniations are postero-
intervention in most patients (Kato et al., 2006). lateral or foraminal.
In the cervical and lumbar regions, alteration in the integrity of the
Disk Herniation disk space is a component of a degenerative condition termed spondy-
Beginning in the third or fourth decade of life, cervical and lumbar losis, characterized by osteoarthritic changes in the joints of the spine,
intervertebral disks are liable to herniate into the spinal canal or inter- the disk per se (desiccation and shrinkage of the normally semisolid,
vertebral foramina and impinge on the spinal cord (in the case of cer- gelatinous nucleus pulposus), and the facet joints. Because it spawns
vical disk herniations), nerve roots (in both cervical and lumbosacral osteophyte formation, spondylosis leads to compromise of the spi-
regions), or both (at the cervical level where on occasion large central nal cord in the spinal canal and the nerve roots in the intervertebral
and paracentral disk herniations may produce a myeloradiculopathy) foramina. Restriction in the dimensions of these bony canals may be
(see Chapter 104). exacerbated by thickening and hypertrophy of the ligamentum flavum,
Two factors contribute to this alteration in the intervertebral disks: which is especially detrimental in patients with congenital cervical or
degenerative change and trauma. An intervertebral disk is composed of lumbar canal stenosis.
a central, gelatinous, nucleus pulposus, and, surrounding, fibrocarti- In the cervical region, nerve root compression in patients older
laginous, annulus fibrosus. With age, the fibers of the annulus fibrosus than 50 years is often due to disk herniation superimposed on chronic
lengthen, weaken, and fray, thereby allowing the disk to bulge poste- spondylotic changes. Isolated “soft” cervical disk herniation tends to
riorly. In the setting of such changes, relatively minor trauma leads to occur in younger people in the setting of neck trauma. In the lum-
further tearing of annular fibers and ultimately to herniation of the bosacral region, isolated acute disk herniation is a common cause of
nucleus pulposus. This “soft-disk” herniation occurs mainly during radiculopathy in the younger patient (<40 years), whereas bony root
the third and fourth decades of life when the nucleus is still gelatinous. entrapment with or without superimposed disk herniation is the more
In fact, although disk herniations may be preceded by unaccustomed typical cause of lumbosacral radiculopathy in the patient older than 50.
L4 Vertebra
Posterior-lateral L4 Spinal nerve
protrusion
of L4-L5 disk L4-5 Central disk protrusion
L5 Vertebra
L5 Spinal nerve
Posterior-lateral
protrusion Lateral protrusion of L5-S1 disk
of L5-S1 disk S1 Spinal nerve
Fig. 105.3 Dorsal View of Lower Lumbar Spine and Sacrum, Showing the Different Types of Hernia-
tions and How Different Roots and the Cauda Equina Can Be Compressed.
Clinical features. Root compression from disk herniation In an S1 radiculopathy, pain radiates to the buttock and down the
gives rise to a distinctive clinical syndrome comprising radicular back of the leg (classic sciatica), often extending below the knee; par-
pain, dermatomal sensory loss, weakness in the myotome, and esthesias are generally felt in the lateral ankle and foot. The ankle jerk
reduction or loss of the deep tendon reflex subserved by the is generally diminished or lost, and weakness may be detected in the
affected root (Carette and Fehlings, 2005). Nerve root pain is plantar flexors, knee flexors, and hip extensors.
variably described as knife-like or aching and is widely distributed, In an L5 radiculopathy, the distribution of pain is similar, but par-
projecting to the sclerotome (defined as deep structures such as esthesias are felt on the dorsum of the foot and the outer portion of the
muscles and bones innervated by the root). Typically, root pain is calf. The ankle reflex is typically normal, but there may be reduction of
aggravated by coughing, sneezing, and straining at stool (actions the medial hamstring reflex. Weakness may be found in L5-innervated
that require a Valsalva maneuver and raise intraspinal pressure). muscles served by the peroneal nerve (including the extensor hallucis
Accompanying the pain are paresthesias referred to the specific longus, tibialis anterior and peronei), tibial nerve (tibialis posterior),
dermatome, especially to the distal regions of the dermatomes; and the superior gluteal nerve (including gluteus medius). Weakness
indeed, these sensations strongly suggest that the pain has its may be restricted to the extensor hallucis longus, or be more extensive
origins in compressed nerve roots rather than spondylotic facet and involve the tibialis anterior, resulting in foot drop.
joints. Sensory loss caused by the compromise of a single root A positive straight leg–raising test result is a sensitive indicator of
may be difficult to ascertain because of the overlapping territories L5 or S1 nerve root irritation. The test is deemed positive when the
of adjacent roots, although loss of pain is usually more easily patient complains of pain radiating from the back into the buttock and
demonstrated than loss of light touch sensation (Fig. 105.4). thigh with leg elevation to less than 60 degrees. The test result is posi-
Most radiculopathies occur in the lumbosacral region; compressive tive in up to 83% of patients with a proven disk herniation at surgery.
root lesions in this area account for 62%–90% of all radiculopathies. A less sensitive but highly specific test is the crossed straight leg–raising
Cervical radiculopathies are less common, comprising 5%–36% of all test when the patient complains of radiating pain on the affected side
radiculopathies encountered. with elevation of the contralateral leg.
In the lumbosacral region, 95% of disk herniations occur at the The less common L4 radiculopathy is characterized by pain and
L4–L5 or L5–S1 levels; L3–L4 and higher lumbar disk herniations are paresthesias along the medial aspect of the knee and lower leg. The
uncommon (Deyo and Weinstein, 2001). In perhaps only 10% of cases patellar reflex is diminished, and weakness may be noted in the quad-
of the disk herniating far laterally into the foramen is there compres- riceps and hip adductors (innervated by the femoral and obturator
sion of the exiting nerve root. More commonly, the posterolateral disk nerves, respectively). When large herniations occur in the midline at
herniation compresses the nerve root passing through the foramen either the L4–L5 or the L5–S1 level, many of the nerve roots running
below that disk, so L4–L5 and L5–S1 herniations usually produce L5 past that level to exit through intervertebral foramina below that level
and S1 radiculopathies, respectively (see Fig. 105.3). may be compressed, producing the cauda equina syndrome of bilateral
Touch
sensation Pain
sensation
Fig. 105.4 The Zones of Radicular Touch and Pain Sensation. The area for touch sensation (dark orange)
supplied by one single root is wider than the area of pain sensation (light orange). Areas of pain sensation do
not overlap or at most overlap incompletely, whereas areas of touch sensation of a single root are completely
overlapped by those of the adjacent roots (A). Accordingly, monoradicular lesions (B) produce a hypalgesic
or analgesic zone, while touch sensation remains intact or only minimally impaired. Only after two roots are
involved is an anesthetic zone present.
radicular pain, paresthesias, weakness, attenuated reflexes below the the lumbar area, it reveals spondylotic changes when present. It also
disk level, and urinary retention. This is a surgical emergency requiring may be useful for identifying less common disorders that produce
urgent decompression. radicular symptoms and signs: bony metastases, infection, fracture,
In the cervical region, it is likely that the greater mobility at levels and spondylolisthesis, for example.
C5–C6 and C6–C7 promotes the development of cervical disk degen- In the cervical region, the best methods for assessing the rela-
eration with annulus fraying and subsequent disk protrusion. As previ- tionship between neural structures (spinal cord and nerve root) and
ously noted, cervical nerve roots emerge above the vertebra that share their fibro-osseous surroundings (disk, spinal canal, and foramen)
their same numerical designation. Therefore, C7 exits between C6 and are post-myelography CT (unenhanced CT reveals little more than
C7, and spondylotic changes with or without additional acute disk her- the presence of bony changes) and MRI. MRI is equivalent in diag-
niation would be expected to compress the C7 nerve root. Similarly, nostic capacity to post-myelography CT and therefore is preferred. In
disk protrusion at C5–C6 and C7–T1 would compress the C6 and C8 the lumbosacral region, CT is an effective method for evaluating disk
roots, respectively. In the classic study of Yoss and associates (1957), disease, but when available, MRI is considered the superior imaging
clinical and radiological evidence of radiculopathy was found to occur study. Its excellent resolution, multiplanar imaging, the ability to see
most often at C7 (70%), less frequently at C6 (19%–25%), and uncom- the entire lumbar spine including the conus, and the absence of ioniz-
monly at C8 (4%–10%) and C5 (2%). Radiculopathy involving the T1 ing radiation make it highly sensitive in detecting structural radicular
root is a clinical rarity (Levin, 1999). disorders (Ashkan et al., 2002).
Involvement of C6 is associated with pain at the tip of the shoulder A variety of neurophysiological tests are used to assess patients
radiating into the upper part of the arm, lateral side of the forearm, and with disk herniation: motor and sensory nerve conduction studies, late
thumb. Paresthesias are felt in the thumb and index finger. The bra- responses, somatosensory evoked potentials, nerve root stimulation,
chioradialis and biceps reflexes are attenuated or lost. Weakness may and needle electrode examination. Sensory conduction studies are use-
occur in the muscles of the C6 myotome supplied by several different ful in the evaluation of a patient suspected of radiculopathy because
nerves, including the biceps (musculocutaneous nerve), deltoid (axil- SNAPs are typically normal (because the lesion is proximal to the DRG
lary nerve), and pronator teres (median nerve). The clinical features of in the intervertebral foramina) even in the face of clinical sensory loss,
C5 radiculopathies are similar, except that the rhomboids and spinati in contrast to the situation in plexopathy and peripheral nerve trunk
muscles are more likely to be weak. lesions, where SNAPs are attenuated or absent. However, in the specific
When the C7 root is compressed, pain radiates in a wide distribu- instance of L5 radiculopathy, because the L5 DRG may reside proximal
tion to include the shoulder, chest, forearm, and hand. Paresthesias to the neural foramen, if intraspinal pathology is severe enough, com-
involve the dorsal surface of the middle finger. The triceps reflex is pression of the L5 DRG may lead to attenuation or loss of the superfi-
usually reduced or absent. A varying degree of weakness usually cial peroneal nerve SNAP (Levin, 1998).
involves one or more muscles of the C7 myotome, especially the triceps Needle EMG is the most useful electrodiagnostic procedure in
the flexor carpi radialis and the pronator teres. the diagnosis of suspected radiculopathy (Wilbourn and Aminoff,
Less common C8 root involvement presents a similar clinical pic- 1998). A study is considered positive if abnormalities—especially
ture with regard to pain. Paresthesias, however, are experienced in the acute changes of denervation including fibrillation potentials and
fourth and fifth digits, and weakness may affect the intrinsic muscles positive sharp waves—are present in two or more muscles that
of the hand, including finger abductor and adductor muscles (ulnar receive innervation from the same root, preferably via different
nerve), thumb abductor and opponens muscles (median nerve), finger peripheral nerves. No abnormalities should be detected in mus-
extensor muscles (posterior interosseous branch of the radial nerve), cles innervated by the affected root’s rostral and caudal neighbors.
and flexor pollicis longus (anterior interosseous branch of the median Reduced motor unit potential (MUP) recruitment (manifested by
nerve). decreased numbers of MUPs firing at an increased rate) and MUP
Variations in cervical root innervation to the brachial plexus can abnormalities of reinnervation (high-amplitude, increased dura-
complicate the interpretation of symptoms and signs of suspected cer- tion, polyphasic MUPs) are also sought by the needle electrode but
vical radiculopathy. A well-appreciated anatomical variant is the “pre- are not as reliable as fibrillation potentials in establishing a defini-
fixed” brachial plexus, whereby cervical root innervation is caudally tive diagnosis of radiculopathy. However, the absence of fibrillation
displaced by one spinal segment, such that the C4 nerve root offers potentials does not exclude the diagnosis of radiculopathy. Two
a greater contribution to the brachial plexus, and the T1 nerve root main reasons for this exist. First, examination in the first 1–3 weeks
has less representation. A pre-fixed variant is believed to be present after onset of nerve root compromise may be negative because it
in 22%–40% of dissected plexi and should be considered when there takes approximately 2 weeks for these potentials to appear. At the
is poor correlation between clinical signs and radiographic findings. early stages in the process of nerve root compression, the only nee-
For example, in one retrospective study of 31 patients with clinical dle electrode examination manifestation of radiculopathy might be
and electrophysiological evidence supporting a C8 radiculopathy, 16% reduced MUP recruitment resulting from axon loss, focal demyelin-
were attributable to compression of the C7 nerve root at the C6–C7 ation with conduction block, or both. Second, fibrillation potentials
spinal level (Hehir et al., 2012). disappear as denervated fibers are reinnervated by axons of the same
Diagnosis. Diagnosis is aided by a variety of imaging techniques or an adjacent myotome beginning 2–3 months after nerve root
(e.g., plain radiography, CT myelography, MRI) and EMG testing compression (Fig. 105.5). Thus, in the later phases of nerve root
(Carette and Fehlings, 2005) (see Chapter 104). Both diagnostic compression, the only needle EMG changes indicative of radiculop-
modalities—the imaging approach that reveals anatomical details and athy might be chronic neurogenic changes of reduced recruitment
the EMG techniques that disclose neurophysiological function—agree and MUP remodeling. The distribution of fibrillation potentials is
in the majority of patients (60%) with a clinical history compatible relatively stereotyped for C5, C7, and C8 radiculopathies, whereas
with cervical or lumbosacral radiculopathy, although only the results C6 radiculopathy has the most variable presentation. In about half
of one study will be positive in a significant minority of patients (40%) of patients, the findings are similar to C5 radiculopathy, whereas
(Nardin et al., 1999). Although plain radiography is unhelpful in in the other half, findings are identical to C7 radiculopathy (Levin
the identification of a herniated disk per se, in both the cervical and et al., 1996).
Acute axon-loss Collateral reinnervation

Normal L5 radiculopathy by L4 axon
L4
L5
Peroneal nerve
Tibialis anterior
muscle
Fig. 105.5 Diagram Illustrating How Muscle Fibers Denervated by a Radiculopathy are Reinnervated
by Collateral Sprouting Despite Persisting Root Compression. (Reprinted with permission from Wilbourn,
A.J., Aminoff, M.J., 1988. AAEE minimonograph #32: the electrophysiologic examination in patients with
radiculopathies. Muscle Nerve 11, 1099–1114.)
Treatment. For cervical disk protrusion and spondylotic characterized as either root effacement without displacement or root
radiculopathy, the mainstay of treatment is conservative displacement with preservation of the periradicular CSF demonstrated
management—a combination of a period of reduced physical activity a significantly higher incidence of subjective pain relief (74%) as com-
with use of a soft cervical collar, physiotherapy, and antiinflammatory pared to patients with more severe root displacement with obliteration
and analgesic agents. Most patients improve, even those with mild of the periradicular CSF or morphological distortion of the nerve root
to moderate motor deficits. Indeed, in some cases, herniated cervical (26%) (Ghahremann and Bogduk, 2011). Lumbosacral level, duration
disks have been observed to regress on MRI images, a circumstance that of pain, and the presence of sensory changes, motor weakness, or lost
appears more likely to occur if disk material has extruded and becomes reflexes did not predict a response to epidural steroid injections. A sin-
exposed to the epidural space (Mochida et al., 1998). Although there gle intravenous (IV) bolus of methylprednisolone (500 mg) given to
appears to be a short-term benefit to surgical decompression of an patients with acute discogenic sciatica of less than 6 weeks’ duration
affected nerve root with regard to pain, weakness, or sensory loss, at 1 provided short-term improvement in leg pain, but the effect was rela-
year there is no significant difference between the outcomes of surgical tively small, with no effect on functional disability, and was quite tran-
or conservative management (physical therapy or hard cervical collar sitory (3 days) (Finckh et al., 2006). When a patient population with
immobilization) (Endquist et al., 2013). However, a surgical approach sciatica due to a herniated lumbar disk is followed at regular intervals
may be warranted in selected cases: (1) if there is unremitting pain for more than 10 years, surgically treated patients report more com-
despite an adequate trial of conservative management; (2) if there is plete relief of leg pain and improved function and satisfaction com-
progressive weakness in the territory of the compromised nerve root; pared with the nonsurgically treated group. However, improvement in
or (3) if there are clinical and radiological signs of an accompanying the patient’s predominant symptom and work or disability outcomes
new onset of myelopathy, although in a group of patients with mild or were similar in the two groups (Atlas et al., 2005). Three situations
moderate myelopathy, those managed surgically had the same outcome occur in which surgical referral is indicated: (1) in patients present-
(degree of functional disability) as those allocated to conservative ing with cauda equina syndrome for whom surgery may be required
treatment (Nikolaidis et al., 2010). urgently, (2) if the neurological deficit is severe or progressing, or
In the lumbosacral region, disk herniation and spondylotic changes (3) if severe radicular pain continues after 4–6 weeks of conservative
respond to conservative management in more than 90% of patients. management.
Bed rest had been recommended as the centerpiece of patient care,
but controlled trials have demonstrated that back-strengthening exer- Diabetic Polyradiculoneuropathy
cises under the direction of a physical therapist, performed within Diabetic neuropathies can be classified anatomically into two major
the limits of the patient’s pain, result in more rapid resolution of groups: symmetrical polyneuropathies and asymmetrical focal or
pain and return to normal function (Dahm et al., 2010). Follow-up multifocal disorders. Examples of the latter include the cranial
MRI studies in conservatively managed patients indicate reduction in mononeuropathies and the conditions covered in this section: cervi-
size or disappearance of herniated nucleus pulposus corresponding cal, thoracoabdominal, and lumbosacral polyradiculoneuropathies.
to improvement in clinical findings (Komori et al., 1996). Epidural Though treated separately in the following paragraphs, they often
corticosteroid injection may help relieve pain but does not improve coexist in an individual patient.
neurological function or reduce the need for surgery (Carette et al., Diabetic polyradiculoneuropathy tends to affect patients in the
1997). Relief of radicular pain due to paracentric lumbosacral disk sixth or seventh decade of life who have noninsulin-dependent dia-
herniations may best be predicted by the severity of root compression betes of several years’ duration. The syndrome of painful polyradicu-
on MRI (Ghahremann and Bogduk, 2011). In a study of 71 patients loneuropathy, whether referable to cervical, thoracic or lumbosacral
receiving epidural steroid injections, those with low-grade herniations, roots, may be the presenting manifestation of diabetes. In 30%–50%
of patients, the disorder is preceded by substantial weight loss of 30–40 involvement, the electrodiagnostic examination generally discloses
pounds. bilateral signs. Imaging studies are almost always necessary to
When there is predominant involvement of the thoracic roots, exclude a structural abnormality of the nerve roots that may simu-
the presenting symptoms are generally pain and paresthesias of rapid late diabetic polyradiculopathy. Both CT and myelography studies
onset in the abdominal and chest wall. The trunk pain may be severe, are typically normal. MRI of the brachial plexus in diabetic cervical
described variably as burning, sharp, aching, and throbbing. It may polyradiculoneuropathy is typically abnormal with an increase in T2
mimic the pain of acute cardiac or intraabdominal medical emer- signaling at the root, trunk, cord, or individual nerve level being the
gencies and may simulate disk disease, but the rarity of thoracic disk most common finding, often in a more extensive distribution than
protrusions and the usual development of a myelopathy help exclude the clinical presentation would suggest (Massie et al., 2012). Nerve
this diagnosis. Findings of diabetic thoracoabdominal polyradiculo- hypertrophy and increased T2 signal in muscle (suggestive of edema)
neuropathy include heightened sensitivity to light touch over affected were also observed. The CSF protein level is usually increased to an
regions; patches of sensory loss on the anterior, lateral, or posterior average of 120 mg/dL, but in some patients, values exceed 350 mg/
aspects of the trunk; and unilateral abdominal swelling due to localized dL; pleocytosis is not a feature of this condition. Biopsy of proximal
weakness of the abdominal wall muscles (Longstreth, 2005). nerve sensory branches reveals axon loss and demyelination; in more
Diabetic lumbosacral polyradiculoneuropathy involves the legs, severely affected patients, inflammatory cell infiltration and vasculi-
especially the anterior thighs, with pain, dysesthesia, and weakness, tis is found (Said et al., 1997). Further studies of nerve biopsy spec-
reflecting the major involvement of upper lumbar roots. A variety of imens indicate that a microscopic vasculitis (involvement of small
names have been used to describe it, including diabetic amyotrophy, arterioles, venules, and capillaries) leads to ischemic injury, which
proximal diabetic neuropathy, diabetic lumbosacral plexopathy, diabetic in turn causes axonal degeneration and secondary segmental demye-
femoral neuropathy, and Bruns–Garland syndrome. Because it is likely lination (Dyck et al., 1999). The presence of a small-vessel vasculitis
that the brunt of nerve pathology falls on the nerve roots, it can be des- with distinctive pathological features including transmural poly-
ignated as diabetic polyradiculoneuropathy. Motor, sensory, and auto- morphonuclear leukocyte infiltration of postcapillary venules and
nomic fibers are all affected by the disease process (Dyck et al., 1999). endothelial deposits of immunoglobulin (Ig)M and activated com-
In most patients, onset is fairly abrupt, with symptoms develop- plement supports an immune-mediated inflammatory pathogenesis
ing over days to a couple of weeks. Early in the course of the condi- for this disorder (Kelkar et al., 2000).
tion, the clinical findings are usually unilateral and include weakness The natural history of diabetic polyradiculoneuropathy is for
of muscles supplied by L2–L4 roots (iliopsoas, quadriceps, and hip improvement to occur in most patients, although the recovery phase is
adductors), reduced or absent patellar reflex, and mild impairment of lengthy, ranging between 1 and 18 months with a mean of 6 months.
sensation over the anterior thigh. As time passes, there may be terri- Pain and dysesthesias improve or disappear entirely in 85% of patients;
torial spread, a term used by Bastron and Thomas (1981) to describe numbness improves or recovers in 50%; and strength is partially or
proximal, distal, or contralateral involvement as the polyradiculoneu- completely restored in 70%. In some patients, episodes recur.
ropathy evolves. Worsening may occur in a steady or a stepwise fash- Therapy is usually directed toward ameliorating the severe pain of
ion, and it may take several weeks to progress from onset to peak of this condition. The tricyclic antidepressants (e.g., amitriptyline and
the disease. At its peak, weakness varies in severity and extent from a nortriptyline), selective serotonin reuptake inhibitors (e.g., sertraline,
mildly affected patient with slight unilateral thigh weakness to a pro- nefazodone hydrochloride), selective serotonin and norepinephrine
found degree of bilateral leg weakness in the territory of the L2–S2 reuptake inhibitors (e.g., duloxetine, venlafaxine), anticonvulsants
nerve roots. Rarely, the process of territorial spread is so extensive (e.g., gabapentin, pregabalin, carbamazepine), and topical capsaicin
that it involves a multiplicity of nerve roots along the entire spinal may have a role separately or in combination. Histopathological find-
cord and leads to profound generalized weakness, a condition desig- ings indicative of an immune-mediated pathogenesis has led to treat-
nated diabetic cachexia. ment of selected patients with intravenous immunoglobulin (IVIG) or
Diabetic cervical polyradiculoneuropathy has also been described other immunosuppressive treatments. A comprehensive and critical
(Massie et al., 2012), and may occur independently or in temporal review of the literature on the role of immunotherapy of diabetic poly-
association with lumbosacral polyradiculoneuropathy. Similar to the radiculopathy concludes that treatment remains controversial because
lumbosacral form, it is characterized as an acute or subacute onset of the natural history is for spontaneous improvement, the side effects
unilateral limb pain, followed by focal hand and forearm weakness that of immunotherapy may be significant, and information on efficacy
may then progress to involve multiple myotomes or focal nerve terri- is lacking from controlled clinical trials (Amato and Barohn, 2001).
tories in the affected limb. Though less common than the polyradic- Prospective studies have suggested a role for immunotherapy in the
uloneuropathy of lumbosacral onset, progression to the contralateral treatment plan of diabetic polyradiculoneuropathy where electro-
upper extremity is seen in up to 35% of patients, and involvement of physiological findings are those of chronic inflammatory demyelinat-
cranial, thoracic, and lumbosacral regions may also occur. ing polyneuropathy (CIDP) (Ayyar and Sharma, 2004), although the
Laboratory studies disclose elevated fasting blood glucose in the degree of improvement has been shown not to be as robust as in the
vast majority of patients; when values are normal, they are found immunotherapy of idiopathic CIDP (Gorson et al., 2000).
in treated diabetics. The erythrocyte sedimentation rate is usually The major differential diagnostic considerations are polyradiculo-
normal. The typical electrodiagnostic findings comprise features of neuropathies related to degenerative disk disease, infection, inflamma-
a sensorimotor axon-loss polyneuropathy (diminished sensory and tory or autoimmune mediated disease, and neoplastic processes. These
motor action potentials, normal or slightly prolonged distal laten- can usually be excluded by history, examination, and routine labora-
cies, and normal or mildly slowed conduction velocities) with addi- tory investigations including CSF analysis. However, in our experience,
tional needle electrode examination findings of active and chronic the clinical presentation provoking the most anxiety is the frail elderly
denervation changes in paraspinal, pelvic girdle, and limb mus- patient not known to be diabetic who has weight loss and abrupt onset
cles. Taken together, the findings reflect multifocal axonal damage of lower-extremity pain and weakness that progresses over months.
to the nerve roots and brachial or lumbosacral plexus (Amato and In such a patient, the specter of neoplasia looms large, and thorough
Barohn, 2001). Although clinical findings may point to unilateral imaging studies of the nerve roots and plexuses are mandatory.
Neoplastic Polyradiculoneuropathy (Neoplastic

Meningitis)
A wide variety of neoplasms are known to spread to the leptome-
ninges. These include solid tumors (carcinoma of the breast and
lung, gastrointestinal tract, and melanoma), non-Hodgkin lympho-
mas, leukemias, and intravascular lymphomatosis (Clarke, 2012).
Although neoplastic polyradiculoneuropathy usually occurs in
patients known to have an underlying neoplasm, meningeal symp-
toms may be the first manifestation of malignancy. Neoplastic
meningitis occurs in approximately 5% of all patients with cancer
(Chamberlain, 2006). The clinical features of neoplastic polyradicu-
loneuropathy include radicular pain, dermatomal sensory loss, are-
flexia, weakness of a lower motor neuron type, and bowel/bladder Fig. 105.6 Cauda Equina in Leptomeningeal Carcinomatosis. Seeding
dysfunction (Mammoser and Groves, 2010). Often the distribution of multiple nerve roots by adenocarcinoma produces a nodular appear-
of the sensory and motor deficits is widespread and simulates a severe ance. (Courtesy Dr. T.W. Smith, Department of Pathology [Neuropathol-
sensorimotor polyneuropathy. Associated clinical manifestations ogy], University of Massachusetts Medical Center, Worcester, MA.)
(e.g., nuchal rigidity, confusion, cranial polyneuropathies) result
from infiltration of the meninges.
At postmortem examination, the cauda equina shows discrete nod-
ules or focal granularity (Fig. 105.6). Microscopy discloses spinal roots Polyradiculopathy Associated with Sarcoidosis
encased by tumor cells, which appear to infiltrate the root. Malignant Sarcoidosis is a systemic, multiorgan, inflammatory granulomatous
cells have the capacity to penetrate the pial membrane and invade the disease. Neurological involvement of any kind is rare, observed in
spinal nerves (Mammoser and Groves, 2010). It is presumed that dis- approximately 5% of patients, and characterized by granulomatous
turbed nerve root function results from several mechanisms including infiltration of CNS parenchyma, meninges, peripheral nerves and their
nerve fiber compression and ischemia. roots. Predominant involvement of motor and sensory roots has been
The most revealing diagnostic procedure is lumbar puncture, described (Koffman et al., 1999), manifesting in the lower extremities
which is usually abnormal, disclosing one or more or the following: with subacute onset of proximal more than distal weakness, sensory
mononuclear pleocytosis, reduced CSF glucose, elevated protein, and loss, and pain in the back or legs. Deep tendon reflexes are often atten-
neoplastic cells (Clark, 2012). By contrast, spinal fluid cytological uated in keeping with a pure radiculopathy, although concomitant
analysis may be initially negative in more than one-third of patients intraparenchymal involvement may occur, leading to upper motor
who have compelling evidence of leptomeningeal carcinomatosis. neurons signs with hyperreflexia and extensor plantar responses. More
Sensitivity of CSF cytology can be improved with repeated sampling, acute onset presentations mimicking the Guillain-Barré syndrome
analysis of larger CSF volumes (>10 cc), and when spinal fluid is (GBS) also have been described (Fahoum et al., 2009).
sampled near the main focus of metastatic involvement (Taillibert Sarcoidosis characteristically presents in late adolescence through
et al., 2005). A sensitive, albeit nonspecific, electrophysiological indi- middle age, with a higher incidence in African Americans in North
cator of nerve root involvement is an abnormal F wave. In the symp- America. Establishing the diagnosis of neurosarcoidosis may be chal-
tomatic patient with cancer, prolonged F-wave latencies or absent F lenging. The gold standard of diagnosis is pathological evidence of
responses should raise suspicion of leptomeningeal metastases. Post- noncaseating granulomas in involved nervous tissue. When this level
myelography CT adds strong evidence in support of the diagnosis of certainty cannot be achieved, clinicians turn to serum, CSF, and
if it demonstrates multiple nodular defects on the nerve roots, but radiological testing to help support the diagnosis. Serum angiotensin-
spinal MRI, especially with gadolinium enhancement, is the initial converting enzyme (ACE) levels are of limited utility, and do not cor-
test of choice in the cancer patient in whom leptomeningeal involve- relate well with CSF ACE levels (Pawate et al., 2009). Elevated serum
ment of the spine is suspected (Gleissner and Chamberlain, 2006). ACE levels should spur further diagnostic investigation, whereas a
Approximately 50% of patients with neoplastic meningitis and spi- negative test result should not dissuade the clinician from a potential
nal symptoms have abnormalities on these studies. Gadolinium- diagnosis of neurosarcoidosis. CSF analysis typically discloses ele-
enhanced MRI of the brain discloses abnormalities, including vated total protein, hypoglycorrhachia, and a lymphocytic pleocytosis,
contrast enhancement of the basilar cisterns or cortical convexities although not all patients will have all three abnormalities. The most
and hydrocephalus. common CSF abnormality is a high protein concentration. MRI may
Standard therapy for neoplastic meningitis is essentially pallia- be most helpful in demonstrating increased T2 signal or post-gado-
tive; it does, however, afford stabilization and protection from further linium enhancement of involved nerve roots, meninges, or brain and
neurological deterioration (Chamberlain, 2006). A multidisciplinary spinal cord parenchyma. When neurosarcoidosis is suspected as the
approach is recommended, with input from medical oncology, neuro- initial manifesting symptom of sarcoidosis, a diagnostic work-up to
oncology, radiation oncology, and neurosurgery (Mammoser and assess for systemic disease should also be pursued. This should include
Groves, 2010). With treatment that includes radiotherapy to sites a plain chest x-ray or high-resolution CT to look for hilar lymph node
of symptomatic disease, intrathecal or intraventricular chemother- or pulmonary involvement. Consideration should also be given to
apy (methotrexate, thiotepa, and cytosine arabinoside), and optimal fluorodeoxyglucose positron emission tomography (FDG-PET) eval-
management of the underlying malignancy, median survivals of 2–5 uating for pulmonary or extrapulmonary involvement that would sub-
months may be achieved (Clarke, 2012; Chamberlain, 2006). On occa- sequently allow for targeted biopsy of a more accessible involved organ
sion, longer-term survival is observed in patients with neoplastic men- (Glaudemans et al., 2013).
ingitis accompanying breast cancer (13% survival rate at 1 year and 6% Formal evaluation of drug therapy in neurosarcoidosis is non-
at 2 years), melanoma, and lymphoma (Jaeckle, 2006). existent, though convention favors initial treatment with oral or IV
corticosteroids. Many patients improve with corticosteroid therapy,

though long-term immunosuppression with corticosteroid-sparing
agents such as azathioprine, mycophenolate mofetil, and methotrexate
may be required. In the spinal column, where granulomatous infil-
tration may be associated with significant mass effect, decompressive
laminectomy may be required.
Infectious Radiculopathy
Tabes Dorsalis
Tabes dorsalis, the most common form of late neurosyphilis, begins as
a spirochetal (Treponema pallidum) meningitis (see Chapter 78). After
10–20 years of persistent infection, damage to the dorsal roots is severe
and extensive, producing a set of characteristic symptoms and signs.
Symptoms are lightning pains, ataxia, and bladder disturbance; signs
include Argyll Robertson pupils, areflexia, loss of proprioceptive sense, Fig. 105.7 Cytomegalovirus Polyradiculoneuropathy. Numerous
Charcot joints, and trophic ulcers. Lancinating or lightning pains are mononuclear inflammatory cells are apparent, and the presence of myelin
brief, sharp, or stabbing in quality and are more apt to occur in the legs ovoids (arrows) reflects axon loss (hematoxylin and eosin stain, ×100).
Inset, Cytomegalic cell with intranuclear inclusion (hematoxylin and eosin
than elsewhere. Sensory disturbances such as coldness, numbness, and
stain, ×150). (Courtesy Dr. T.W. Smith, Department of Pathology [Neuro-
tingling also occur and are associated with impairment of light touch,
pathology], University of Massachusetts Medical Center, Worcester, MA.)
pain, and thermal sensation. Episodes of visceral crisis, characterized
by the abrupt onset of epigastric pain that spreads around the body or
up over the chest, occur in some 20% of patients. tendon reflexes, reduced or absent sphincter tone, and variable loss of
Most of the features of tabes dorsalis can be explained by lesions light touch, vibration, and joint position sense. The upper extremities
of the dorsal roots, dorsal root ganglia, and posterior columns (Gilad and cranial nerves may be involved in advanced cases (Robinson-Papp
et al., 2007). Ataxia is due to the destruction of proprioceptive fibers, and Simpson, 2009).
insensitivity to pain follows partial loss of small myelinated and unmy- A gadolinium-enhanced MRI of the lumbosacral spine is necessary
elinated fibers, and bladder hypotonia with overflow incontinence, to exclude a compressive lesion of the cauda equina and is generally
constipation, and impotence is the result of sacral root damage. the first study performed (Robinson-Papp and Simpson, 2009). The
Pathological studies disclose thinning and grayness of the posterior MRI in CMV polyradiculoneuropathy is usually normal, but adhesive
roots, especially in the lumbosacral region, and the spinal cord shows arachnoiditis has been described. The CSF has an elevated protein level,
degeneration of the posterior columns. A mild reduction of neurons depressed glucose level, polymorphonuclear pleocytosis, and a positive
in the DRG occurs, and there is little change in the peripheral nerves. CMV polymerase chain reaction (PCR) (Anders and Goebel, 1998).
Inflammation may occur all along the posterior root. CMV may be isolated from CSF cultures. The needle EMG discloses
The CSF may be normal in tabes dorsalis or may show a mild lym- widespread fibrillation potentials in lower-extremity muscles, and sen-
phocytic pleocytosis (10–50 cells/μL) and elevated protein concentra- sory conduction studies may reveal an associated distal sensory neurop-
tion (45–75 mg/dL). While up to 25% of patients are found to have athy that is common in the late stages of HIV infection. The pathological
nonreactive CSF-Venereal Disease Research Laboratory (VDRL), the features are marked inflammation and extensive necrosis of dorsal and
serum treponemal tests fluorescent treponemal antibody absorption ventral roots. Cytomegalic inclusions may be found in the nucleus and
(FTA-ABS), Treponema pallidum particle agglutination assay (TPPA), cytoplasm of endothelial and Schwann cells (Fig. 105.7).
and syphilis enzyme immunoassay (EIA)), remain reactive for life in Untreated CMV polyradiculoneuropathy is rapidly fatal within
virtually all patients regardless of previous treatment (Marra, 2014). approximately 6 weeks of onset. The antiviral nucleoside analog ganciclo-
The preferred treatment is aqueous penicillin G, 2–4 million units vir may benefit some patients if treatment is instituted early; improvement
IV every 4 hours for 10–14 days, with careful CSF follow-up. CSF occurs over weeks to months. Viral resistance to ganciclovir is suggested
examination 6 months after treatment should demonstrate a normal by persistent pleocytosis and depressed CSF glucose (Cohen et al., 1993)
cell count and decreasing protein content. If not, a second course of and should prompt consideration of alternate, or combination therapy
therapy is indicated. The CSF examination should be repeated every 6 with an antiviral agent such as foscarnet, which, unlike ganciclovir, does
months for 2 years or until the fluid is normal. not require intracellular phosphorylation for its effect.
Other causes of rapidly progressive lumbosacral polyradiculoneu-
Polyradiculoneuropathy in Human Immunodeficiency ropathy in the HIV-infected patient are meningeal lymphomatosis,
Virus-Infected Patients Mycobacterium tuberculosis, and axonal polyradiculoneuritis associated
Cytomegalovirus (CMV) polyradiculoneuropathy is a rapidly progres- with HIV infection per se (Corral et al., 1997). Additionally, one must
sive opportunistic infection that usually occurs late in the course of consider acute inflammatory demyelinating polyradiculoneuropathy,
human immunodeficiency virus (HIV) infection when the CD4 count syphilitic polyradiculoneuropathy (which often has an accelerated
is very low (<50 cells/mL) and acquired immunodeficiency syndrome course in the patient with AIDS), herpes simplex virus type 2 and var-
(AIDS)-defining infections are present. Uncommonly, it is the initial icella-zoster virus infections. Toxoplasma gondii may also cause myeli-
manifestation of AIDS (Anders and Goebel, 1998). Patients often have tis, presenting as a subacute conus medullaris syndrome that simulates
evidence of systemic CMV infection (retinitis, gastroenteritis). The the clinical features produced by CMV polyradiculoneuropathy. In the
presentation is marked by rapid onset of pain and paresthesias in the case of T. gondii, MRI may reveal abscess formation.
legs and perineal region, associated with urinary retention and pro-
gressive ascending weakness of the lower extremities (Robinson-Papp Lyme Radiculoneuropathy
and Simpson, 2009). Examination discloses a severe cauda equina syn- Lyme disease is caused by the spirochete Borrelia burgdorferi, trans-
drome, the combination of flaccid paraparesis, absent lower-limb deep mitted by the deer tick Ixodes dammini, and is most prevalent in the
American northeast and upper Midwest, where risk of infection is Herpes Zoster
greatest during the spring and summer months. A European form, Herpes zoster, also known as shingles, is a common painful vesicular
caused by the spirochetes B. afzelii and B. garinii, is also well recognized eruption occurring in a segmental or radicular (dermatomal) distri-
in temperate climates of central Europe and Asia. Lyme is a multisystem bution and due to reactivation of latent varicella-zoster virus in DRG
disease affecting the skin, peripheral nervous system, CNS (referred to (see Chapter 77). Primary infection presents as varicella (chickenpox)
as neuroborreliosis), musculoskeletal system, and heart. To help bring earlier in life (Cohen, 2013), usually in epidemics among susceptible
order to the understanding of this illness, it may be divided into three children. Involvement may occur at any level of the neuraxis but is
clinical stages (Bratton et al., 2008). Stage 1 follows within 1 month most commonly seen in the thoracic dermatomes, followed by the
of the tick bite and is marked by a characteristic rash in 60%–80% of face. Zoster, when involving the ophthalmic division of the trigeminal
patients, designated erythema chronica migrans (oval or annular shape nerve (herpes zoster ophthalmicus), may be accompanied by keratitis,
with a clear center in the area of the bite), and influenza-like symptoms a potential cause of blindness requiring immediate treatment. When
of fatigue, fever, headache, stiff neck, myalgias, and arthralgias. Stage 2, isolated to the seventh nerve, it is associated with a facial palsy and
the stage of dissemination of the spirochete from the initial lesion, may ipsilateral external ear or hard palate vesicles known as Ramsay Hunt
occur within weeks of the rash, and may result in peripheral nerve, syndrome (Cohen, 2013). Rarely, the viral episode can present as der-
joint, and cardiac abnormalities. Stage 3, caused by late or persistent matomal pain without a rash, known as herpes sine herpete.
infection, may occur up to 2 years after the tick bite and is charac- Zoster occurs during the lifetime of 10%–20% of all people, with
terized by chronic neurological syndromes, among them neuropathy, an incidence in the general population of approximately 3–5 per 1000
myelopathy, psychiatric disturbances, and migratory oligoarthritis. per year. The incidence is low in young people and increases with
Nerve root and peripheral nerve abnormalities that characterize age—among persons older than 75 years it exceeds 10 cases per 1000
stage 2 develop in about 4%–5% of untreated patients (Halperin, person-years—and when immunocompetence is compromised. For
2010). Possible manifestations occurring within weeks after the onset example, the incidence among HIV-positive individuals was reported
of erythema chronica migrans most commonly include headache as 15-fold greater than that of a control group (Gnann and Whitley,
with lymphocytic (aseptic) meningitis, cranial neuropathy (especially 2002).
facial mononeuropathies, bilateral in 25% of cases), and a multi- During primary infection, the virus colonizes the DRG and remains
focal radiculoneuropathy or mononeuritis multiplex. With nerve latent for many decades until it is reactivated, either spontaneously
root involvement there may be an associated myelitis at adjacent or when virus-specific cell-mediated immunity declines secondary
spinal cord levels, with accompanying long tract signs on examina- to specific conditions (e.g., lymphoproliferative disorders, treatment
tion (Halperin, 2010). The clinical features of nerve root involve- with immunosuppressive drugs, organ transplant recipients, seropos-
ment include burning radicular pain with sensory loss, weakness, itivity for HIV) or normal aging, and travels down sensory nerves.
and hyporeflexia in the territory of the involved roots. Nerve con- Pathological changes, which are characterized by lymphocytic infiltra-
duction studies provide evidence for an associated primarily axon- tion and variable hemorrhage, are found in the skin, DRG, and spinal
loss polyneuropathy. The rare patient with chronic neuroborreliosis, roots. Involvement of the ventral roots and, on occasion, the spinal
seen in stage 3, may develop a stocking-glove patterned axon-loss cord, explains the development of motor signs in some patients (see
polyneuropathy, that may in fact represent confluence of multiple later discussion).
mononeuropathies (Bratton et al., 2008; Halperin, 2008). In a non- Herpes zoster is characterized by sharp or burning radicular pain
human primate model of neuroborreliosis, the spread of B. burgdor- associated with itching, numbness, dysesthesias (altered sensation),
feri within the nervous system—leptomeninges, motor and sensory and/or allodynia (a painful response to normally non-noxious stimu-
roots, DRG, but not the brain parenchyma—has been demonstrated. lation) typically in a single dermatome (Cohen, 2013). The cutaneous
In peripheral nerves from such animals, spirochetes were seen in the eruption, unilateral and respecting the midline, begins as an erythem-
perineurium (Steere, 2001). atous maculopapular rash and progresses to grouped clear vesicles that
The diagnosis of Lyme disease can be made on the grounds of his- continue to form for 3–5 days (Cohen, 2013). These become pustules
tory and clinical presentation alone especially when there is evidence by 3–4 days and form crusts by 10 days. In the normal immunocompe-
of erythema migrans. Serological testing for antibodies against B. tent host, lesions resolve in 2–4 weeks, often leaving a region of reduced
burgdorferi (and confirmatory Western blot in those with borderline sensation, scarring, and pigmentation. Pain usually disappears as ves-
or positive results) can be beneficial, though neurological manifes- icles fade, but 10%–50% of patients experience persistent severe pain,
tations can be seen prior to the appearance of IgM antibodies in the that when present for more than 30 days after rash onset or follow-
blood as part of the early humeral response. Thus, antibody testing in ing cutaneous healing is termed postherpetic neuralgia (PHN; Cohen,
a patient with suspected exposure within 3–6 weeks of presentation 2013). This complication is more likely to develop in the elderly,
may be negative (Halperin, 2013). CSF analysis may be reserved for occurring in 50% of patients over 60 years of age. In half of patients
those with suspected CNS involvement, and will typically be abnor- affected with PHN, the pain resolves within 2 months, and 70%–80%
mal with a lymphocytic pleocytosis, elevated protein, and normal of patients are pain free by 1 year. Rarely, pain persists for years.
glucose. In the immunologically normal host, dissemination of the virus is
Treatment of Lyme radiculoneuropathy with IV ceftriaxone (cefo- rare, occurring in fewer than 2% of patients. In the immunocompro-
taxime and penicillin G are acceptable alternates) for 2–4 weeks is mised patient, however, dissemination occurs in 13%–50% of patients.
associated with resolution of symptoms and signs in most patients. Most often, spread is to distant cutaneous sites, but involvement of the
Oral doxycycline (100 mg twice daily), has been shown to be equally viscera (lung, gastrointestinal tract, and heart) and CNS may occur. A
efficacious in the treatment of European forms of neuroborreliosis, serious complication of herpes zoster ophthalmicus is delayed contra-
including radiculopathy (Ljøstad et al., 2008), while studies comparing lateral hemiparesis caused by cerebral angiitis. The syndrome usually
IV versus oral antibiotics for the treatment of North American Lyme develops 1 week to 6 months after the onset of zoster and occurs in
disease are lacking. After successful treatment, serum antibodies will patients of all ages, 50% of whom are immunologically impaired. The
often remain positive and their presence or absence offers no clinical mortality rate from cerebrovascular complications is 25%, and only
utility in determining efficacy of treatment. approximately 30% of survivors recover fully.
A complication of cutaneous herpes zoster is segmental motor

weakness, which occurs in up to 30% of patients with zoster reacti-
vation (Bahadir et al., 2008). Segmental zoster paresis is about equally
divided between the arms and legs, with predominantly proximal mus-
cle weakness reflecting weakness in cervical and lumbar—C5, C6, and
C7 or L2, L3, and L4—myotomes, respectively. The diaphragm and
abdominal muscles may be affected, and bladder and bowel dysfunc-
tion may occur in the setting of lumbosacral zoster (Gilden et al., 2013).
The interval between skin eruption and paralysis is approximately 2
weeks, with a range of 1 day to 5 weeks and a rare instance reported
of delayed (4.5 months) onset of diaphragmatic paralysis. Weakness
peaks within hours or days and generally follows the dermatomal dis-
tribution of zoster eruptions (Yaszay et al., 2000); spread to muscles
served by unaffected segments is very uncommon (<3% of cases). The
prognosis for recovery is good, with nearly complete return of function Fig. 105.8 Cauda Equina in Guillain–Barré Syndrome. A dense
in two-thirds of patients over the course of 1–2 years, 55% showing full mononuclear infiltrate in the connective tissue surrounding the nerve
recovery, and another 30% showing significant improvement. One in roots is shown (hematoxylin and eosin stain). (Courtesy Dr. T.W. Smith,
five patients is left with severe and permanent residua. Department of Pathology [Neuropathology], University of Massachu-
setts Medical Center, Worcester, MA.)
Prognosis for recovery in patients with diaphragmatic paralysis is
not as good as it is with segmental paresis involving the limb muscles,
probably owing to the challenge of axonal regeneration along the long
course of the phrenic nerve (Bahadir et al., 2008). The histopathologi- remitting and is designated CIDP. These disorders are described in
cal correlate of herpes zoster is inflammation and neuronal loss in the detail in Chapter 106 but are mentioned here briefly because patholog-
DRG that correspond to the affected segmental levels. In the case of ical changes may be pronounced in the spinal nerve roots, especially
segmental zoster paresis, there is lymphocytic inflammation and vas- the ventral roots. There is a dense mononuclear inflammatory infil-
culitis involving adjacent motor roots and the spinal cord gray matter, trate of lymphocytes, monocytes, and plasma cells (Fig. 105.8), and
with resulting motor fiber degeneration (Gilden et al., 2013). A low- segmental demyelination with relative sparing of axons. Neuroimaging
grade viral ganglionitis may contribute to PHN (Quan et al., 2005). with MRI discloses contrast enhancement of lumbosacral roots in both
The major goals of treatment are to relieve local discomfort, pre- GBS and CIDP (Bertorini et al., 1995; Koller et al., 2005). The predi-
vent dissemination, and reduce the severity of PHN (Sandy, 2005). lection for nerve root involvement in these conditions helps explain
Acyclovir, valacyclovir, and famciclovir are indicated for the immuno- certain features, including CSF and some neurophysiological findings,
competent patient older than 50 years with herpes zoster and should be as well as disturbances in autonomic function that may be especially
started within 48 hours of the viral episode to receive the most benefit problematic in patients with GBS.
from therapy. These drugs reduce the duration of viral shedding, limit A CSF profile of albuminocytological dissociation is characteristic
the duration of new lesion formation, and accelerate healing and pain of this syndrome and is seen in 50%–66% of patients in the first week
resolution. They are all safe and well tolerated, but because of superior of symptoms and in more than 75% of patients 2 weeks after symp-
pharmacokinetic profiles and simpler dosing regimen, the latter two tom onset. A high lumbar CSF protein concentration in the face of a
are preferred to acyclovir (Cohen, 2013). IV acyclovir is the treatment normal cisternal protein level supports the hypothesis that increased
of choice in immunocompromised patients, having been shown to CSF protein derives largely from capillaries of the spinal roots. Nerve
halt disease progression, prevent dissemination, and speed recovery in conduction studies usually disclose slowed motor conduction veloc-
immunocompromised patients (Robinson-Papp and Simpson, 2009). ities, dispersed motor responses, and partial conduction block, but
In 2017, the US Food and Drug Administration (FDA) approved a additional abnormalities include delayed or unobtainable F-wave
non-live recombinant glycoprotein E vaccine for use in the United responses or H-reflexes, reflecting demyelination in nerve roots (Koller
States to reduce the risk for herpes zoster in older adults (≥60 years). et al., 2005). Indeed, abnormalities of these late responses may be the
The vaccine requires two intramuscular injections, separated by 2–6 sole finding in 10%–20% of patients with GBS in the first few weeks of
months, and is effective in preventing herpes zoster and reducing risk the illness. The autonomic disturbances that occur in GBS may be due
of post-herpetic neuralgia (Lal et al., 2015). to involvement of preganglionic sympathetic fibers, which travel in the
The pain of PHN—described variably as continuous deep aching, ventral roots en route to the paravertebral sympathetic ganglia.
burning, sharp, stabbing, and shooting, and triggered by light touch There is increasing recognition of rare variants of CIDP with a
over the affected dermatomes—is often debilitating and difficult to clear predilection for the dorsal or ventral spinal roots, with appar-
treat (Johnson and Rice, 2014). Singly or in combination, tricyclic ent sparing of more peripheral structures: termed chronic inflam-
antidepressants, selective serotonin reuptake inhibitors (sertraline or matory sensory (CISP), sensorimotor (CISMP) or motor (CIMP)
nefazodone hydrochloride), anticonvulsants (carbamazepine and gab- polyradiculopathy, based on the preferential involvement of sensory
apentin), oral opioids (oxycodone), and topical capsaicin cream or and/or motor roots (Khaldikar et al., 2017; O’Ferrall et al., 2013;
lidocaine patches are helpful for about 50% of patients. IV acyclovir Sinnreich et al., 2004). CISP is a chronic, progressive syndrome of
followed by oral valacyclovir was found to reduce the pain of PHN in ataxia, numbness, and paresthesias involving the limbs and/or trunk.
more than 50% of treated patients (Quan et al., 2005). Neurological examination reveals normal strength, marked large fiber
sensory abnormalities with absent vibratory and joint position sense,
Acquired Demyelinating Polyradiculoneuropathy less severe decrements in small fiber sensory modalities, and hypo- or
Acquired demyelinating polyradiculoneuropathy has two major areflexia. Distal nerve conduction studies are normal with abnormal
clinical forms. One develops acutely and is known as Guillain-Barré late responses (prolonged or absent F-waves or H-reflexes) or absent
syndrome (GBS); the other is chronic, progressive, or relapsing and somatosensory evoked potentials. MRI of the brain and spinal cord
parenchyma is normal with thickened and/or enhanced lumbar spinal DRG. PSN is associated with the presence of specific antineuronal
nerve roots. CSF analysis demonstrates albuminocytological dissocia- (anti-Hu) antibodies that are complement-fixing polyclonal IgG anti-
tion without oligoclonal bands. Pathological analysis of lumbar dorsal bodies that react with the nuclei of the neurons of the CNS and sensory
rootlets reveals thickened rootlets, endoneurial edema with prominent ganglia but not with non-neuronal nuclei; most (80%–85%) but not all
staining for macrophages, and onion-bulb formations. There is a nor- patients with PSN are found to have anti-Hu antibodies and therefore
mal density of myelinated nerve fibers though with an abnormal size CT imaging of the chest is recommended when patients present with
distribution of myelinated fibers, with a preferential decrease in the an acute to subacute onset of a sensory neuronopathy (Gozzard and
number of large-diameter myelinated nerve fibers. Peripheral sensory Maddison, 2010). The antigens recognized by the anti-Hu antibodies
nerve biopsies are normal. Treatment of this inflammatory sensory or have been characterized as proteins with molecular weights of 35–40
sensorimotor polyradiculopathy with oral or IV methylprednisolone, kD. The presence of identical protein antigens in small-cell lung cancer
or immunoglobulin, is associated with favorable outcomes. cells and neuronal nuclei supports the view that the pathogenesis of
CISMP presents similar to CISP, though with concurrent weak- paraneoplastic subacute sensory neuropathy is immunologically medi-
ness of proximal and distal muscles, predominantly in the lower limbs ated, with tumor antigens triggering the production of cross-reactive
(Khaldikar et al., 2017). Nerve conduction studies, MRI findings, and antibodies. Morphological studies provide evidence for both cytotoxic
CSF abnormalities are the same, and treatment with glucocorticoids T-cell-mediated attack and humoral mechanisms in the pathogenesis
was met with clear functional improvement in both patients, which of this condition. Response to immunotherapy is disappointing; how-
was sustained with transitions to steroid-sparing immunomodulators. ever, early diagnosis of cancer gives the best chance of helping the neu-
A single case report of a pure motor variant, CIMP, has also been rological disorder before it becomes devastating (Kuntzer et al., 2004).
reported (O’Ferrall et al., 2013), characterized by insidious onset of Other causes of DRG neuronopathy include hereditary, toxic,
progressive, symmetric weakness of the bilateral distal lower extremi- and autoimmune disorders (Kuntzer et al., 2004). Hereditary sensory
ties, and attenuated reflexes, with sparing of sensation as well as bowel neuropathies are usually marked by their chronicity, acrodystrophic
and bladder function. Nerve conductions show attenuated lower ulcerations, fractures, bouts of osteomyelitis, and lack of paresthesias.
extremity compound motor action potentials (CMAPs) and normal Pyridoxine (vitamin E) abuse and cisplatin neurotoxicity are generally
SNAPs, and needle EMG shows denervation and partial reinnervation easily recognized. Sjögren syndrome, an autoimmune disease involv-
changes in muscles of multiple myotomes. MRI again shows hypertro- ing lymphocytic infiltration of exocrine glands (notably the lacrimal
phied lumbar spinal roots. Pathological analysis showed onion-bulb and salivary glands) resulting in marked dry eyes and dry mouth, may
formations and a decreased number of large-diameter myelinated be accompanied by ataxia and kinesthetic sensory loss very similar to
nerve fibers on root biopsy. This patient had a poor response to IVIG subacute sensory neuropathy. Diagnosis of primary Sjögren syndrome
and Solu-Medrol (methylprednisolone) but had functional improve- is made independent from any associated neurological manifestations.
ment in lower-extremity strength with plasma exchange. Following American and European consensus criteria (Vitali et al.,
2002), diagnosis is based on four of six criteria, including subjective
Acquired Disorders of the Dorsal Root Ganglia ocular or oral symptoms by patient history, objective measures of ocu-
The dorsal root ganglia may be selectively vulnerable to a variety of lar or oral symptoms, histopathological evidence on minor salivary
malignant and nonmalignant conditions. The resulting neurological gland biopsy, and autoantibodies to extractable nuclear antigens Ro
disorder is a sensory neuronopathy syndrome whose clinical features (SSA) or La (SSB), with one of the latter two criteria being required.
are explained by the loss of large- and small-diameter DRG neurons. In some cases of Sjögren sensory neuronopathy, cervical MRI shows
Large-cell dropout leads to kinesthetic sensory impairment, poor cervical cord atrophy with increased T2 signal intensity at the dorsal
coordination, loss of manual dexterity, ataxia, and areflexia, whereas columns, which probably stems from Wallerian degeneration of neu-
small-cell depletion contributes to a hyperalgesic state marked by rons in the dorsal root ganglia (Lin and Chiu, 2008). Improvement
burning pains and painful paresthesias. The sensory neuronopathies from courses of IVIG may occur in some patients when treated early in
are characterized by asymmetric, non-length-dependent abnormalities the course of the illness.
of SNAPs, a global decrease in SNAP amplitudes, and hyperintensities
on T2-weighted MR images of the dorsal spinal cord (Kuntzer et al., Radiculopathies Simulating Motor Neuron Disease
2004; Lin and Chiu, 2008). Clinical and electrophysiological crite- Disorders of the motor roots may lead to clinical features that resem-
ria have been proposed to help separate patients with sensory neu- ble those encountered in motor neuron disease. Detailed study of such
ronopathy from those with predominantly sensory polyneuropathy motor neuron syndromes is important because it might provide clues
(Camdessanche et al., 2009). Favoring the diagnosis of neuronopathy to the pathogenesis of the most common form of motor neuron dis-
are the following findings: the presence of limb ataxia early in the disease, ALS. Clinicians should consider the possibility of an ALS-mimic
ease, asymmetrical sensory loss at onset, upper-limb sensory loss, lost syndrome when a patient with clinical features of lower motor neuron
or attenuated upper-limb sensory action potentials, and relatively nor- involvement is found to have a monoclonal gammopathy (Chad and
mal motor conduction studies. Harris, 1999). In this instance, investigations must vigorously pursue
Perhaps the best known of these uncommon conditions is paraneo the possibility that physical findings stem from ventral root involve-
plastic sensory neuronopathy (PSN), a disorder developing over weeks ment rather than anterior horn cell degeneration. An elevated CSF
to months and characterized by ataxia and hyperalgesia while muscle protein level, the presence of a monoclonal gammopathy, along with a
strength is well preserved (Graus and Dalmau, 2013). Some patients demyelinating process identified by nerve conduction studies, suggest a
have clinical signs of brainstem and cerebral dysfunction, reflecting a potentially treatable lymphoproliferative disease manifesting as motor
more widespread encephalomyelitis. The neuronopathy may antedate polyradiculoneuropathy. In some instances of IgM monoclonal gam-
the diagnosis of cancer, usually small-cell lung carcinoma, by months mopathy, there is antibody specificity for the gangliosides GM1, asialo-
to years. The CSF profile discloses elevated protein concentration and GM1, and GD1b, among others. In rare instances, immunotherapy
a mild mononuclear cell pleocytosis. Nerve conduction studies reveal that reduces the serum concentrations of IgM gangliosides is associ-
widespread loss of sensory potentials. Neuropathological features ated with improvement in the lower motor neuron syndrome, thereby
include inflammation and phagocytosis of the sensory neurons in the suggesting a possible pathogenic role of antiganglioside antibodies.
The association between lower motor neuron findings and lym- C5, C6, and C7 (the long thoracic nerve) and the levator scapulae
phoma has been known for many years and is designated subacute and rhomboids from branches of C5 (the dorsal scapular nerve). The
motor neuronopathy, but the site of major pathology is not certain and supraspinatus and infraspinatus muscles are supplied by the supra
could be at the root and/or neuronal level. It is characterized by subscapular nerve, a branch of the upper trunk of the plexus.
acute, progressive, painless, often patchy and asymmetric weakness of
the lower motor neuron type, with greater involvement of the arms Clinical Features and Diagnosis
than the legs. The illness often progresses independently of the activity Not surprisingly, disorders of the brachial plexus are determined in
of the underlying lymphoma and tends to follow a relatively benign large part by its anatomical relationships (Ferrante, 2012). Because of
course, with some patients demonstrating spontaneous improvement. its location between two highly mobile structures, the neck and the
A post-radiation lower motor neuron syndrome affecting the lum- shoulder, it is vulnerable to trauma. In addition, with its spatial prox-
bosacral region, probably a polyradiculopathy, has been described imity to neighboring tissues such as lymph nodes, blood vessels, and
occurring 4 months to 25 years after radiation therapy to the lower the lung parenchyma (which may themselves be targets of a variety
spine and cauda equina for treatment of testicular cancer, vertebral of disease processes), the brachial plexus may be secondarily affected.
metastases, and lymphoma (Hsia et al., 2003). In some patients, MRI
shows gadolinium enhancement of the conus medullaris and cauda Neurological Examination
equina that may mimic a leptomeningeal tumor (Hsia et al., 2003). Patients with a brachial plexopathy present with a variety of patterns
Neuropathological study in a case of testicular cancer disclosed radi- of weakness, reflex changes, and sensory loss, depending on whether
ation-induced vasculopathy of proximal spinal roots with preserved the whole or a portion of the plexus is disturbed. Most commonly
motor neurons (Bowen et al., 1996). The course of the disorder is typi- encountered are three patterns resulting from involvement of the
cally one of progression for 1–2 years followed by eventual stabilization. entire plexus, the upper trunk, or the lower trunk; less commonly seen
are partial plexopathies caused by selective cord lesions.
DISORDERS OF THE BRACHIAL PLEXUS In a panplexopathy, paralysis of muscles supplied by segments C5
through T1 occurs. The arm hangs lifelessly by the side, except that an
Anatomical Features intact trapezius allows shrugging of the shoulder. The limb is flaccid
The brachial plexus is formed by five spinal nerve ventral rami (C5– and areflexic, with complete sensory loss below a line extending from
T1), each of which carries motor, sensory, and postganglionic sym- the shoulder diagonally downward and medially to the middle of the
pathetic fibers to the upper limb. It is a large and complex peripheral upper arm.
nervous system structure that contains more than 100,000 individual Lesions of the upper trunk produce weakness and sensory loss in a
nerve fibers (Ferrante, 2012). The five rami unite above the level of the C5–C6 distribution. Affected muscles include the supraspinatus and
clavicle to form the three trunks of the brachial plexus (Fig. 105.9): infraspinatus, deltoid, biceps, brachialis, and brachioradialis, so the
C5 and C6 join to form the upper trunk; T1 and C8 unite to form patient is unable to abduct the arm at the shoulder or flex at the elbow.
the lower trunk; and C7, the largest of the five rami, continues as the If a lesion is so proximal that it involves the C5 ramus, the rhomboids
middle trunk. Beneath the clavicle, each trunk divides into an ante- and levator scapulae are also affected. The arm hangs at the side inter-
rior and posterior branch leading to six divisions, which become the nally rotated at the shoulder, with the elbow extended and the forearm
three cords of the brachial plexus: the lateral, medial, and posterior. pronated in a “waiter’s tip” posture. The biceps and brachioradialis
The cords, which lie behind the pectoralis minor, take their names reflexes are diminished or absent, and sensory loss is found over the
from their relationship to the subclavian artery. The lateral and medial lateral aspect of the arm, forearm, and thumb.
cords carry motor fibers to the ventral muscles of the limb. The lat- Lesions of the lower trunk produce weakness, sensory loss, and
eral cord is formed from anterior divisions of the upper and middle reflex changes in a C8–T1 distribution. Weakness is present in both
trunks, the medial cord from the anterior division of the lower trunk. median- and ulnar-supplied intrinsic hand muscles and in the medial
The posterior cord carries motor fibers to the dorsal muscles of the finger and wrist flexors. The finger flexion reflex is diminished or
limb; it is formed from posterior divisions of the upper, middle, and absent, and there is sensory loss over the medial two fingers, the medial
lower trunks. aspect of the hand, and the forearm.
The major named nerves of the upper limb are derived from the Cord lesions are usually found in the setting of trauma. A posterior
cords. After contributing a branch to the formation of the median cord lesion produces weakness in the territory of muscles innervated
nerve, the lateral cord continues as the musculocutaneous nerve. by both radial and axillary nerves. Sensory loss occurs in the distribu-
Similarly, after making its contribution to the median nerve, the tions of the posterior cutaneous nerve of the forearm and the radial and
medial cord continues as the ulnar nerve. The posterior cord divides axillary nerves. This results in sensory loss over the posterior aspect of
into a smaller axillary nerve (which leaves the axilla via the quadran- the arm, the dorsal surface of the lateral aspect of the hand, and a patch
gular space to supply the deltoid and teres minor) and the larger radial of skin over the lateral aspect of the arm. Lateral cord injuries produce
nerve. Also, from the level of the cords, branches are distributed to weakness in muscles supplied by the musculocutaneous nerve, as well
the pectoralis major and minor muscles (from the lateral and medial as weakness in the muscles of the median nerve supplied by the C6 and
cords, respectively) and to the subscapularis, latissimus dorsi, and teres C7 roots (the pronator teres and flexor carpi radialis muscles). The
major muscles (from the posterior cord). Cutaneous sensory branches median and ulnar nerve fibers originating from C8 and T1 segments
also originate at the cord level, with the posterior cutaneous nerve of are spared, and thus there is no intrinsic hand muscle weakness. In
the arm arising from the posterior cord, and the medial cutaneous medial cord lesions, there is weakness in all ulnar nerve–supplied mus-
nerve of the arm and medial cutaneous nerve of the forearm emerging cles and in the C8 and T1 median nerve–supplied muscles.
from the medial cord.
Nerve branches to the serratus anterior, levator scapulae, rhom- Electrodiagnostic Studies
boids, supraspinatus, and infraspinatus muscles derive from more Nerve conduction studies and needle EMG provide helpful infor-
proximal levels of the plexus. The first three muscles are supplied mation for confirming the clinical diagnosis of brachial plexopathy,
by branches of the anterior primary rami: the serratus anterior from determining the character of the lesion—predominantly axon loss,
Roots
Trunks
Sub-
divisions
Subclavian
nerve Dorsal scapular
Cords nerve
Suprascapular
nerve
5 5
Subscapular 6
6
nerves
Axillary
r 7 7
nerve pe
Radial Up 8
nerve le
A dd
A Mi 1 1
r
P P we
Lo
2
P
l
ra A
te
La
r
rio
te
s
Po
l
ia Long thoracic
ed
M nerve (nerve to
serratus anterior)
Medial and
lateral anterior
thoracic nerves
Thoracodorsal nerve
Musculocutaneous (Nerve to latissimus dorsi)
nerve
Medial cutaneous
Median nerve of arm
nerve
Ulnar Medial cutaneous
nerve nerve of forearm
Fig. 105.9 Brachial Plexus. Components of the plexus have been separated and drawn out of scale. The
five ventral rami (C5–T1) unite to form the upper, middle, and lower trunks of the plexus above the clavicle.
Beneath the clavicle, each trunk divides into anterior (A) and posterior (P) divisions. Three cords (lateral, pos-
terior, and medial) lie below the pectoralis minor muscle (not shown). Major upper limb nerves originate from
the cords. (Reprinted with permission from Haymaker, W., Woodhall, B., 1953. Peripheral Nerve Injuries,
second ed. Saunders, Philadelphia.)
demyelinating, or both—and arriving at a judgment with respect to Axon-loss brachial plexus neuropathies fall along a spectrum of
prognosis for recovery of function. In axon-loss brachial plexopathies, severity that may be determined by the results of the electrodiagnostic
SNAPs and CMAPs are attenuated or lost depending on the severity study. In the context of a minimal lesion affecting both sensory and
of the disease process as the amplitude of these responses correlates motor fibers, SNAPs and CMAPs will typically be unaffected, but nee-
directly with the number of conducting fibers. In preganglionic lesions dle examination will disclose fibrillation potentials because the loss of
(at a root level) sensory responses are expected to be spared, and only one motor axon will result in denervation of hundreds of muscle fibers.
motor responses will be affected. As long as at least some fast-con- With an increase in lesion severity, SNAPs become attenuated while
ducting fibers are spared, the conduction velocities and distal latencies CMAPs are still spared. The most severe lesions compromise sensory
are unaffected. Conversely, in the case of demyelinating lesions, nerve and motor responses. Ferrante and Wilbourn (2002) also observed
conduction velocities are typically slowed, motor evoked responses that it is the CMAPs that are most useful for quantifying the amount
dispersed, and distal latencies prolonged. Most brachial plexus lesions of loss suffered by a nerve. In contrast, SNAPs may be attenuated, even
are axon loss in nature (Ferrante, 2012). The needle examination is absent, with only partial lesions; and needle electrode examination, as
very sensitive for detecting even mild motor fiber loss because fibrilla- we have seen, may reveal prominent fibrillation potentials with only
tion potentials develop in affected muscles by 3 weeks after the onset mild motor axon loss. The needle examination is helpful in evaluat-
of a disease process. ing recovery from axon-loss lesions as features of MUP remodeling
(increased duration and complexity of MUPs) indicate an ongoing objective in management is to restore as much neurological function
process of collateral reinnervation, distal-to-proximal reinnervation, as possible with the hope of returning the limb to its pre-injury status,
or both. but one must first ensure that the cardiovascular and respiratory sys-
In a postganglionic plexopathy, numbness and sensory loss are asso- tems are stable. In open injuries, there may be damage to great vessels
ciated with reduced or absent SNAPs because the lesion is located distal in the neck and injury to the lung, in which case immediate operative
to the DRG. By contrast, in a pure radiculopathy, sensory loss is found intervention is necessary. At the time of this early acute intervention, it
in the face of a normal SNAP because the lesion is proximal to the DRG. is important to assess to what degree the various elements of the plexus
In certain conditions, preganglionic and postganglionic lesions coex- have been injured. As far as possible, disrupted elements should be
ist, so electrodiagnostic studies disclose paraspinal muscle fibrillation tagged for later repair. It may be difficult to suture damaged fascicles,
and absent SNAPs. This situation is encountered most commonly in and the formation of scar may prevent successful nerve regeneration.
patients with trauma that damages both the plexus and avulses nerve Most researchers agree that nerve resection, grafting, and anastomosis
roots. It is also found in some peripheral radiculoplexus neuropathies are all very difficult in the acute situation because nerve continuity may
such as diabetes and in malignant plexopathies in which tumor not be difficult to assess. However, if portions of a plexus have been sharply
only injures the plexus but also infiltrates the nerve roots by tracking transected, then primary repair should be carried out.
through the intervertebral foramina. Specific EMG changes are covered
under individual disorders of the plexus, later in the chapter. Long-Term Management
Once the patient’s general condition has stabilized, a careful assess-
Radiological Studies ment of motor and sensory function should be made. At this stage,
Plain films of the neck and chest are often very helpful in evaluating an important issue is whether there has been root avulsion. This is a
arm weakness that is thought to be caused by a disorder of the bra- critical determination with implications for management because the
chial plexus. The presence of a cervical rib or long transverse process outlook for return of motor and sensory function in territories supplied
of C7 may provide an explanation for hand weakness and numbness, by avulsed roots is currently not good, although promising results of
as seen in neurogenic thoracic outlet syndrome. A lesion in the pul- surgical repair have recently been noted. Root avulsion and its manage-
monary apex, erosion of the head of the first and second rib, or the ment are discussed in the section on Disorders of Nerve Roots, earlier
transverse processes of C7 and T1 may reveal the cause of a lower brain this chapter. If the plexus elements are in continuity and the nerve
chial plexopathy, as found in cases of Pancoast tumor. High-resolution fibers have received a neuropraxic injury with minimal axonotmesis,
CT and MRI scanning are also useful in detecting mass lesions of the return of normal strength and sensation is expected. In the face of axo-
plexus and may allow early diagnosis and specific therapy (Amrami notmesis, the main factor limiting return of function is the distance the
and Port, 2005). Magnetic resonance neurography, incorporating regenerating axon sprouts must traverse before contacting end organs.
diffusion-weighted imaging and diffusion tensor imaging, is an emerg- Unless the muscles and sensory receptors are reinnervated within about
ing imaging modality offering both morphometric data and infor- 1 year, a good functional result is unlikely. Thus, recovery of proximal
mation regarding pathophysiology in plexus lesions (Noguerol et al., muscle strength from upper portions of the plexus is more likely than
2017). CT-guided biopsy can be used to obtain cytological or histolog- recovery of hand function when lower elements have been damaged.
ical material for precise diagnosis. Often, surgery must be performed to provide an exact intraoper-
ative definition of the lesion’s extent (see Chapter 63). Intraoperative
Traumatic Plexopathy motor evoked potentials are helpful in assessing the functional state
Three general categories of traumatic brachial plexus injury exist: of anterior motor roots and motor fibers. Depending on the findings,
(1) direct trauma; (2) secondary injury from damage to structures innovative microsurgical techniques are available to provide an array
around the shoulder and neck, such as fractures of the clavicle and of options: direct nerve repair, nerve grafting, replantation, nerve
first rib; and (3) iatrogenic injury, most commonly seen as a compli- transfers, and free-functioning muscle transfers (Giuffre et al., 2010).
cation of the administration of nerve blocks. The most pronounced of Primary nerve reconstruction combined with joint fusion and tendon
the lesions affecting the brachial plexus are preganglionic, character- transfers provides a worthwhile return of function to many patients.
ized by a nerve root avulsion when rootlets are torn from the spinal The joint and tendon surgeries are best performed as secondary oper-
cord. Lesions affecting the postganglionic portion of the plexus may ations after a period of physiotherapy. Intensive physiotherapy and
be severe because of nerve rupture or of lesser severity if caused by use of orthoses are often necessary to help restore maximum function.
nerve stretch (Giuffre et al., 2010). Direct injury may be either open In general, the outcome after nerve grafting is relatively good for the
(gunshot wounds and lacerations) or closed (stretch or traction). The recovery of elbow flexors and extensors and for those of the shoul-
main causes of traumatic brachial plexus palsies are traction and heavy der girdle, but it is very poor for forearm and hand intrinsic muscles.
impact. Injuries are usually secondary to motorcycle and snowmobile Quality-of-life surveys after brachial plexus surgery indicate that 83%
accidents, but sporting accidents in football, bicycling, skiing, and of patients report satisfaction with the surgical outcome (Kretschmer
equestrian events are also important. Supraclavicular injuries are more et al., 2009). In a large series of more than 1000 patients treated over
common and more severe and have a worse prognosis than infracla- a 30-year period (Kim et al., 2003), the results of repair by suture and
vicular injuries (Ferrante, 2012). Another form of brachial plexus trac- grafts were best for injuries located at the C5, C6, and C7 levels, the
tion is seen in rucksack paralysis. The straps of a rucksack or backpack upper and middle trunk, the lateral cord to the musculocutaneous
pressed to the shoulders may exert heavy pressure in the region of the nerve, and the median and posterior cords to the axillary and radial
upper trunk of the brachial plexus and thus lead to weakness in the nerves. Results were poor for injuries at the C8 and T1 levels and for
muscles supplied by the suprascapular and axillary nerves, with sen- lower trunk and medial cord lesions, and the chance of recovery was
sory loss in the C5–C6 distributions. reduced with delays of more than 6 months in undertaking repair.
Early Management Neurogenic Thoracic Outlet Syndrome

The consequences of brachial plexus injury are weakness and sen- True neurogenic thoracic outlet syndrome is a rare entity, seen only a
sory loss referable to a part or the whole of the plexus. The ultimate few times a year in our EMG laboratory. Most patients are women. The
mean age at onset is 32 years, but patients as young as 13 and as old as In most patients, a fibrous band extending from the tip of a rudi-
73 have been reported. The clinical and electrophysiological findings mentary cervical rib to the scalene tubercle of the first rib causes angu-
point to a lesion of the lower trunk of the brachial plexus. Pain is usu- lation of either the C8 and T1 roots or the lower trunk of the brachial
ally the first symptom, with either aching noted on the inner side of the plexus (Fig. 105.10). Surgical division of the fibrous band can be
arm or soreness felt diffusely throughout the limb. Tingling sensations expected to relieve pain and paresthesias and arrest muscle wasting and
accompany pain and are felt along the inner side of the forearm and in weakness in the majority of patients; however, return of muscle bulk
the hand. Most patients note slowly progressive wasting and weakness and strength is unlikely.
of the hand muscles. The physical examination discloses hand muscle
weakness and atrophy, most marked in the lateral part of the thenar Metastatic and Radiation-Induced Brachial Plexopathy
eminence. In a smaller number of patients, there is mild atrophy and in Patients with Cancer
weakness in the forearm muscles. Sensory loss is present along the Metastatic Plexopathy
inner side of the forearm. Except for the occasional Raynaud-type epi- Damage to the brachial plexus in patients with cancer is usually sec-
sode, vascular symptoms and signs are uncommon. Electrodiagnostic ondary to either metastatic plexopathy or radiation-induced injury
studies on the affected side disclose a reduced median motor response (Jaeckle, 2010). Lung and breast carcinoma are the tumors that most
with normal median sensory amplitudes, along with a mildly reduced commonly metastasize to the brachial plexus; lymphoma, sarcoma,
ulnar motor response and reduced ulnar sensory amplitude. The nee- melanoma, and a variety of other types are less common. Tumor metas-
dle electrode examination typically discloses features of chronic axon tases spread via lymphatics, and the area most commonly involved, the
loss with mild fibrillation potential activity in C8- and T1-innervated C8 and T1 nerve roots along with the lower trunk of the plexus, is
muscles. adjacent to the lateral group of axillary lymph nodes.
In many cases, cervical spine roentgenograms disclose small bilat- The hallmark of metastatic plexopathy is pain, which is often
eral cervical ribs or enlarged down-curving C7 transverse processes. severe. It is generally located in the shoulder girdle and radiates to the
When not visualized in anteroposterior radiographs of the cervical elbow, medial portion of the forearm, and fourth and fifth digits of
spine, they can be seen on oblique views. MRI of the thoracic outlet is the hand. In many patients, the neurological examination discloses
a useful diagnostic method, revealing deviation or distortion of nerves signs referable to the lower plexus and its divisions; more than half of
or blood vessels and suggesting the presence of vascular or nervous patients have Horner syndrome, whereas few have lymphedema of the
compressions (Aralasmak et al., 2012). Levin and colleagues (1998) affected limb. Some patients have signs indicating involvement of the
have refined our understanding of the precise lesion localization of entire plexus. However, in most of these patients, cervical CT myelog-
the neurogenic thoracic syndrome. They compared electrophysiolog- raphy or MRI discloses epidural deposits that involve the C5 and C6
ical results between a group of patients with true neurogenic thoracic nerve roots, thereby explaining the upper plexus signs on examination.
outlet syndrome and a group with “brachial plexopathy” stemming An important syndrome first described by Pancoast in 1932 is a
from median sternotomy. In the former group, the findings pointed superior pulmonary sulcus tumor, the vast majority of which are non–
to severe axon loss in the medial antebrachial cutaneous nerve and small- cell bronchogenic carcinomas. The tumor arises near the pleural
the abductor pollicis brevis, both sharing T1 root innervation. In the surface of the apex of the lung and grows into the paravertebral space
latter, an iatrogenic disorder resulting from rib retraction, the findings and posterior chest wall, invading the C8 and T1 extraspinal nerves,
indicated axon loss in the ulnar sensory and motor nerves, conforming the sympathetic chain and stellate ganglion, the necks of the first three
most to involvement predominantly of C8. These findings suggest that ribs, and the transverse processes and borders of the vertebral bodies
thoracic outlet syndrome and median sternotomy brachial plexopathy of C7 through T3. The tumor may eventually invade the spinal canal
are due to damage to the mixed spinal nerve fibers at the level of the and compress the spinal cord. Presenting signs and symptoms include:
anterior primary rami distal to the C8 or T1 nerve roots but proximal severe shoulder pain radiating to the head and neck, axilla, chest, and
to the lower trunk of the brachial plexus (Levin, 2002). arm; pain and paresthesias of the medial aspect of the arm and the
Scalenus
medius
Scalenus
anticus
Brachial
plexus
Subclavian
artery
Subclavian
vein
First rib
A B
Fig. 105.10 A, Normal relationships of subclavian artery and brachial plexus as they course over the first rib
between the scalenus medius and anterior muscles. B, From the end of a short cervical rib arises a fibrous
band (arrow), which attaches to the upper surface of the normal first rib. This stretches and angulates chiefly
the lower trunk of the brachial plexus, causing neurogenic thoracic outlet syndrome.
fourth and fifth digits; and weakness with atrophy of intrinsic hand The natural history of radiation-induced plexopathy is that of
muscles. steadily increasing deterioration, although at times a plateau may
On occasion, metastatic brachial plexopathy may be difficult to be reached after 4–9 years of progression. Unfortunately, treatment
distinguish from radiation plexopathy (see the following section on options are not very satisfactory. Surgical treatment using neurolysis
Radiation-Induced Plexopathy). Imaging studies are usually infor- has been reported to relieve pain in some patients, but there is little
mative. In patients with metastatic disease, MRI may identify a mass information on the long-term outcome, and surgery may cause signif-
adjacent to the brachial plexus and reveal whether the tumor has icant deterioration in motor and sensory function (Dropcho, 2010).
encroached on the epidural space. Magnetic resonance neurogra- Combination therapy with a phosphodiesterase inhibitor, pentoxifyl-
phy is a noninvasive means of helping to exclude radiation-induced line, tocopherol (vitamin E), and a bisphosphonate, clodronate, have
tumor in patients presenting with brachial plexopathy who have been reported to improve motor strength in patients with radiation-
undergone prior radiation therapy to the brachial plexus (Du et al., induced radiculopathy, presumably by reducing radiation-induced
2010). fibrosis and myelin destruction (Delanian et al., 2008).
Results of the treatment of metastatic plexopathy are disappoint- A diagnostic dilemma arises when symptoms and signs of brachial
ing. Radiotherapy to the involved field and chemotherapy of the plexopathy develop in a patient who is known to have had cancer and
underlying tumor are the mainstays of treatment. Radiotherapy may radiation in the region of the brachial plexus, raising concern for tumor
relieve pain in 50% of patients but has little effect on return of muscle recurrence, a radiation-induced tumor, or radiation-induced plexopa-
strength. A variety of procedures have been implemented to ameliorate thy. A painful lower-trunk lesion with Horner syndrome strongly sug-
the severe pain of this condition, including opioid analgesics and non- gests metastatic plexopathy, whereas a relatively painless upper-trunk
opioid adjuvant analgesics such as antidepressants and antiepileptic lesion with lymphedema favors radiation-induced plexopathy. MRI
drugs, transcutaneous stimulation, paravertebral sympathetic block- does not always discriminate between metastatic tumor infiltration
ade, and dorsal rhizotomies. and radiation-induced nerve fibrosis, as each may be associated with
In the patient with Pancoast tumor, trimodal treatment with pre- high signal intensity of nerves on T2-weighted images and contrast
operative chemotherapy and radiotherapy followed by extended sur- enhancement on T1-weighted images (Wouter van Es et al., 1997).
gical resection is the most common treatment, with an overall 5-year Features which favor radiation fibrosis include thickening and diffuse
survival rate of 41%–53% (Nikolaos et al., 2014). enlargement of the brachial plexus without a focal mass (Wittenberg
and Adkins, 2000). Magnetic resonance neurography may be useful to
Radiation-Induced Plexopathy exclude intrinsic nerve tumor (Du et al., 2010) and FDG-PET scanning
Delayed injury to the structures of the brachial plexus following may be useful for identifying metastatic breast cancer in or near the
radiation exposure is thought to involve two factors: (1) radia- brachial plexus, not clearly imaged by CT or MRI (Dropcho, 2010). In
tion-induced endoneural and perineural fibrosis with obliteration the early and middle stages of radiation plexopathy, nerve conduction
of blood vessels, triggered by small-vessel or microvascular endo- studies disclose features of demyelinating conduction block, but as time
thelial injury, and (2) direct radiation-induced damage to myelin passes, there is conversion to axon loss (Ferrante and Wilbourn, 2002).
sheaths and axons. Dropcho (2010) points out that breast carci- Needle EMG is helpful in separating radiation-induced plexopathy
noma is the tumor most often associated with radiation plexopathy, from neoplastic plexopathy by the presence of myokymic discharges in
accounting for 40%–75% of patients, followed by lung carcinoma the former. These are spontaneously occurring grouped action poten-
then lymphoma. tials (triplets or multiplets) followed by a period of silence, with sub-
Radiation-induced plexopathy is unlikely to occur if the dose is less sequent repetition of a grouped discharge of identical potentials in a
than 6000 cGy. If more than 6000 cGy is given, the interval between the semi-rhythmic manner. They appear to result from spontaneous activ-
end of radiation therapy and the onset of symptoms and signs of radi- ity in single axons induced by local membrane abnormalities. They
ation plexopathy ranges from 3 months to 26 years, with a mean inter- have not been reported in cases of tumor plexopathy.
val of approximately 6 years. Improvements in irradiation techniques
over the past several decades have allowed the use of lower radiation Idiopathic Brachial Plexopathy
doses, and as such the incidence of delayed post-radiation brachial The terms idiopathic brachial plexopathy, brachial plexus neuritis,
plexopathy has declined precipitously (66% in the 1950s, compared neuralgic amyotrophy, and Parsonage–Turner syndrome all refer to
to <1%–2% today; Delanian et al., 2012). In addition to fraction size, the clinical syndrome of severe pain followed by rapid paresis and
concomitant cytotoxic therapy adds additional risk in developing a atrophy of muscles in an upper extremity. It occurs in all age groups,
delayed radiation-induced plexopathy. particularly between the third and seventh decades of life. Men are
Limb paresthesias and swelling are common complaints. affected two to three times more often than women. Although half the
Although the pain of radiation plexopathy is usually less intense cases seem unrelated to any precipitating event, in others the plexopa-
than that of metastatic plexopathy, it may nonetheless be problem- thy follows an upper respiratory tract infection, a flu-like illness, vigor-
atic (severe and persistent), requiring opioids and chemical sympa- ous exercise (weight lifting, gymnastics, wrestling), strenuous activity
thectomy (Fathers et al., 2002). Weakness is usually most prominent (yard work), an immunization, surgery, psychological stress, or in the
in muscles innervated by branches of the upper trunk, but involve- postpartum period (van Alfen and van Engelen, 2006).
ment of the entire limb from damage to the upper and lower por- Beyond the two cardinal manifestations of pain and weakness, the
tions of the plexus has also been described. Indeed, in a group of clinical phenotype of idiopathic brachial plexopathy is quite hetero-
women with radiation plexopathy following treatment for carci- geneous (Van Alfen, 2011). Patients often describe abrupt onset of
noma of the breast, progressive weakness resulted in loss of hand a sharp, stabbing, throbbing, or aching pain involving the shoulder,
function in 90% of patients (Fathers et al., 2002). The relative resis- scapular area, trapezius ridge, or upper arm, forearm, or hand. Within
tance of the lower trunk of the brachial plexus to radiation injury hours, this pain will have escalated to a peak severity that is often
is perhaps explained by the protective effect of the clavicle and the beyond anything the patient will have previously experienced, and
relatively shorter course of the lower trunk and its divisions through then will persist for up to 4 weeks on average before gradually resolv-
the radiation field. ing (though rapid resolution of pain within 24 hours and intractable
pain lasting months may be seen in 5% and 10% of cases, respectively). consideration might be a focal presentation of motor neuron disease,
During this period, the patient may hold their arm in a characteris- but, in such cases, pain is not a feature, and sensation is always spared.
tic posture, flexed at the elbow and adducted against the body, in an Electrodiagnostic testing is helpful in confirming the diagnosis and
effort to minimize traction on the plexus, which may exacerbate pain ruling out other conditions. Findings suggest axonal lesions of periph-
symptoms. eral nerves occurring singly (mononeuritis) or in various combinations
Weakness of the upper extremity likely evolves during this period (mononeuritis multiplex) (van Alfen and van Engelen, 2006). Sensory
of intense pain, but may not be immediately appreciated by the patient, studies are abnormal in up to one-third of patients; the most common
who is reluctant to move the limb and further exacerbate their pain. abnormality is reduced amplitude of one or more sensory action poten-
This often results in the classic description of weakness that is coinci- tials of the median, ulnar, and radial nerves and the lateral and medial
dent with a lessening or resolution of the patient’s pain. The pattern of antebrachial cutaneous nerves. Van Alfen and colleagues (2009b) found
weakness seen is highly variable, with the majority of patients having sensory abnormalities in less than 20% of nerves studied, even when
weakness referable to the upper brachial plexus, a third with weakness the nerve was clinically affected, suggesting that the pathology may be
involving both upper and lower parts of the plexus, and approximately in the nerve roots. Needle EMG is helpful because it shows an absence
15% with evidence of lower plexus involvement alone. of fibrillation potentials in the cervical paraspinal muscles, thereby
Patchy weakness is common, with sparing of one or more muscles pointing to a pathological process distal to the DRG. Needle EMG is
in the same root, trunk, or cord distribution. Similarly, there is increas- also helpful in sorting out the problems of localization, identifying
ing recognition that this illness need not always be associated with lesions localized to the brachial plexus, individual peripheral nerves,
circumscribed lesions of trunks or cords but may present as discrete or peripheral nerve branches. Finally, in a small number of patients,
lesions of individual peripheral nerves, including the suprascapular, needle EMG is abnormal on the asymptomatic side as well as the symp-
axillary, musculocutaneous, long thoracic, median, and anterior inter- tomatic side, indicating that brachial plexus neuropathy can sometimes
osseous or posterior interosseous nerves. A minority of patients may be subclinical. MRI of the brachial plexus is important in excluding
have involvement of nerves outside the brachial plexus proper, includ- structural lesions that might simulate this disorder and should be per-
ing the phrenic nerves, cranial nerves VII and X, and the lumbosacral formed where there is failure to recover function (van Alfen and van
plexus (van Alfen, 2011). In a small number of patients, unilateral or Engelen, 2006). The MRI appearance in idiopathic brachial plexopathy
bilateral diaphragmatic paralysis occurs with no abnormalities on clin- reveals findings of diffuse high T2 signal intensity abnormalities and
ical or electrodiagnostic examinations of the limbs (Tsao et al., 2006). fatty atrophy of involved muscles (Gaskin and Helms, 2006). There are
In such cases, the combination of acute shoulder pain with respiratory additional laboratory findings of interest (van Alfen and van Engelen,
symptoms should suggest the diagnosis. 2006). Among the group of patients with severe bilateral brachial plexus
Sensory loss, found in two-thirds of patients and most commonly neuropathy with phrenic nerve involvement, elevated liver enzymes are
over the outer surface of the upper arm and the radial surface of the found, possibly reflecting an antecedent subclinical hepatitis. In 25% of
forearm, is usually less marked than the motor deficit, although the patients, antiganglioside antibodies are found, and CSF protein eleva-
spectrum of brachial plexus neuropathy includes patients with isolated tions with oligoclonal bands are also noted in some patients, reflecting
clinical and electrophysiological sensory deficits (Seror, 2004). One- the likelihood of an immune pathogenesis for this condition.
third of cases are bilateral, but few are symmetrical. Rarely, symptoms
may recur episodically for a year or more (van Alfen and van Engelen, Pathophysiology and Etiology
2006). The pathophysiology and pathogenesis of the disorder are unclear,
A familial form of brachial plexus neuropathy, so-called hereditary though genetic factors, immune-mediated mechanisms, and biome-
neuralgic amyotrophy, is an autosomal dominant disorder causing chanical factors have each been implicated (van Alfen, 2011). A likely
repeated episodes of intense pain, paralysis, and sensory disturbances genetic predisposition for some patients with idiopathic brachial plex-
in an affected limb (Chance, 2006). Like the idiopathic disorder, there opathy is based on the discovery of the SEPT9 gene in the hereditary
may be similar antecedent triggering events. Onset is at birth or early form of the disorder. The SEPT9 gene gives rise to six isoforms of
childhood, with a good prognosis for recovery after each attack. Three- septin-9, a cytoskeletal protein involved in cell division and cell polar-
point mutations have been found in the gene SEPT9 encoding the ity. How exactly mutations in this gene confer susceptibility to brachial
septin-9 protein, in 49 pedigrees with hereditary neuralgic amyotrophy plexus injury remains unclear. Nerve biopsy studies of patients with
linked to chromosome 17q25 (Hannibal et al., 2009; Kuhlenbaumer autosomal dominant attacks of brachial plexus neuropathy during
et al., 2005). In some individuals, associated findings include relative symptomatic phases disclosed prominent perivascular inflammatory
hypertelorism, occasional cleft palate, and skin folds or creases on the infiltrates with vessel wall disruption, suggesting that the hereditary
neck or forearm (Hannibal et al., 2009). disorder has an immune pathogenesis possibly caused by genetic
abnormalities of immune regulation (Klein et al., 2002). Complement-
Diagnosis dependent antibody-mediated demyelination may have participated in
The major differential diagnostic consideration in a patient with acute the peripheral nerve damage and nerve biopsy findings in four cases
arm pain and weakness is radiculopathy related to cervical spine dis- of brachial plexus neuropathy revealed florid multifocal mononuclear
ease. However, in this condition pain is usually persistent, neck stiff- infiltrates, suggesting a cell-mediated component as well (Suarez et al.,
ness is invariable, and it is unusual for radicular pain to subside as 1996). Antecedent illness or vigorous exercise raises the possibility for
weakness increases. Nonetheless, an upper trunk brachial plexopathy a mechanistic role of both autoimmune disease and biomechanical
can simulate a C5 or C6 radiculopathy. The cervical paraspinal needle injury in the pathogenesis of idiopathic brachial plexopathy as well. As
EMG done several weeks after the onset of pain should be normal in an example, an increased incidence of brachial plexopathy in north-
brachial plexus neuropathy but show increased insertional activity and east Czechoslovakia occurred following contamination of the water
fibrillation potentials in cervical radiculopathy. Another differential supply with Coxsackie virus type A2 (indicating a possible post-viral
diagnostic consideration is neoplastic plexopathy, discussed earlier in immune-mediated pathophysiology), yet was particularly prevalent
this chapter. This entity is usually unremittingly painful, and neurolog- in knitting factory workers in this region that were required to bend
ical findings are most often referable to lower plexus elements. A third and stretch their arms repeatedly throughout the day (suggesting an
additional biomechanical component to injury) (van Alfen, 2011). management becomes the mainstay of therapy for these individuals
Clinical features of the illness have also suggested other pathophys- and requires a multidisciplinary approach that blends pharmacother-
iological mechanisms. An abrupt onset might suggest an ischemic apy with physical and occupational modalities.
mechanism. In some cases, rapid recovery bespeaks demyelination and The natural history of brachial plexus neuropathy is benign;
remyelination; in others, a long recovery period is more in keeping with improvement occurs in the vast majority of patients, even in those
axonal degeneration followed by axonal regeneration. Indeed, a biopsy with considerable muscle atrophy. Thirty-six percent have recovered
of a cutaneous radial branch in a severe case of plexopathy showed by the end of 1 year, 75% by the end of 2 years, and 89% by the end
profound axonal degeneration. In most patients, electrophysiological of 3 years. Although some patients think they have made a full func-
abnormalities are restricted to the affected limb, while in a small num- tional recovery, careful examination may disclose mild neurological
ber of cases there is evidence of a more generalized polyneuropathy. abnormalities such as isolated winging of the scapula, slight proximal
or distal weakness, mild sensory loss, or reduced reflex activity. In two-
Treatment and Prognosis thirds of patients, onset of improvement is noted in the first month
In the acute stage of the disorder, long-acting nonsteroidal antiinflam- after symptoms begin. Those who continue to be bothered by pain and
matory drugs (NSAIDs) and opioid analgesics are required to control lack any signs of improvement within the first 3 months of the illness
pain (van Alfen, 2007). Evidence from one open-label retrospective take a longer time to recover.
series suggests that oral prednisone given in the first month after the
onset can shorten the duration of the initial pain and leads to earlier DISORDERS OF THE LUMBOSACRAL PLEXUS
recovery in some patients (van Alfen et al., 2009b). Arm and neck
movements often aggravate pain, so immobilization of the arm in a Anatomical Features
sling is helpful. With the onset of paralysis, range-of-motion exercises The lumbar plexus is formed within the psoas major muscle by the
help prevent contractures. Following the phase of acute pain, van Alfen anterior primary rami of lumbar spinal nerves L1, L2, L3, and L4.
(2007) reported two additional categories of pain. The first, experi- Branches of the lumbar plexus include the iliohypogastric and ilioin-
enced by nearly 80% of patients, is a shooting or radiating neuropathic guinal nerves arising from L1 (with a contribution from T12), the
pain, believed to originate from the heightened mechanical sensitivity lateral femoral cutaneous nerve of the thigh originating from the pos-
of damaged nerves of the plexus and lasting for weeks to months. This terior divisions of L2 and L3, and the genitofemoral nerve arising from
pain may respond to gabapentin and tricyclic medications. A second the anterior division of L1 and L2. Other branches are the femoral
type of pain that develops in many is a musculoskeletal-type pain local- nerve, formed from the posterior divisions of L2, L3, and L4 within the
ized to the origin or insertion of the paretic or compensating muscles, substance of the psoas muscle, and the obturator nerve, formed by the
especially in the periscapular, cervical, and occipital regions. This pain anterior divisions of L2, L3, and L4.
requires physical therapy modalities. Up to 30% of patients who have The lumbar plexus communicates with the sacral plexus via
experienced neuralgic amyotrophy will have long-standing pain for the anterior division of L4 (Fig. 105.11, A), which joins with L5 to
an average follow-up of 6 years (van Alfen, 2007). Accordingly, pain form the lumbosacral trunk at the medial border of the psoas at the
Lumbosacral
L1 trunk
L1
Superior
Iliohypogastric gluteal nerve
2
nerve 2
Inferior 3
Ilioinguinal gluteal nerve 4
nerve 3
3 Inferior
Sciatic nerve hemorrhoidal
Lateral cutaneous nerve
nerve of thigh
4 4
Dorsal nerve
Genitofemoral of penis
nerve
5 Perineal
nerve
Femoral nerve
Pudendal
nerve
Obturator Lumbosacral Posterior cutaneous
nerve trunk nerve of thigh
A B
Fig. 105.11 A, Lumbar plexus is formed by anterior primary rami of lumbar spinal nerves L1, L2, L3, and
L4 (note branches that arise from plexus). B, Sacral plexus is connected to lumbar plexus by the lumbosa-
cral trunk (note branches that arise from plexus in pelvis). (Reprinted with permission from Haymaker, W.,
Woodhall, B., 1953. Peripheral Nerve Injuries, second ed. Saunders, Philadelphia.)
ala of the sacrum. The trunk enters the pelvis and joins the sacral findings may strongly suggest a particular type of plexopathy; for
plexus in the piriformis fossa. The sacral plexus, derived from the example, myokymic discharges point to the diagnosis of radiation
anterior rami of spinal nerves L4, L5, S1, S2, and S3, forms in front plexopathy.
of the sacroiliac joint (see Fig. 105.11, B). Like the lumbar plexus, Routine nerve conduction studies may help establish the diag-
the sacral plexus has anterior and posterior divisions. The anterior nosis of plexopathy. Reduced SNAP amplitude (sural and superfi-
division contributes to the tibial portion, and the posterior division cial peroneal) indicates loss of axons distal to the DRG of S1 and L5,
contributes to the peroneal portion of the sciatic nerve, which leaves respectively. Prolongation in F-wave latency with normal motor nerve
the pelvis through the greater sciatic notch. A number of import- conduction studies distally suggests a proximal lesion, either at a root
ant branches come from the sacral plexus in the pelvis; the superior or a plexus level.
and inferior gluteal nerves arise from posterior divisions of the sacral
plexus and supply the gluteus medius and minimus muscles and the Neuroimaging Studies
gluteus maximus, respectively. The posterior cutaneous nerve of the Bone destruction found in plain radiographs of lumbar and sacral ver-
thigh is formed by the anterior divisions of S1, S2, and S3. It passes tebrae and the pelvis provides evidence for a structural plexopathy. CT
through the greater sciatic foramen into the buttock. The pudendal scanning of the abdomen and pelvis from a rostral point at the level of
nerve originates from the undivided anterior primary rami of spi- L1–L2 to a caudal point below the level of the symphysis pubis allows
nal nerves S2, S3, and S4 and extends into the gluteal region via the the regional anatomy of the entire lumbosacral plexus to be scrutinized
greater sciatic foramen. (see Chapter 40).
The resolution of modern CT and MRI scanners allows identifica-
Clinical Features tion of individual plexus components. The administration of contrast
Neurological Examination is usually required to demonstrate the extent of structural abnormali-
Lumbar plexopathy produces weakness, sensory loss, and reflex ties of the lumbosacral plexus, but it may not differentiate benign and
changes in segments L2 through L4, whereas sacral plexopathy leads malignant neoplasms, inflammatory masses, and hematoma. A normal
to similar abnormalities in segments L5 through S3. Characteristic MRI makes a structural plexopathy very unlikely. Clues to the nature
findings in lumbar plexopathy include weakness and sensory loss in of a plexopathy are given in Box 105.1. An approach to evaluation of a
both obturator- and femoral-innervated territories. Weakness of hip plexopathy is summarized in Fig. 105.12.
flexion, knee extension, and hip adduction, with sensory loss over
the anteromedial aspect of the thigh occurs; the knee jerk is absent Differential Diagnosis
or depressed. This combination of hip flexor and adductor weakness The differential diagnosis of lumbosacral plexopathy includes spinal
marks the disorder as either a plexopathy or radiculopathy. More pre- root disorders (e.g., lumbosacral radiculopathy, polyradiculoneurop-
cise localization depends on laboratory studies, including needle EMG, athy, cauda equina syndrome, anterior horn cell disorders) and myo-
CT, and MRI. pathic conditions. Radiculopathies are usually painful, and the pain
Findings in sacral plexopathy include weakness and sensory loss in follows a predictable radicular distribution. Weakness is usually found
the territories of the gluteal (motor only), peroneal, and tibial nerves. in several muscles supplied by the same root, and the EMG usually
Leg weakness is typically extensive and involves the hip extensors demonstrates paraspinal muscle involvement. It is sometimes difficult
and abductors, knee flexors, and ankle plantar flexors and dorsiflex- to separate plexopathy from radiculopathy on clinical grounds alone,
ors. Sensory loss is found over the posterior aspect of the thigh, the especially if several roots are involved.
anterolateral and posterior aspects of the leg below the knee, and the Anterior horn cell disorders give rise to painless progressive weak-
dorsolateral and plantar surfaces of the foot. Vasomotor and trophic ness with atrophy and fasciculation in the absence of sensory loss.
changes also may be found in these areas. The ankle jerk is reduced or When fully developed, such disorders should not be confused with
absent. Weakness of the gluteal muscles points to involvement of sacral lumbosacral plexopathy. However, in rare cases, a restricted anterior
plexus fibers proximal to the piriformis muscle in the true pelvis or to horn cell disorder (focal spinal muscular atrophy involving one leg) is
a more proximal sacral root level. As in lumbar plexopathy, accurate seen. Absence of pain and sensory loss, normal imaging studies, and
diagnosis often depends on electrodiagnostic studies and neuroimag- absence of diabetes and vasculitis all help point away from a distur-
ing procedures. bance of the lumbosacral plexus.
Myopathies are rarely confused with lumbosacral plexopathy.
Electrodiagnostic Studies Myopathies with a focal lower-extremity onset can be distinguished
Electrodiagnostic studies are performed for several reasons. First, from lumbosacral plexopathy by elevation of muscle enzymes, myopa-
the EMG is helpful in identifying a motor-sensory syndrome as a thic features on EMG, and muscle biopsy.
plexopathy and not a radiculopathy. The diagnosis of plexopathy is
confirmed if the EMG discloses denervation (fibrillation potentials Structural Lumbosacral Plexopathy
and positive sharp waves) and reduced recruitment (reduced num- Hematoma
bers of motor units, firing rapidly) in muscles innervated by at least Patients with hemophilia and those receiving anticoagulants can
two lumbosacral segmental levels and involving at least two differ- develop hemorrhage in the iliopsoas muscle complex. It is import-
ent peripheral nerves. An isolated plexopathy should not be asso- ant to recall that major components of the lumbar plexus, the fem-
ciated with EMG abnormalities in paraspinal muscles. However, as oral and obturator nerves, course from their origins in the lumbar
will be seen, a number of pathological processes including diabetes, paravertebral regions to their destinations in the thigh under cover
radiation-induced changes, inflammation, vasculitis, and neoplasia of a tight layer of fascia. Over the iliac muscle, it is referred to as
may all involve the roots in addition to the plexus and produce a the fascia iliaca, and it becomes progressively thicker as it passes
radiculoplexopathy. Second, EMG findings help determine whether down behind the inguinal ligament; at this site, it forms a dense and
a lumbosacral plexopathy is associated with a polyneuropathy. In nondistensible funnel enclosing the lower portions of the iliacus
the presence of the latter, signs of denervation and reinnervation and psoas.
are found bilaterally, especially in the distal muscles. Third, EMG
BOX 105.1 Clues to the Nature of a

Plexopathy
Structural disorders:
History or presence of malignancy
Hemophilia or treatment with an anticoagulant
Pelvic trauma
Known atherosclerotic vascular disease and hypertension (aortic, hypogas-
tric, common iliac aneurysm)
Pregnancy, labor, delivery
Abdominal (pelvic) surgery
Nonstructural disorders:
Diabetes mellitus*
Vasculitis
Previous pelvic radiation
R L
* Diabetics may develop a polyradiculoneuropathy that simulates a
lumbosacral plexopathy.
Suspect lumbosacral plexopathy

Fig. 105.13 Hemorrhagic Lumbosacral Plexopathy. Computed
(by history and physical examination)
tomographic scan at L5–S1 level shows enlargement of iliacus muscles,
especially on left side, owing to iliacus hematoma (large arrow). Small
arrows indicate plexal elements. This large hematoma compresses the
Electrodiagnostic studies femoral and obturator nerves and the lumbosacral trunk.
in the iliacus muscle and extends into the psoas. In this case, other
components of the plexus, the obturator and lateral femoral cutaneous
Radiculopathy Lumbosacral plexopathy Polyneuropathy nerves, are involved.
demonstrated† confirmed demonstrated† Pain, often severe, is usually the first manifestation of a retro-
peritoneal hematoma. The pain is present in the groin and radiates
to the anterior thigh and lumbar region. It is associated with gradu-
CT scan (ensure patient is not ally increasing paresthesias and weakness. When the femoral nerve is
pregnant before performing scan) or MRI involved, weakness and sensory loss occur in its territory; when other
components of the plexus are involved, changes are more extensive
and conform to the territories supplied by the involved branches of
the plexus. If the hemorrhage is large, a mass may develop in the lower
Abnormal CT Normal CT or MRI scan abdominal quadrant and be associated with systemic signs like tachy-
or MRI scan (nonstructural plexopathy) cardia, hypotension, and a falling hematocrit (Parmer et al., 2006). It
(structural plexopathy) typically arises from the lateral wall of the pelvis and can be seen in
a CT scan to obscure the normal concavity of the inner aspect of the
wing of the ilium (Fig. 105.13). Because of iliacus muscle spasm, the
Determine precise Possibilities include patient usually lies in a characteristic posture with the hip flexed and
nature of the lesion diabetic, vasculitic, radiation- laterally rotated because hip extension aggravates the pain. Several days
with the aid of history, induced, and idiopathic
general physical plexopathies (determine exact
after the onset of the hematoma, a bruise may appear in the inguinal
examination, and cause with the help of history, area or anterior thigh. In some patients, especially those with rela-
laboratory studies physical examination, tively small hematomas and mild neurological deficits, recovery may
and other laboratory studies) be satisfactory with conservative measures including reversing anti-
Fig. 105.12 Approach to Evaluation of Lumbosacral Plexopathy. coagulation, although 10%–15% of patients show no improvement.
Electrophysiological identification of radiculopathy may require spi- Accordingly, some centers explore the abdomen through a limited
nal computed tomographic (CT) myelography or magnetic resonance retroperitoneal incision after reversing the coagulopathy; a complete
imaging (MRI) for confirmation and precise diagnosis. *Radiculopathy is iliacus fasciotomy is performed and the hematoma is evacuated, thus
associated with plexopathy in diabetes, vasculitis, radiation, and malig- relieving compression on the femoral nerve and enhancing the pros-
nancy. †Polyneuropathy may accompany plexopathies due to diabetes, pects for full recovery (Parmer et al., 2006). Clear indications for surgi-
vasculitis, and certain malignancies (paraneoplastic neuropathies). cal exploration would include hemodynamic instability or worsening
neurological dysfunction.
Two major anatomical syndromes are associated with iliopsoas Abscess

hematoma. In the first, the femoral nerve is the sole affected portion Psoas abscess was more common when tuberculosis was prevalent, but
of the lumbar plexus. The hematoma arises in the iliacus and causes neurological complications, such as lumbar plexopathy and femoral
distention of the dense overlying fascia above the inguinal ligament. In neuropathy, were rare. This phenomenon was explained by the slow
the second syndrome, hemorrhage arises in the psoas muscle or begins distention of the psoas sheath and by the fact that the abscess ruptured
through the psoas fascia before the femoral nerve could be damaged by bed, she notes difficulty walking because of foot dorsiflexor weakness.
raised intrapsoas compartment pressure. Similarly, an acute nontuber- Examination discloses weakness in dorsiflexion and inversion, with
culous psoas abscess rarely produces nerve compression, presumably reduced sensation over the lateral aspect of the leg and dorsal surface
because the psoas fascia is distensible. However, femoral neuropathy of the foot. Nerve conduction studies disclose attenuation or absence
does occur with iliacus muscle abscess because the fascia iliaca is rel- of the superficial peroneal SNAP on the affected side, and needle EMG
atively nondistensible. Rarely, lumbar plexopathy is a complication reveals denervation in muscles innervated by L5 below the knee (Katirji
of pelvic hydatidosis caused by the tapeworm Echinococcus granulosus et al., 2002). The primary pathology is predominantly demyelination,
(Serradilla et al., 2002). and the prognosis for complete recovery within 5 months is very good.
In subsequent pregnancies, a trial of labor can be allowed so long as
Aneurysm there is no evidence of disproportion or malpresentation. If labor pro-
Back and abdominal pains are often early manifestations of abdom- ceeds, forceps should be used with great caution. Mid-forceps use in
inal aortic aneurysms. Knowledge of abdominal and pelvic regional a woman with a previous obstetrical lumbosacral trunk palsy invites
anatomy helps explain the radiating characteristics of these pains. An danger. It is prudent to perform cesarean section if the trial of labor is
expanding abdominal aortic aneurysm may compress the iliohypogas- unsuccessful or if the infant is large.
tric or ilioinguinal nerve, leading to pain radiating into the lower abdo- Femoral neuropathy may occur in a thin patient during cesarean
men and inguinal areas. Pressure on the genitofemoral nerve produces section in cases managed with self-retaining retractors (Alsever, 1996).
pain in the inguinal area, testicle, and anterior thigh. Compression of In the thin abdominal wall, a deep lateral insertion of retractor blades
nerve trunks L5 through S2, which lie directly posterior to the hypo- exerts pressure on the psoas and may injure the femoral nerve. After
gastric artery, may give rise to sciatica (Shields et al., 1997); 13% of surgery, the patient notes weakness and numbness in the territory of
patients with aneurysms of the iliac artery will present with features of the femoral nerve. Recovery is usually rapid and full. The obturator
sciatica (Delgado-Garcia et al., 1999). nerve may be compressed by the fetal head or forceps near the pel-
Hemorrhage from an abdominal aortic aneurysm may produce vic brim. Patients note pain in the groin and anterior thigh as well as
prominent neurological problems because of the retroperitoneal loca- weakness and sensory loss in the territory of this nerve.
tion of the hemorrhage or false aneurysm formation. In the case of an
abdominal aortic aneurysm, a large retroperitoneal hematoma may Neoplasia
injure the femoral and obturator nerves and even branches of the sacral The lumbosacral plexus may be damaged by tumors that invade the
plexus. Rupture of a hypogastric or common iliac artery aneurysm plexus either by direct extension from intraabdominal neoplasm or
extends into the pelvis, compressing the L5 through S2 nerve trunk. by metastases. Most tumors involve the plexus by direct extension
Early recognition of an aneurysm is important because the mor- (73%), whereas metastases account for only one-quarter of cases. The
tality rate for operation on unruptured aneurysms is 5%–7%, whereas primary tumors most frequently encountered are colorectal, cervical,
that for ruptured aneurysms is 35%–40%. Unexplained back pain, leg and breast, as well as sarcoma and lymphoma (Jaeckle, 2010). Three
pain, or pain radiating in the distribution of cutaneous nerves coming clinical syndromes occur: upper plexopathy with findings referable
from the lumbar plexus should raise the suspicion of an aneurysm of to the L1–L4 segments (31%); lower plexopathy with changes in the
the aorta or its major branches. A pulsatile mass felt while palpating L4–S1 segments (51%); and panplexopathy with abnormalities in
the abdomen or, rarely, on rectal examination strongly suggests the the L1–S3 distribution (18%). Neoplastic plexopathy typically has an
presence of an aneurysm. Lumbosacral radiographs show a curvilinear insidious onset over weeks to months. Severe and unrelenting pain is
calcific density, and abdominal sonography or CT scanning can con- a prominent early manifestation and is aching or cramping in quality;
firm an aneurysm. it typically radiates from the low back to the lower extremities. Weeks
to months after pain begins, numbness, paresthesias, weakness, and leg
Trauma edema develop. Incontinence or impotence occurs in fewer than 10%
Because of the relatively protected position of the lumbosacral plexus, of patients. The most commonly encountered tumors are colorectal in
traumatic lesions are uncommon. However, fracture of the pelvis, ace- upper plexopathy, sarcomas in lower plexopathy, and genitourinary in
tabulum, or femur, or surgery on the proximal femur and hip joint panplexopathies. The majority of neoplastic plexopathies are unilat-
may injure the lumbosacral plexus. Sacral fractures or sacroiliac joint eral, although bilateral plexopathies, caused usually by breast cancer,
separation accounts for most cases of traumatic lumbosacral plex- occur in approximately 25% of patients. The prognosis in lumbosa-
opathy (68%), while acetabular and femoral fractures are much less cral plexopathy due to neoplasm is poor, with a median survival of 5.5
frequently implicated (14% and 9%, respectively) (Kutsy et al., 2000). months.
However, the latter are more likely to cause injury to proximal nerves Three special syndromes do not fit easily into upper, lower, or pan-
originating from the plexus. The mechanism of posttraumatic paresis plexopathy categories. In the first, there are paresthesias or pain in the
in lumbosacral plexopathies may involve a number of factors, includ- lower abdominal quadrant or groin, with little or no motor abnor-
ing nerve crush caused by fractured bone fragments; retroperitoneal mality. These patients are found to have a tumor next to L1, leading
hemorrhage; and traction as a result of hyperextension, hyperflexion, to involvement of the ilioinguinal, iliohypogastric, or genitofemoral
or rotation around the hip joint. Conservative measures appear to be nerves. A second group has numbness over the dorsomedial portion
the most appropriate way to manage posttraumatic injuries. More of the foot and sole, with weakness of knee flexion, ankle dorsiflexion,
than two-thirds of patients show good or moderate recovery of paresis and inversion. These patients have a lesion at the level of the sacral
after 18 months of follow-up after injury. ala, with involvement of the lumbosacral trunk. A third group present
with perineal sensory loss and sphincter weakness and have neoplastic
Pregnancy involvement of the coccygeal plexus, caused usually by rectal tumors.
The lumbosacral trunk may be compressed by the fetal head during Neuroimaging with CT or MRI usually establishes the diagnosis of
the second stage of labor. This tends to occur in prolonged labor with neoplastic plexopathy, but MRI is probably more sensitive (Taylor et al.,
mid-forceps rotation in a small primigravida mother carrying a rela- 1997). Because pelvic neoplasms may extend into the epidural space,
tively large baby. A day or so after delivery when the patient gets out of most often below the conus medullaris, MRI of the lumbosacral spine
is indicated in most patients. On occasion, a plexus neoplasm is diffi- also been described, including painful lumbosacral plexopathy. The
cult to discern by the best neuroimaging procedures. Two main expla- portions of the peripheral nervous system most susceptible to vascu-
nations for this phenomenon exist. First, patients who have received litis-induced ischemia are the segments of peripheral nerve located at
previous radiotherapy may have developed tissue fibrosis that cannot the midhumerus and midfemur levels, regions of nerve that appear to
be distinguished from recurrent tumor. Second, some tumors track be watershed zones between vascular territories of the vasa nervorum.
along the plexus roots and do not produce an identifiable mass. In these Proximal nerve trunks and nerve roots may also be vulnerable to the
instances, ancillary imaging tests (high-resolution MRI, bone scan, vasculitic process.
plain films, intravenous pyelography [VP]), a biopsy of the plexus, or When a lumbosacral plexopathy syndrome occurs in a patient
both may be required to determine the etiology. Prostate cancer may known to have a vasculitis, such as polyarteritis nodosa or rheu-
cause a lumbosacral radiculoplexopathy when tumor advances into the matoid arthritis, vasculitic plexopathy is an obvious diagnosis. The
lumbosacral plexus by perineural spread, a process that may evolve for clinical diagnosis is more difficult in the setting of a seemingly idio-
up to 8 years, is associated with prominent urinary dysfunction, and pathic polyneuropathy or plexopathy because the process may be
leads to an MRI appearance of asymmetrical nerve enlargement but monosystemic and restricted to the peripheral nervous system. In
otherwise normal pelvic and abdominal imaging (Ladha et al., 2006). such a case, a nerve biopsy may be required to establish the correct
diagnosis.
Nonstructural Lumbosacral Plexopathy
Radiation Plexopathy Idiopathic Lumbosacral Plexopathy
Radiation plexopathy usually produces slowly progressive painless Because lumbosacral plexopathy may occur in the absence of a recog-
weakness (Jaeckle, 2010). Dropcho (2010) points out that the radia- nizable underlying disorder, it can be considered a counterpart of
tion injury to the plexus most commonly occurs after treatment of pel- idiopathic brachial plexus neuropathy (van Alfen and van Engelen,
vic tumors, testicular tumors, or tumors involving para-aortic lymph 2006). It may begin suddenly with pain, followed by weakness, which
nodes. Pain develops in approximately half of patients with radiation progresses for days or sometimes many weeks. In many patients, the
plexopathy but is usually not early or severe (Dropcho, 2010). Most condition stabilizes, but in some, the course is chronic progressive
patients with radiation plexopathy eventually develop bilateral weak- or relapsing/remitting. Weakness is found in the distribution of the
ness, which is often asymmetrical and affects any muscles innervated upper and lower portions of the lumbosacral plexus in 50% of cases;
by L2 through S1 but typically has an L5–S1 predominance (Dropcho, major involvement occurs in the territory of the upper portion in
2010). In most patients, leg reflexes are absent, and superficial sen- 40% and in the lower portion in only 10% of patients. Most patients
sation is impaired. Symptoms referable to bowel or urinary tract are recover over a period of months to 2 years, although recovery is
usually the result of proctitis or bladder fibrosis. The latent interval often incomplete. The EMG discloses a patchy pattern of denerva-
between radiation and the onset of neurological manifestations is tion in the distribution of part or all of the lumbosacral plexus, but
between 1 and 31 years (median 5 years), although very short latencies the paraspinal muscles are spared, indicating that the process does
of less than 6 months have also been reported. An acute presentation not affect the lumbosacral roots. Dyck and colleagues (2001) desig-
of lumbosacral plexopathy 10 weeks following completion of radiation nated idiopathic lumbosacral plexopathy as nondiabetic lumbosacral
therapy for cervical cancer has also been observed (Abu-Rustum et al., radiculoplexus neuropathy and found that it resembles diabetic poly-
1999). No consistent relationship is evident between the duration of radiculoplexopathy in terms of its clinical presentation (subacute,
the symptom-free interval and the amount of radiation. asymmetrical, and painful with delayed and incomplete recovery)
In most patients, radiation plexopathy is gradually progressive and and pathological findings (ischemic injury and microvasculitis)
results in significant or severe disability. CT and MRI of the abdomen and suggested that it probably has an immune pathogenesis. MRI
and pelvis are typically normal though may be useful in ruling out has been reported to show gadolinium enhancement in the lumbar
metastatic disease involving the lumbosacral plexus (Dropcho, 2010). plexus that disappeared in association with resolution of symptoms
EMG discloses paraspinal fibrillation potentials in 50% of patients, and signs of plexopathy following IV gamma globulin treatment
suggesting that radiation damages the nerve roots in addition to the (Ishii et al., 2004). Immune-modulating therapy may be beneficial
plexus; hence, a more appropriate designation is radiation radiculo- for a subgroup of patients with idiopathic lumbosacral plexopathy
plexopathy. In almost 60% of patients, the EMG discloses myokymic (Dyck and Windebank, 2002).
discharges, a feature that is only rarely seen in neoplastic plexopathy.
The complete reference list is available online at https://expertconsult.
Vasculitis
inkling.com.
Vasculitic neuropathy has generally been associated with the pattern
of multiple mononeuropathy, but other neuropathic syndromes have
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106
Disorders of Peripheral Nerves
Bashar Katirji
OUTLINE
Clinical Approach to Disorders of Peripheral Nerves, 1854 Endocrine Disorders Associated with Peripheral Neuropathy, 1920
Structure of Peripheral Nerves, 1854 Ischemic Monomelic Neuropathy, 1920
Pathological Processes Involving Peripheral Nerves, 1854 Peripheral Neuropathy in Chronic Obstructive Lung Disease, 1920
Classification of Peripheral Nerve Disorders, 1855 Critical Illness Polyneuropathy, 1920
Diagnosis of Peripheral Nerve Disorders, 1857 Toxic and Drug-Induced Neuropathies, 1921
Diagnostic Clues from the History, 1857 Amiodarone, 1922
Diagnostic Clues from the Examination, 1858 Bortezomib, 1922
Electrodiagnostic Studies, 1860 Chloramphenicol, 1923
Imaging, 1860 Chloroquine and hydrochloroquine, 1923
Skin Biopsy, 1861 Cisplatin, 1923
Nerve Biopsy, 1862 Colchicine, 1923
Other Laboratory Tests, 1862 Dapsone, 1923
Mononeuropathies, 1863 Dideoxynucleosides, 1923
Definition and Classification of Mononeuropathies, 1863 Disopyramide, 1923
Mononeuropathies of the Upper Extremities, 1863 Disulfiram, 1923
Mononeuropathies of the Lower Extremities, 1870 Ethambutol, 1923
Hereditary Neuropathies, 1874 Etoposide, 1924
Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Gold, 1924
Neuropathy), 1874 Heroin, 1924
Hereditary Neuropathy with Liability to Pressure Palsies, 1880 Hydralazine, 1924
Hereditary Neuralgic Amyotrophy, 1880 Immune Checkpoint Inhibitors, 1924
Inflammatory Demyelinating Polyradiculoneuropathies, 1881 Isoniazid, 1924
Guillain-Barré Syndrome, 1881 Leflunomide, 1924
Chronic Inflammatory Demyelinating Linezolid, 1924
Polyradiculoneuropathy, 1889 Lipid-Lowering Agents, 1924
Multifocal Motor Neuropathy, 1894 Metronidazole and Misonidazole, 1925
Peripheral Neuropathies Associated with Monoclonal Proteins, 1896 Nitrofurantoin, 1925
Monoclonal Gammopathy of Undetermined Significance, 1896 Nitrous Oxide, 1925
Waldenström Macroglobulinemia, 1899 Perhexiline, 1925
Multiple Myeloma, 1899 Phenytoin, 1925
Osteosclerotic Myeloma and Polyneuropathy, Organomegaly, Pyridoxine, 1925
Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Suramin, 1925
Syndrome, 1900 Tacrolimus, 1925
Cryoglobulinemia, 1901 Taxanes, 1926
Primary Systemic Amyloidosis, 1901 Thalidomide and Lenalidomide, 1926
Neuropathies Associated with Systemic Disorders, 1903 L-Tryptophan, 1926
Diabetic Neuropathies, 1903 Tumor Necrosis Factor-α Blockers, 1926
Peripheral Neuropathy in Malignancies, 1909 Vinca Alkaloids, 1926
Peripheral Nerve Vasculitis, 1912 Neuropathies Associated With Infections, 1927
Alcoholic Neuropathy and Nutritional Deficiencies, 1915 Chronic Idiopathic Axonal Polyneuropathy, 1927
Uremic Neuropathy, 1919 Pain In Peripheral Neuropathy, 1927
Peripheral Neuropathy in Liver Disease, 1919 Management of Neuropathic Pain, 1928

1853
CLINICAL APPROACH TO DISORDERS OF potentials) are typically seen on needle EMG in some affected mus-
cles (mostly proximal ones) 10–14 days after injury and become full
PERIPHERAL NERVES after 3 weeks from acute nerve injury. Axonal interruption initiates
Peripheral nerve disorders are common neurological problems secondary morphological changes of the nerve cell body, termed
caused by dysfunction of peripheral motor, sensory, or autonomic chromatolysis, and the proximal axonal caliber becomes smaller.
nerves. The causes of neuropathies are disparate and their clinical Regeneration from the proximal stump begins as early as 24 hours
presentations highly variable. The main causes of neuropathy are following transection but proceeds slowly at a maximal rate of 2–3
entrapments, systemic diseases, inflammatory and autoimmune mm/day and is often incomplete. Sprouting of intact axons also
disorders, inherited disorders, ischemic settings, paraneoplastic starts locally in partial lesions, becoming noticeable on needle EMG
conditions, deficiency states, infections, and toxins. after 1 month of axonal injury. The quality of recovery depends on
the degree of preservation of the Schwann cell/basal lamina tube
Structure of Peripheral Nerves and the nerve sheath and surrounding tissue, the distance of the site
The peripheral nerve is a cable-like structure containing bundles of injury from the cell body, and the patient’s age.
of both unmyelinated and myelinated fibers and their supporting Axonal degeneration (or axonopathy), the most common patho-
elements. The unmyelinated axons are surrounded only by the logical reaction of peripheral nerve, signifies distal axonal break-
plasma membrane of a Schwann cell. The myelinated axons are down and is presumably caused by metabolic derangement within
engulfed by a Schwann cell that wraps around the axons multiple neurons or vascular compromise leading to ischemia. Systemic
times, thereby insulating the axon with multiple layers of lipid-rich metabolic disorders, toxin exposure, vasculitis, and some inher-
cell membrane. The myelinated axon is surrounded completely by ited neuropathies are the usual causes of axonal degeneration. The
myelin and Schwann cells except at regular gaps called the nodes myelin sheath breaks down concomitantly with the axon in a pro-
of Ranvier, which measure approximately 1 μm in adults (see Fig. cess that starts at the most distal part of the nerve fiber and pro-
64.2 in Chapter 64, Peripheral Nerve Trauma). The propagation gresses toward the nerve cell body: hence the term dying-back or
of action potentials from one node of Ranvier to the next (salta- length-dependent polyneuropathy (Fig. 106.1). A similar sequence
tory conduction) is maintained by a thick myelin sheath with low of events may occur simultaneously in centrally directed sensory
capacitance and high resistance to electric current and by a high axons, resulting in distal degeneration of rostral dorsal column
concentration of voltage-gated sodium channels at the nodes of fibers. The selective length-dependent vulnerability of distal axons
Ranvier. could result from failure of the perikaryon to synthesize enzymes or
structural proteins, from alterations in axonal transport, or from
regional disturbances of energy metabolism. In some axonopathies,
Pathological Processes Involving Peripheral Nerves alterations in axon caliber, either axonal atrophy or axonal swell-
Despite the large number of causes for neuropathy, the pathological ing, may precede distal axonal degeneration. Clinically, dying-back
reactions of peripheral nerves to various insults remain limited. In polyneuropathy presents with symmetrical distal loss of sensory
general, these pathological processes are divided into four main cat- and motor function in the lower extremities that extends proxi-
egories: (1) wallerian degeneration, which is the response to axonal mally in a graded manner. The result is sensory loss in a stock-
interruption, (2) axonal degeneration or axonopathy, (3) primary ing-like pattern, distal muscle weakness and atrophy, and loss of
neuronal (perikaryal) degeneration or neuronopathy, and (4) seg- distal limb myotatic reflexes. As the polyneuropathy ascends, it
mental demyelination or myelinopathy. The patient’s symptoms, affects the hands and distal upper extremities, giving a glove-like
the type and pattern of distribution of signs, and the characteris- sensory loss (hence the term stocking and glove sensory loss), and
tics of nerve conduction study abnormalities provide information hand weakness and atrophy. Axonopathies result in low-amplitude
about the underlying pathological changes. SNAPs and CMAPs, but they affect distal latencies and conduction
Compression, traction, laceration, thermal, chemical, or isch- velocities only slightly. Needle EMG of distal muscles shows acute
emic nerve injury that causes interruption of axons leads to walle- and/or chronic denervation changes (see Chapter 36). Because axo-
rian degeneration—that is, distal degeneration of axons and their nal regeneration proceeds at a maximal rate of 2–3 mm/day, recov-
myelin sheaths. Immediately following injury, motor weakness and ery may be delayed and is often incomplete.
sensory loss occur in the distribution of the damaged nerve. On nee- Neuronopathy designates loss of nerve cell bodies with resultant
dle electromyography (EMG), there is complete loss of voluntary degeneration of their entire peripheral and central axons. Either
activity (with a complete lesion) or a decrease in motor unit action anterior horn or dorsal root ganglion cells may be affected. Focal
potential (MUAP) recruitment (with a partial lesion). However, the weakness without sensory loss occurs when anterior horn cells
axons remain excitable distally since distal conduction failure is not are affected, as in anterior poliomyelitis or motor neuron disease.
completed until 10–11 days later as the distal nerve trunk becomes Sensory neuronopathy, or dorsal polyganglionopathy, means damage
progressively unexcitable. On nerve conduction studies, the ampli- to dorsal root ganglion neurons that results in sensory ataxia, sen-
tude of the compound muscle action potential (CMAP), evoked by sory loss, and diffuse areflexia (Fig. 106.2). A number of toxins,
stimulation distal to the lesion site, begins to decline by the second such as organic mercury compounds, doxorubicin, and high-dose
day after injury and reaches its nadir by the fifth to sixth. For sensory pyridoxine, or deficiency states, such vitamin E deficiency, pro-
axons, the loss of sensory nerve action potential (SNAP) is delayed duce primary sensory neuronal degeneration. Immune-mediated
by another 2–3 days; distal SNAP remains normal for 5–6 days and inflammatory damage of dorsal root ganglion neurons occurs in
then decreases rapidly to reach its nadir by 10–11 days after injury paraneoplastic sensory neuronopathy (anti-HU syndrome) and
(see Fig. 36.9 in Chapter 36). The temporal sequence of wallerian Sjögren syndrome (Hlubocky and Smith, 2014). It is often difficult
degeneration is length dependent, occurring earlier in shorter than to distinguish between neuronopathies and axonopathies on clin-
in longer distal nerve stumps. Denervation potentials (fibrillation ical grounds alone. Once the pathological processes are no longer
CHAPTER 106 Disorders of Peripheral Nerves 1855
Astrocyte
proliferation
CNS
PNS
Axon
regeneration
Normal Early Late Recovering

Fig. 106.1 Diagram of the Main Pathological Events of Distal Axonal Degeneration or Axonopathy. Jag-
ged lines indicate that either a toxin or a metabolic insult acts at multiple sites along motor and sensory axons
in the peripheral nervous system (PNS) and central nervous system (CNS). Axonal degeneration begins at the
most distal part of the nerve fiber and progresses proximally by the late stage. Recovery occurs by axonal
regeneration but is impeded by astroglial proliferation in the CNS. (Adapted from Herskovitz, S., Scelsa, S.,
Schaumburg, H.H., 2008. Disorders of Peripheral Nerves, Oxford University Press, New York.)
active, sensory deficits become fixed, and little or no recovery takes and small-diameter myelinated fibers. Early generalized loss of
place. reflexes, disproportionately mild muscle atrophy in the presence
The term segmental demyelination (or myelinopathy) implies of proximal and distal weakness, neuropathic tremor, and palpa-
injury of either myelin sheaths or Schwann cells, resulting in break- bly enlarged nerves are all clinical clues that suggest demyelinat-
down of myelin with sparing of axons (Fig. 106.3). This occurs ing polyneuropathy. Nerve conduction studies or analysis of single
mechanically by acute nerve compression or chronic nerve entrap- teased nerve fiber preparations stained with osmium can confirm
ment and in immune-mediated demyelinating neuropathies and demyelination. Demyelination is present if motor and sensory
hereditary disorders of Schwann cell/myelin metabolism. Primary nerve conduction velocities (NCVs) are reduced to less than 70%
myelin damage may be produced experimentally by myelino- of the lower limits of normal, with relative preservation of CMAP
toxic agents such as diphtheria toxin or by acute nerve compres- and SNAP amplitudes. The presence of partial motor conduction
sion. Remyelination of demyelinated segments usually occurs block, temporal dispersion of CMAPs, and marked prolongation
within weeks. The newly formed remyelinated segments have of distal motor and F-wave latencies are all features consistent with
thinner-than-normal myelin sheaths and internodes of shortened acquired demyelination (see Chapter 36). Recovery depends on the
length. Repeated episodes of demyelination and remyelination extent of remyelination, and therefore clinical improvement may
produce proliferation of multiple layers of Schwann cells around occur within weeks. In many demyelinating neuropathies, axonal
the axon, termed an onion bulb. The physiological consequence of degeneration may also coexist, as evidenced by some distal limb
acquired demyelination, such as in inflammatory or compressive atrophy and active denervation and reinnervation changes on nee-
demyelination but not hereditary myelinopathies, is conduction dle EMG.
block, which results in loss of the ability of the nerve action poten-
tial to reach the muscle, thereby producing weakness. Because the Classification of Peripheral Nerve Disorders
axon remains intact, there is little muscle atrophy. Relative spar- There are several patterns of peripheral nerve disease (Box 106.1).
ing of temperature and pinprick sensation in many demyelinat- Brachial, lumbar, and sacral plexopathy are discussed in Chapter 105,
ing polyneuropathies reflects preserved function of unmyelinated and radiculopathies are discussed in Chapter 97.
Astrocyte
proliferation
CNS
PNS
Normal Toxic attack on DRG 1 week later 6 months later

Fig. 106.2 Diagram of the Main Pathological Events of a Sensory Neuropathy or Gangliopathy. A toxin
(jagged lines) produces destruction of dorsal root ganglion (DRG) neurons, which results in degeneration of
the peripheral-central axonal processes. Recovery is poor, as no axonal regeneration can take place. CNS,
Central nervous system; PNS, peripheral nervous system. (Adapted from Herskovitz, S., Scelsa, S., Schaum-
burg, H.H., 2008. Disorders of Peripheral Nerves. Oxford University Press, New York.)
CNS
PNS
Normal Attack by Segmental demyelination Remyelinated fibers

inflammatory cells
Fig. 106.3 Diagram of the Main Pathological Events of Primary Segmental Demyelination in Immune-
mediated Inflammatory Polyradiculoneuropathies. Attack by inflammatory cells causes patchy multifocal
demyelination along nerve fibers but spares their axons. Recovery occurs by remyelination. Demyelinated
segments become invested by several Schwann cells, resulting in a decrease in internodal length of those
areas. CNS, Central nervous system; PNS, peripheral nervous system. (Adapted from Herskovitz, S., Scelsa,
S., Schaumburg, H.H., 2008. Disorders of Peripheral Nerves. Oxford University Press, New York.)
misdiagnoses. Further laboratory or pathological studies to determine

BOX 106.1 Classification of Peripheral
a specific diagnosis are sometimes performed based on the findings of
Nerve Disease the initial evaluation.
Mononeuropathy
Plexopathy: Diagnostic Clues from the History
Brachial plexopathy The symptoms of peripheral nerve disorders are due to motor, sensory,
Lumbar plexopathy or autonomic disturbances. The inquiry should seek both negative and
Sacral plexopathy positive symptoms. Negative motor symptoms are weakness, atrophy,
Radiculopathy: and walking difficulties. Muscle cramps, fasciculations, myokymia, and
Cervical radiculopathy tremor are positive motor manifestations. In polyneuropathies, negative
Thoracic radiculopathy motor symptoms include early distal toe and ankle extensor weakness,
Lumbosacral radiculopathy resulting in tripping on rugs or uneven ground. However, a complaint
Multiple mononeuropathy (mononeuropathy multiplex) of difficulty walking in itself does not distinguish muscle weakness from
Polyneuropathy: sensory, pyramidal, extrapyramidal, or cerebellar disturbance. If the fin-
Symmetrical polyneuropathy gers are weak, patients may complain of difficulty opening jars or turn-
Asymmetrical polyneuropathy ing a key in a lock.
Polyradiculoneuropathy Positive sensory symptoms include prickling, searing, burning,
and tight band-like sensations. Paresthesias are unpleasant sensa-
tions arising spontaneously without apparent stimulus. The presence
of spontaneously reported paresthesias is helpful in distinguishing
acquired (>60% of patients) from inherited (<20% of patients) poly-
A mononeuropathy means focal involvement of a single nerve and neuropathies. Allodynia refers to the perception of nonpainful stim-
implies a local process. Direct trauma, compression, entrapment, vas- uli as painful, and hyperalgesia is painful hypersensitivity to noxious
cular lesions, and neoplastic compression or infiltration are the most stimuli. Neuropathic pain, the extreme example of a positive symp-
common causes. Electrophysiological studies provide a more precise tom, is a cardinal feature of many neuropathies. Neuropathic pain
localization of the lesion than may be possible by clinical examina- often has a deep, burning, or drawing character that may be associ-
tion, distinguish axonal loss from focal segmental demyelination, and ated with jabbing or shooting pains that typically increase at night or
sometimes may reveal a more widespread change indicating an under- during periods of rest.
lying generalized polyneuropathy that has made the nerve susceptible Negative sensory manifestations include loss or reduction of pain,
to entrapment, as occurs in diabetes mellitus (DM), hypothyroidism, temperature, or touch sensation. Imbalance and gait disturbance are
acromegaly, alcoholism, hereditary amyloidosis, and hereditary neu- common negative sensory symptoms of polyneuropathy, implying loss
ropathy with liability to pressure palsy (HNPP). of proprioception. However, the negative sensory symptoms may be
Multiple mononeuropathies, or mononeuropathy multiplex, signify caused by a central myelopathic disorder, including dorsal column dys
simultaneous or sequential damage to multiple noncontiguous nerves. function as occurs with vitamin B12 deficiency.
Confluent multiple mononeuropathies may give rise to motor weak- Symptoms of autonomic dysfunction are helpful in directing atten-
ness with sensory loss that can simulate a length-dependent peripheral tion toward specific neuropathies that have prominent autonomic
polyneuropathy. symptoms. It is important to ask about orthostatic intolerance
Polyneuropathy is most commonly characterized by symmetri- (lightheadedness, presyncopal symptoms, or syncope), reduced or
cal distal motor and/or sensory deficits that typically have a graded excessive sweating, heat intolerance, and bladder, bowel, and sexual
increase in severity distally and distal attenuation of reflexes. The dysfunctions. Anorexia, early satiety, nausea, and vomiting are symp-
sensory and motor deficits generally follow a length-dependent toms suggestive of gastroparesis. The degree of autonomic involve-
stocking-glove pattern. Most polyneuropathies are fairly symmet- ment can be documented by noninvasive autonomic function studies
rical, but some are asymmetrical and sometimes the result of a (see Chapter 107).
confluent mononeuropathy multiplex. A small number of polyneu- Historical information regarding onset, duration, and evolution of
ropathies (e.g., that associated with acute intermittent porphyria symptoms provides important clues to diagnosis. Knowledge about
[AIP]) may be predominantly proximal. It is helpful to deter- the time course of disease (acute, subacute, or chronic) and the course
mine the relative extent of sensory, motor, and autonomic neuron (monophasic, progressive, or relapsing) narrows diagnostic possi-
involvement, although most polyneuropathies produce mixed sen- bilities. Guillain-Barré syndrome (GBS), acute porphyria, vasculitis,
sorimotor deficits and some degree of autonomic dysfunction. neuralgic amyotrophy, and some forms of toxic neuropathies have
acute presentations. A relapsing course is found in chronic inflam-
Diagnosis of Peripheral Nerve Disorders matory demyelinating polyradiculoneuropathy (CIDP), acute por-
The “shotgun” approach of ordering several panels of diagnostic tests phyria, Refsum disease, HNPPs, hereditary neuralgic amyotrophy, and
without an adequate understanding of their significance and usefulness repeated episodes of toxin exposure.
should be avoided. A logical systematic diagnostic approach to periph- In patients with a chronic indolent course over many years, inquiries
eral neuropathies consists of a detailed history, comprehensive physi- about similar symptoms and bony deformities (such as pes cavus) in
cal and neurological examinations, a limited set of laboratory studies, immediate relatives often point to a familial polyneuropathy. Inherited
and detailed electrodiagnostic (EDX) studies. Additional ancillary test- polyneuropathies are a major cause of undiagnosed polyneuropathies,
ing, such as autonomic testing, skin biopsy, or nerve biopsy, may be accounting for about 30% of patients referred to tertiary centers for
considered in special clinical situations. This approach confirms the diagnosis. Molecular genetic testing or the clinical and electrophysio-
presence of a peripheral nerve disorder; characterizes the fiber type, logical evaluation of relatives of patients with undiagnosed neuropathy
pattern, time course, and type of deficit of the peripheral nerve disease; may corroborate that the disorder is familial. The presence of consti-
shortens the list of diagnostic and etiological possibilities; and prevents tutional symptoms such as weight loss, malaise, and anorexia suggests
BOX 106.2 Causes of Mononeuropathy BOX 106.4 Neuropathies with Facial Nerve
Multiplex Involvement
Axonal Mononeuropathy Multiplex Guillain-Barré syndrome
Vasculitis (systemic, nonsystemic) Lyme disease
Diabetes mellitus Sarcoidosis
Sarcoidosis Chronic inflammatory demyelinating polyradiculoneuropathy (rare)
Leprosy (Hansen disease) Human immunodeficiency virus 1 infection
Human immunodeficiency virus 1 infection Gelsolin familial amyloid neuropathy (Finnish)
Tangier disease
Demyelinating Mononeuropathy Multiplex
Multifocal motor neuropathy
Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM,
BOX 106.5 Polyneuropathies with
Lewis-Sumner syndrome)
Multiple compressive neuropathies (hypothyroidism, diabetes) Predominantly Upper-Limb Motor
Hereditary neuropathy with liability to pressure palsies (HNPPs) Involvement
Multifocal motor neuropathy
Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM,
BOX 106.3 Polyneuropathies with Lewis-Sumner syndrome)
Predominantly Motor Manifestations Lead neuropathy*
Porphyria
Guillain-Barré syndrome Tangier disease
Acute motor axonal neuropathy* Familial amyloid neuropathy type 2
Chronic inflammatory demyelinating polyradiculoneuropathy Hereditary motor neuropathy (uncommon forms)
Multifocal motor neuropathy*
Neuropathy with osteosclerotic myeloma * Frequently presents with wrist drop.
Diabetic lumbar radiculoplexopathy
Charcot-Marie-Tooth disease (hereditary motor sensory neuropathies) systemic or nonsystemic vasculitis or microangiopathy in DM should
Lead intoxication be considered. Other less common causes are disorders affecting inter-
* Pure motor syndromes with normal sensory nerve action potentials.
stitial structures of nerve—namely, infectious, granulomatous, leukemic,
or neoplastic infiltration—including leprosy and sarcoidosis. In the
event focal demyelination or motor conduction blocks lead to multi-
an underlying systemic disorder as a cause of the polyneuropathy. ple mononeuropathies, multifocal acquired demyelinating sensory and
Inquiry should be made about preceding or concurrent associated med- motor neuropathy (MADSAM, Lewis-Sumner syndrome), multifocal
ical conditions (DM, hypothyroidism, chronic renal failure, liver dis- motor neuropathy (MMN), or HNPP should be considered.
ease, intestinal malabsorption, malignancy, connective tissue diseases, In polyneuropathy, the sensory deficits generally follow a length-
and human immunodeficiency virus [HIV] seropositivity); drug use, dependent stocking-glove pattern. By the time sensory disturbances of the
including over-the-counter vitamin preparations (vitamin B6); alcohol longest nerves in the body (lower limbs) have reached the level of the knees,
and dietary habits; and exposure to solvents, pesticides, or heavy metals. paresthesias are usually noted in the distribution of the second-longest
nerves (i.e., those in the upper limbs) at the tips of the fingers. When sen-
Diagnostic Clues from the Examination sory impairment reaches the midthigh, involvement of the third-longest
The first step in the examination of patients with neuropathy is to nerves, the anterior intercostal and lumbar segmental nerves, gives rise to
determine the anatomical pattern and localization of the disease pro- a tent-shaped area of hypoesthesia on the anterior chest and abdomen.
cess and whether motor, sensory, or autonomic nerves are involved. Involvement of the recurrent laryngeal nerves may occur at this stage, with
In mononeuropathy, the neurological deficit follows the distribu- hoarseness. Motor weakness follows a dying-back pattern and usually is
tion of a single nerve. For example, in a patient with foot drop due to a greater in extensor foot muscles than in corresponding flexors. Hence,
common fibular (peroneal) nerve lesion, the neurological examination heel walking is affected earlier than toe walking in most polyneuropa-
reveals weakness of ankle and toe dorsiflexion and ankle eversion, but thies. It is helpful to determine the relative extent of sensory, motor, and
ankle inversion, toe flexion, and plantar flexion are normal, since muscles autonomic fiber involvement, although most polyneuropathies produce
controlling these functions are innervated by the tibial nerve. Similarly, mixed sensorimotor deficits and some degree of autonomic dysfunction.
sensory loss is restricted to the lower two-thirds of the lateral leg and dor- Motor deficits tend to dominate the clinical picture in acute and
sum of the foot, but sensation on the sole of the foot is normal. chronic inflammatory demyelinating polyneuropathies, hereditary motor
In multiple mononeuropathies (mononeuropathy multiplex), the and sensory neuropathies (Charcot-Marie-Tooth disease), and in neu-
neurological findings should point to simultaneous or sequential dam- ropathies associated with osteosclerotic myeloma, porphyria, lead toxic-
age to two or more noncontiguous peripheral nerves. Confluent mul- ity, organophosphate intoxication, and hypoglycemia (Box 106.3). The
tiple mononeuropathies, such as with involvement of the fibular and distribution of weakness provides important information. Asymmetrical
tibial nerves or median and ulnar nerves, may give rise to motor weak- weakness without sensory loss suggests a motor neuronopathy such as
ness with sensory loss that can simulate a length-dependent peripheral motor neuron disease or MMN. The facial nerve can be affected in sev-
polyneuropathy. EDX studies ascertain whether the primary patholog- eral peripheral nerve disorders (Box 106.4). In most polyneuropathies,
ical process is axonal degeneration or segmental demyelination (Box the legs are more severely affected than the arms, with several notable
106.2). Approximately two-thirds of patients with multiple mononeu- exceptions (Box 106.5). Polyradiculoneuropathies cause both proximal
ropathies display a picture of axonal damage. Ischemia caused by and distal muscle weakness. For example, proximal and distal weakness
is encountered in acute and chronic inflammatory demyelinating poly- acquired immunodeficiency syndrome (AIDS), vitamin B12 deficiency,
radiculoneuropathies, osteosclerotic myeloma, porphyria, and diabetic celiac disease (CD), inherited and idiopathic sensory neuropathies, and
lumbar radiculoplexopathy (amyotrophy). Nerve root involvement intoxications with cisplatin, thalidomide, or pyridoxine. Loss of sensa-
is confirmed by denervation in paraspinal muscles on needle EMG or tion in peripheral neuropathies often involves all sensory modalities.
enhancing roots on gadolinium magnetic resonance imaging (MRI). However, the impairment may be restricted to selective sensory modal-
Autonomic dysfunction of clinical importance is seen in associa- ities in many situations, which makes it possible to correlate the type of
tion with specific acute (e.g., GBS) or chronic (e.g., amyloidosis and sensory loss with the diameter size of affected afferent fibers (Fig. 106.4).
diabetes) sensorimotor polyneuropathies. Rarely, an autonomic neu- Pain and temperature sensation are mediated by unmyelinated and small
ropathy may be the exclusive manifestation of a peripheral nerve dis- myelinated Aδ fibers, whereas vibratory sense, proprioception, and the
order, without somatic nerve involvement (Box 106.6). afferent limb of the tendon reflex are subserved by large myelinated Aα
Predominant sensory involvement may be a feature of polyneuropa- and Aβ fibers. Light touch is mediated by both large and small myelin-
thies caused by diabetes, carcinoma, Sjögren syndrome, dysproteinemia, ated fibers. In polyneuropathies preferentially affecting small fibers,
diminished pain and temperature sensation predominate, along with
spontaneous burning pain, painful dysesthesias, and autonomic dys-
BOX 106.6 Neuropathies with Autonomic function. There is preservation of tendon reflexes, balance, and motor
Nervous System Involvement strength, and hence few abnormal objective neurological signs are found
on examination. A pattern of sensory loss that is very characteristic is dis-
Acute
tal loss of pinprick sensation, above which is a band of hyperalgesia (exag-
Acute pandysautonomic neuropathy (autoimmune, paraneoplastic)
gerated pain from noxious stimuli), with normal sensation above this
Guillain-Barré syndrome
level. Relatively few disorders cause selective small-fiber neuropathies
Porphyria
(Mendell and Sahenk, 2003; Box 106.7). Selective large-fiber sensory loss
Toxic: vincristine, Vacor (rodenticide)
is characterized by areflexia, sensory ataxia, and loss of joint position and
Chronic vibration sense. Loss of joint position may also manifest as pseudoatheto-
Diabetes mellitus sis (involuntary sinuous movements of fingers and hands when the arms
Amyloid neuropathy (familial and primary) are outstretched and the eyes are closed) and/or a Romberg sign (dispro-
Paraneoplastic sensory neuronopathy (malignant inflammatory sensory portionate loss of balance with eyes closed compared with eyes open).
polyganglionopathy) Striking sensory ataxia, together with pseudoathetosis or asymmetrical
Human immunodeficiency virus-related autonomic neuropathy truncal or facial sensory loss, directs attention to a primary disorder of
Hereditary sensory and autonomic neuropathy sensory neurons or polyganglionopathies. The differential diagnosis of
ataxic sensory neuropathies is limited (Box 106.8).
1000 µV
50 µV
1 msec 10 msec
6090 46,682
MF/mm2 UF/mm2
Fiber number/1 µm
of diameter/mm2
1000
4000
Fiber number/mm2
3000
2000
1000
0
0 4 8 12 0 0.5 1.0 1.5
Diameter (µm) Diameter (µm)
Fig. 106.4 Myelinated fiber (MF) and unmyelinated fiber (UF) size-frequency histograms of a normal sural
nerve. Fiber size distribution is bimodal for MF but unimodal for UF. MF density in normal sural nerve ranges
from 6000 to 10,000 fibers/mm2 of fascicular area. Number of UFs is normally about four times that of MFs.
Corresponding compound nerve action potential recorded from the sural nerve in vitro is shown at top. Three
distinct peaks indicated by arrows are, from left to right, Aa, Aa, and C-potentials, which correspond to large
MF, small MF, and UF peaks, respectively.
BOX 106.7 Small-Fiber Neuropathies TABLE 106.1 Neuropathies with Skin,

Nail, or Hair Manifestations
Diabetes mellitus and impaired glucose tolerance
Sjögren (sicca) syndrome Skin, Nail, or Hair
Celiac disease Disease Manifestations
Amyloid neuropathy (early familial and primary) Vasculitis Purpura, livedo reticularis
Human immunodeficiency virus-associated sensory neuropathy Cryoglobulinemia Purpura
Hereditary sensory and autonomic neuropathies Fabry disease Angiokeratomas
Fabry disease Leprosy Skin hypopigmentation
Tangier disease Osteosclerotic myeloma (POEMS syndrome) Skin hyperpigmentation
Cryptogenic small-fiber neuropathy Variegate porphyria Bullous lesions
Refsum disease Ichthyosis
Arsenic or thallium intoxication Mees lines
Thallium poisoning Alopecia
BOX 106.8 Sensory Ataxic Neuropathies Giant axonal neuropathy Curled hair
Sensory neuronopathies (polyganglionopathies): POEMS, Polyneuropathy, organomegaly, endocrinopathy, monoclonal

Paraneoplastic sensory neuronopathy (malignant inflammatory sensory gammopathy, and skin changes.
polyganglionopathy):
Sjögren syndrome Because routine sensory nerve conduction studies assess only large
Idiopathic myelinated fibers, such studies may be entirely normal in selective
Toxic (cisplatin and analogs, vitamin B6 excess) small-fiber neuropathies. Quantitative sensory testing assessing cold
Chronic immune sensory polyradiculopathy and heat pain thresholds, tests of sudomotor function, and skin biopsy
Demyelinating polyradiculoneuropathies: with analysis of intraepidermal nerve fiber density (IENFD) may be
Guillain-Barré syndrome (Miller-Fisher variant) helpful in confirming the unmyelinated nerve fiber abnormalities
Immunoglobulin M monoclonal gammopathy MAG** antibody (Devigili et al., 2008). Since sweating mediated by unmyelinated sym-
CANOMAD:* pathetic cholinergic fibers is often impaired, the quantitative sudomo-
Tabes dorsalis tor axon reflex (QSART) that evaluates sweating is a highly specific
and sensitive method (sensitivity of 80%) to confirm small nerve fiber
* Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein,
cold agglutinins, and anti-GD1b disialosyl antibodies.
damage. Quantitative sensory testing assessing both vibratory and
** Myelin-Associated Glycoprotein. thermal detection thresholds has become a useful addition to the bed-
side sensory examination in controlled clinical trials. Its use in routine
clinical practice remains limited because the test is still subjective in
Palpation of peripheral nerves is an important though unreliable that it requires patient cooperation and is time consuming.
part of the examination. Hypertrophy of a single nerve trunk suggests
either a neoplastic process (e.g., neurofibroma, schwannoma, malig- Imaging
nant nerve sheath tumor) or localized perineurial hypertrophic neu- High-resolution neuromuscular ultrasound, which is readily available
ropathy. Generalized or multifocal nerve hypertrophy is found in a and painless, is increasingly used in the diagnosis of neuromuscular
limited number of peripheral nerve disorders, including leprosy, neu- disorders (Hommel et al., 2017). This technique is an extremely help-
rofibromatosis, Charcot-Marie-Tooth (CMT) disease types 1 and 3, ful tool in the diagnosis of mononeuropathies, including entrapment
acromegaly, Refsum disease, and rarely CIDP. neuropathies and traumatic nerve injuries. Focal nerve enlargement,
Certain telltale signs of the skin and its appendages may direct the measured as cross-sectional area (CSA), is the most common indica-
experienced examiner to a specific diagnosis (Table 106.1): alopecia is tor of nerve entrapment, including carpal tunnel syndrome (CTS) and
seen in thallium poisoning; tightly curled hair in giant axonal neurop- ulnar neuropathy at the elbow (Beekman et al., 2011; Cartwright et al.,
athy (GAN); white transverse nail bands, termed Mees lines, in arse- 2012). More recent studies have also shown important values of neu-
nic or thallium intoxications; purpuric skin eruptions of the legs in romuscular ultrasound in the diagnosis of CIDP and in distinguishing
cryoglobulinemia and some vasculitides; skin hyperpigmentation or acquired demyelinating polyneuropathies from axonal polyneuropa-
hypertrichosis in POEMS syndrome (polyneuropathy, organomegaly, thies. Multifocal enlargement of peripheral nerves at non-entrapment
endocrinopathy, monoclonal gammopathy, and skin changes); telan- sites and of elements of brachial plexus, measured by CSA, is highly
giectasias over the abdomen and buttocks in Fabry disease; enlarged diagnostic. In addition, muscle ultrasound visualizes fasciculations in
yellow-orange tonsils in Tangier disease; pes cavus and hammer toes limb muscles and tongue more readily than needle EMG and increases
in CMT disease; and overriding toes and ichthyosis in Refsum disease. the sensitivity of diagnosis in patients with suspected advanced life
support (ALS) (Misawa et al., 2011). Muscle ultrasound is also use-
Electrodiagnostic Studies ful in myopathies including inflammatory myopathies and muscular
It is helpful to follow a decision-making pathway based initially on the dystrophies by showing increased echogenicity of muscles, and delin-
overall pattern of distribution of deficits, followed by the electrophysi- eating the distribution of muscle involvement, thus helping in diagno-
ological findings, and finally the clinical course (Fig. 106.5). EDX stud- sis and selection of muscle biopsy sites (Noto at al., 2014; Pillen et al.,
ies, carefully performed and directed to the particular clinical situation, 2008). It also distinguishes neurogenic from myopathic disorders such
play a key role in the evaluation by (1) confirming the presence of neu- as Duchenne muscular dystrophy with severe, homogeneous increase
ropathy, (2) precisely locating focal nerve lesions, and (3) giving infor- of muscle echo intensity from spinal muscular atrophy with an inho-
mation as to the nature of the underlying nerve pathology (Gooch and mogeneous increase of echo intensity with severe muscle atrophy
Weimer, 2007; Shapiro et al., 2014; Wilbourn, 2002; see Chapter 36). (Aydinli et al., 2003).
APPROACH TO EVALUATION OF PERIPHERAL NEUROPATHIES
History and examination
Multifocal mononeuropathy Mononeuropathy
Peripheral neuropathy
EMG EMG
EMG
Axonal Demyelination +/– Focal Widespread

Conduction block changes
Axonal
Systemic, or Multifocal variant Compression Subclinical

nonsystemic of CIDP Entrapment neuropathy
vasculitis Multifocal motor Consider diabetes
Acute Subacute Chronic
Diabetes neuropathy or other systemic
Sarcoidosis HNPP* diseases
Leprosy
Porphyria Systemic Hereditary

Axonal GBS diseases neuropathies
Toxins Deficiency CMT II
Critical illness states Dysproteinemias
Toxins
Amyloid
Carcinoma
Demyelination
Uniform slowing, Nonuniform slowing +/–

chronic Conduction block
Hereditary Acute Relapsing or chronic

neuropathies
CMT I*, III*, CMTX*
Refsum disease*
Leukodystrophies*
GBS CIDP
Diphtheria Dysproteinemia
Osteosclerotic
myeloma
Fig. 106.5 Diagnostic Approach to Evaluation of a Patient with Peripheral Neuropathy. Electromyography
(EMG) denotes electrodiagnostic studies including nerve conduction studies and needle EMG. DNA diagnostic
testing or specific biochemical tests are available for conditions marked with asterisks. CIDP, Chronic inflam-
matory demyelinating polyradiculoneuropathy; CMT, Charcot-Marie-Tooth disease; CMTX, Charcot-Marie-Tooth
disease X-linked; GBS, Guillain-Barré syndrome; HNPP, hereditary liability to pressure palsies.
Skin Biopsy 9.5, studied best with the use of confocal microscopy. Age, gender,
Skin punch or blister biopsies that demonstrate loss of intraepider- and site of skin biopsy have a profound effect on epidermal nerve
mal nerve fibers are alternative methods for documenting small- fiber density. The density of intraepidermal nerve fibers is reduced
fiber neuropathy (Panoutsopoulou et al., 2009). Only unmyelinated in skin biopsies obtained from patients with sensory and sensorim-
intraepidermal networks of nerve fibers can be demonstrated by otor polyneuropathies including idiopathic, HIV-associated, dia-
immunostaining with the panaxonal marker protein gene product betic polyneuropathies (Kennedy, 2004). Skin punch biopsy is most
BOX 106.9 Indications for Nerve Biopsy TABLE 106.2 Neuropathies Associated
with Serum Autoantibodies
Nerve Biopsy Is Diagnostic and Essential for Diagnosis
Vasculitis* Autoantibody Disease (% Positive)
Amyloidosis* Antibodies Against Gangliosides
Sarcoidosis* GM1 (polyclonal IgM) Multifocal motor neuropathy (70%)
Hansen disease (leprosy) GM1, GD1a (polyclonal IgG) Guillain-Barré syndrome (30%)
Giant axonal neuropathy GQ1b (polyclonal IgG) Miller-Fisher variant of Guillain-Barré
Tumor infiltration syndrome (>90%)
Polyglucosan body disease GD1b (monoclonal IgM) Chronic ataxic neuropathy with ophthalmople-
gia, IgM paraprotein, cold agglutinins and
Nerve Biopsy Is Suggestive and Only Supportive of Diagnosis
anti-GD1b disialosyl antibodies, CANOMAD
Charcot-Marie-Tooth disease types 1 and 3
Chronic inflammatory demyelinating polyradiculoneuropathy Antibodies Against Glycoproteins
Paraproteinemic neuropathy (immunoglobulin M monoclonal gammopathy Myelin-associated glycoprotein Distal acquired demyelinating sensory (DADS)
with anti-myelin-associated glycoprotein antibody) (MAG; monoclonal IgM) neuropathy or IgM neuropathy (50%–70%)
* Consider combined distal nerve and muscle biopsies.
Antibodies Against RNA-Binding Proteins
Anti-Hu, antineuronal nuclear Malignant inflammatory polyganglion-
useful in patients with suspected small-fiber neuropathy, when nerve antibody 1 (ANNA1) opathy: that is, paraneoplastic sensory
conduction studies are normal. The diagnosis of small-fiber neu- neuronopathy (>95%)
ropathy is best accomplished when at least two abnormal results are
met, including positive clinical findings, quantitative sensory testing, Ig, Immunoglobulin.
QSART, and skin biopsy (Devigili et al., 2008). Skin punch biopsy
only detects the presence of skin nerve abnormalities and leads to a vasculitis, amyloid neuropathy, and leprosy. It is helpful in the recog-
specific etiological diagnosis only rarely such as in amyloidosis. The nition of CIDP, hereditary demyelinating polyneuropathies, and some
skin biopsy also does not permit the study of myelinated fibers unless rare axonal polyneuropathies in which distinctive axonal changes occur,
a thicker biopsy, including dermis, is obtained. Finally, unlike sural such as in giant axonal neuropathy and polyglucosan body disease. The
nerve biopsy, the interstitial pathological processes of the nerves can- availability of molecular genetic tests for several CMT neuropathies,
not be studied. HNPP, and familial transthyretin amyloidosis has decreased the neces-
sity for nerve biopsy in these conditions.
Nerve Biopsy Nerve biopsy is an invasive procedure and is associated with as
Nerve biopsy (other than for the diagnosis of vasculitis and neoplasia) high as 15% complication rate—particularly minor wound infections,
should be performed only in centers with established experience with the wound dehiscence, and stump neuromas. Approximately one-third of
surgical procedure, handling of nerve specimens, and pathological tech- patients (particularly those without much sensory loss initially) report
nique; otherwise little useful information is likely to be obtained. The unpleasant sensory symptoms at the sural nerve biopsy site that are still
sural nerve is selected most commonly for biopsy, because the resultant present 1 year after the biopsy (Gabriel et al., 2000). The area of the orig-
sensory deficit is restricted to a small area over the heel and dorsolateral inal sensory deficit declines by 90% after 18 months because of collateral
aspect of the foot, and because its morphology has been well character- reinnervation (Theriault et al., 1998). The complications may be greater
ized in health and disease. The superficial fibular (peroneal) nerve is an if substantial foot ischemia is present or if the patient smokes cigarettes.
alternative lower-extremity cutaneous nerve suitable for biopsy and has
the advantage of allowing simultaneous biopsy of the peroneus brevis Other Laboratory Tests
muscle through the same incision. This combined distal nerve and mus- The clinical neuropathic patterns and the results of EDX studies guide
cle biopsy procedure increases the yield of identifying suspected vasculi- the experienced clinician to select the most appropriate laboratory tests.
tis (Collins et al., 2000; Vital et al., 2006). In contrast, adding a proximal A few laboratory tests should be obtained routinely in all patients with
muscle (e.g., quadriceps) to a cutaneous nerve biopsy (e.g., sural) does peripheral polyneuropathy. These include complete blood cell count
not significantly increase the diagnostic yield compared to nerve biopsy (CBC), sedimentation rate, C-reactive protein, renal functions, fasting
alone (Bennett et al., 2008). In patients with proximal involvement of blood sugar, hemoglobin A1C, thyroid studies, vitamin B12 level, and
the lower limbs, the intermediate cutaneous nerve of the thigh combined serum protein electrophoresis with immunofixation electrophoresis.
with a muscle biopsy can be performed. When the risk of complication It is important to screen for monoclonal proteins in all patients with
is increased from a biopsy of the lower limbs (e.g., in significant distal leg chronic undiagnosed polyneuropathy, particularly those older than 60
ischemia, edema) or the neuropathy is preferentially more pronounced years, because 10% of such patients have a monoclonal gammopathy.
in the upper limbs, a cutaneous nerve biopsy of superficial radial or one Cerebrospinal fluid (CSF) examination is helpful in the evaluation of
of the antebrachial sensory nerves may be performed. When the imag- suspected demyelinating neuropathies and polyradiculopathies related
ing studies indicate a plexus or nerve root pathological process (e.g., to meningeal carcinomatosis or lymphomatosis.
inflammatory, infiltrative), a fascicular biopsy of the affected nerve by Several serum autoantibodies with reactivity to various compo-
an expert surgeon may provide invaluable information. Nerve biopsy nents of peripheral nerve have been associated with peripheral neu-
has proved to be particularly informative when techniques such as sin- ropathy syndromes, and reference laboratories offer panels of nerve
gle teased fiber preparations, semi-thin sections, ultrastructural studies, antibodies for sensory, sensorimotor, and motor neuropathies. It must
and morphometry are applied to quantitate the nerve fiber pathology. be emphasized that the clinical relevance of most autoantibodies has
Nowadays, relatively few disorders remain in which a nerve biopsy is not been established for patient treatment, and their use is not cost-
essential for diagnosis (Pleasure, 2007; Said, 2002; Box 106.9). In general, effective (Vernino and Wolfe, 2007). Those of greatest clinical utility
nerve biopsy is most frequently diagnostic in suspected peripheral nerve are listed in Table 106.2 (Kissel, 1998). An ever-increasing number of
molecular genetic tests for inherited neuropathies are available at ref- Entrapment neuropathy is defined as a mononeuropathy caused by
erence laboratories (see Hereditary Neuropathies, later). focal compression or mechanical distortion of a nerve within a fibrous
In patients with initially undiagnosed peripheral neuropathy or fibro-osseous tunnel or less commonly by other structures such as
referred to specialized centers, a definite diagnosis can be made in bone, ligament, other connective tissues, blood vessels, or mass lesions.
more than 75% of cases. Inherited neuropathies, CIDP, and neuropa- Compression, constriction, angulation, and stretching are important
thies associated with other systemic diseases accounted for most diag- mechanisms that produce nerve injury at certain vulnerable anatomi-
noses. The improved diagnostic rate resulted in large measure from cal sites (see Tables 106.3 and 106.5). The term entrapment is a useful
detailed clinical, EDX, and laboratory evaluations and study of rela- one in that it implies that compression occurs at particular sites where
tives of patients with undiagnosed neuropathy. surgical intervention is often required to release the entrapped nerve,
such as in the case of the median nerve at the wrist in moderate to
MONONEUROPATHIES severe CTS. Overuse has been implicated as the cause of entrapment
neuropathies in certain occupations, including playing of musical
Definition and Classification of Mononeuropathies instruments by professional musicians.
Mononeuropathy is defined as a disorder of a single peripheral nerve. In chronic entrapment, mechanical distortion of the nerve fibers
This may result from compression, traction, laceration, thermal, or leads to focal demyelination or, in severe cases, to wallerian degener-
chemical injury. The damage may involve one or more structural ation. Morphological studies show a combination of active demyelin-
components of the peripheral nerve, while the pathophysiological ation, remyelination, wallerian degeneration, and axonal regeneration
responses to peripheral nerve lesions include axon loss, demyelination, at the site of entrapment. Endoneurial swelling, collagen prolifera-
or a combination of both. tion, and thickening of perineurial sheaths accompany the nerve fiber
Peripheral nerve injuries are classified based on functional status of the changes. Ischemia is not a significant contributing factor to nerve fiber
nerve and histological findings. Seddon divided peripheral nerve injury damage in chronic compression. In contrast, ischemia plays a more
into three classes: neurapraxia, axonotmesis, and neurotmesis. This classi- significant role in nerve injury associated with acute compression sec-
fication remains popular, particularly among surgeons, because of its cor- ondary to space-occupying lesions such as hematoma or compartment
relation to outcome (Seddon, 1975). Later, Sunderland (1991) revised the syndromes.
classification into five degrees that have better prognostic implications. The characteristic electrophysiological feature of entrapment neu-
ropathy is either short-segment conduction delay (i.e., focal slowing)
Neurapraxia or conduction block across the site of entrapment (see Chapter 36). In
First-degree nerve injury. Neurapraxia, or first-degree nerve severe cases, wallerian degeneration gives rise to denervation and rein-
injury, usually results from brief or mild compression on the nerve that nervation in affected muscles. Nerve conduction studies together with
distorts the myelin, resulting in segmental demyelination but leaving the needle EMG are essential for diagnosis and reliable documentation of
axons intact. The nerve conducts normally distal to but not across the the site and severity of nerve entrapment. Neuromuscular ultrasound
lesion, resulting in conduction block, which is the electrophysiological has had an increasing role in the diagnosis of entrapment neurop-
correlate of neurapraxia. With this type of injury, recovery is usually athies, particularly when EDX studies are more difficult (such as in
complete following remyelination that occurs within 1–3 months if the young children) or show only signs of nonlocalizing axonal loss such
offending cause (such as a compression) is removed. as with severe ulnar neuropathies (Alrajeh and Preston, 2018). In con-
trast, plain radiography, computed tomography (CT), and MRI may
Axonotmesis be of occasional value in identifying rare structural abnormalities, but
Axonotmesis injury is characterized by axonal damage that results these imaging procedures are often not necessary for routine diagnosis.
in wallerian degeneration; distal to the injury, the axons and their
investing myelin sheath degenerate (wallerian degeneration) and the Mononeuropathies of the Upper Extremities
end organs (muscle fibers and sensory receptors) become denervated. Entrapment neuropathies of the upper extremities are shown in Table
Sunderland divided this type of nerve lesion into three further sub- 106.3.
types based on the disruptions of the supporting structures (endoneu-
rium, perineurium, and epineurium). Median Nerve
Second-degree nerve injury. The axonal loss is associated with Applied anatomy. The median nerve, formed from contributions
intact endoneurial tubes as well as intact perineurium and epineurium. of the lateral cord (C6 and C7 fibers) and medial cord (C8 and T1
These lesions have fairly good prognosis, since nerve regeneration fibers) of the brachial plexus, runs into the forearm between the two
between the site of nerve injury and the target organs is well guided by heads of the pronator teres. It then gives off branches to the pronator
the intact endoneurial tubes. teres, flexor carpi radialis, flexor digitorum sublimis, and the palmaris
Third-degree nerve injury. The axons and endoneurium are longus muscles, as well as the anterior interosseous nerve. The anterior
damaged while leaving the perineurium and epineurium intact. These interosseous nerve is the largest branch of the median nerve and is
lesions have fair prognosis and may require surgical intervention, a pure motor nerve. It arises from the median nerve distal to these
mostly because of axonal misdirection and formation of neuromas. motor branches in the upper forearm and innervates the flexor pollicis
Fourth-degree nerve injury. The axons, endoneurium, and longus, pronator quadratus, and median part of the flexor digitorum
perineurium are disrupted, but the epineurium is intact. These lesions profundus muscles of the index and middle fingers. The median
have poor prognosis and often require surgical repair. nerve then enters the wrist through the carpal tunnel, formed by the
carpal bones and the transverse carpal ligament, the latter forming its
Neurotmesis roof. Before reaching the wrist, the median nerve gives off the palmar
Fifth-degree nerve injury. Neurotmesis, or fifth-degree nerve injury, cutaneous sensory branch, which runs subcutaneously (not through
is the most severe type of nerve injury. It involves complete disruption the carpal tunnel) to innervate the skin over the thenar eminence.
of the nerve and all supporting structures. The nerve is transected, with Distal to the carpal tunnel, the median nerve divides into motor and
loss of continuity between its proximal and distal stumps. sensory divisions. The motor division innervates the first and second
TABLE 106.3 Entrapment/Compressive Neuropathies of Upper Limbs

Nerve Site of Compression Predisposing Factors Major Clinical Features
Median Wrist (carpal tunnel syndrome) Tenosynovitis, arthritis, repetitive wrist Nocturnal paresthesia, pain, hypesthesia lateral 3
motions fingers, thenar atrophy
Anterior interosseous Strenuous exercise, trauma, neuralgic Abnormal pinch sign, normal sensation
amyotrophy
Elbow (pronator teres syndrome) Repetitive elbow motions Tenderness of pronator teres, no weakness,
sensory loss
Ulnar Elbow (ulnar groove or cubital tunnel Elbow leaning, remote trauma (tardy ulnar), Clawing, Froment sign, sensory loss of fourth and
syndrome) trauma, entrapment fifth fingers
Guyon canal Mechanics, cyclists, ganglion cyst Interosseous atrophy, normal sensation of dorsum
of fourth and little fingers
Radial Axilla Crutches Wrist drop, triceps involved, sensory loss extend-
ing into forearm and sometimes arm
Spiral groove Abnormal sleep postures Wrist drop, triceps spared, sensory loss of dorsum
of hand only
Posterior interosseous Elbow synovitis, neuralgic amyotrophy Paresis of finger extensors, radial wrist deviation
Superficial sensory branch (cheiralgia Wrist bands, hand cuffs Paresthesias in dorsum of hand
paresthetica)
Suprascapular Suprascapular notch Blunt trauma, neuralgic amyotrophy Atrophy of supraspinatus and infraspinatus
muscles
Axillary Axilla Shoulder dislocation or surgery Weakness of arm abduction
Long thoracic Shoulder Neuralgic amyotrophy, stretch Posterior scapular winging
Lower trunk of the Thoracic outlet Cervical rib, cervical band with enlarged C7 Atrophy of intrinsic hand muscles (mostly thenar),
brachial plexus or transverse process paresthesias of medial hand and forearm
T1 roots
lumbricals and most muscles of the thenar eminence including the

opponens pollicis, abductor pollicis brevis, and superficial head of the
flexor pollicis brevis. The sensory fibers of the median nerve innervate
the skin of the thumb, index, middle, and lateral half of the ring fingers.
Median nerve entrapment at the wrist (carpal tunnel
syndrome). CTS is by far the most common entrapment neuropathy
seen in clinical practice. CTS prevalence in a primary care population
is about 36 per 10,000 people, with an annual incidence of 19 per
10,000 for men and 36 per 10,000 for women (Burton et al., 2018).
Both the incidence and prevalence of CTS seem to be increasing.
This entrapment occurs in the tunnel through which the median
nerve and long finger flexor tendons pass. Because the transverse car-
pal ligament is an unyielding fibrous structure forming the roof of the
Fig. 106.6 Thenar Atrophy in Chronic Bilateral Carpal Tunnel Syn-
tunnel, tenosynovitis or arthritis in this area often produces pressure
drome.
on the median nerve. The syndrome is frequently bilateral and usually
of greater intensity in the dominant hand.
Symptoms consist of nocturnal pain and paresthesias, most often the symptoms; it is present in about 80% of patients, and is rarely false
confined to the thumb, index, and middle fingers, but may be reported positive (Padua et al., 2016). A positive Tinel sign, in which percussion
to involve the entire hand. Patients complain of tingling numbness, of the nerve at the carpal tunnel causes paresthesias in the distribution
and burning sensations, which often awaken them from sleep. Referred of the distal distribution of the median nerve, is present in approxi-
pain may radiate to the forearm and even as high as the shoulder mately 60% of affected patients but is not as specific for CTS and may
(Stevens et al., 1999). Symptoms are often provoked after excessive use be false positive.
of the hand or wrist or during ordinary activities such as driving or Work-related wrist and hand symptoms (repetitive motion injury)
holding a phone, book, or newspaper, in which the wrist is assumed from cumulative trauma in the workplace have received increasing
in either a flexed or extended posture. Objective sensory changes may attention by the general public in recent years (Thomsen et al., 2002).
be found in the distribution of the median nerve, most often impaired Although a proportion of these cases have bona fide CTS, longitudi-
two-point discrimination, pinprick and light touch sensation, or occa- nal natural history data suggest that the majority of industrial workers
sionally hyperesthesia, in the thumb, index, and middle fingers, most do not develop symptoms of CTS (Nathan et al., 1998). Symptoms
evident in finger tips, with sparing of the skin over the thenar emi- consistent with hand and wrist arthritis in a variety of occupational
nence. Thenar (abductor pollicis brevis muscle) weakness and atrophy settings are now recognized as being much more common than CTS
may be present in advanced cases of CTS (Fig. 106.6). Phalen maneuver (Dillon et al., 2002). CTS appears to occur in work settings that include
(flexing the patient’s hand at the wrist for 1 minute) or reversed Phalen repetitive forceful grasping or pinching, awkward positions of the
maneuver (hyperextension of the wrist for 1 minute) often reproduces hand and wrist, direct pressure over the carpal tunnel, and the use of
TABLE 106.4 Internal Comparison of Nerve Conduction Studies in the Evaluation of Carpal
Tunnel Syndrome
Median-Ulnar Palmar Mixed Median-Ulnar Sensory Median-Ulnar Motor Study to Median-Radial Sensory
Study Study Study to Ring Finger Second Lumbrical Interossei Study to Thumb
Technique Palm stimulation of median and ulnar Median and ulnar nerves stim- Median and ulnar nerves stimulation Median and radial nerves stim-
nerves, recording at the wrist ulation at the wrist, recording at the wrist, recording second ulation at the wrist, recording
ring fingers lumbrical and second interossei, thumb
respectively (second interosseous
space)
Abnormal values Median-ulnar peak latency difference Median-ulnar peak latency Median-ulnar onset latency difference Median-radial peak latency
≥ 0.4 ms difference ≥ 0.4 ms ≥ 0.5 ms difference ≥ 0.4 ms
handheld vibrating tools. Increased risk for the syndrome has been
found in meat packers, garment workers, butchers, grocery checkers,
electronic assembly workers, musicians, dental hygienists, and house-
keepers. The highest reported incidence of work-related CTS, based
on the number of carpal tunnel surgeries performed, was 15% among +1
a group of meat packers. Though using the computer keyboard may
aggravate symptoms of CTS, keyboard use does not increase the risk of
developing CTS (Mediouni et al., 2014; Shiri and Falah-Hassani, 2015;
CSA = 21.6 mm2
Stevens et al., 2001).
Diseases and conditions that have been found to predispose to Fig. 106.7 Ultrasound of the median nerve at the wrist showing a
the development of CTS include pregnancy, diabetes, obesity, age, hypoechoic and enlarged median nerve at the carpal tunnel inlet with a
rheumatoid arthritis, hypothyroidism, amyloidosis, gout, acro- cross-sectional area (CSA) measuring 21.6 mm2 (normal < 10–13 mm)
megaly, certain mucopolysaccharidoses, arteriovenous shunts for
hemodialysis, old fractures at the wrist, and inflammatory diseases et al., 2018). Withdrawal of provoking factors is also important.
involving tendons or connective tissues at the wrist level (Becker Although nonoperative treatments have been advocated (Osterman
et al., 2002). On rare occasions, CTS may be familial, and some et al., 2002), a comparison of splinting versus surgery suggested that
patients with CTS have carpal tunnels that are significantly narrower the latter may have a better long-term outcome than the former
than average. (Gerritsen et al., 2002). Use of a range of devices and appliances to
The most commonly performed EDX tests for CTS are the median protect the hand against CTS, including gel-padded gloves, has shown
nerve sensory and motor conduction studies, which exhibit delayed little if any improvement in objective measures of nerve function.
sensory or motor latencies across the wrist in about 70% of patients. There is conflicting evidence that NSAIDs, diuretics, laser, and ultra-
However, these studies are not sensitive enough in the diagnosis of sound are effective. Exercise therapy is not useful (Piazzini et al., 2007).
CTS and fail to detect up to a third of patients with CTS, particularly Methylprednisolone injections for CTS significantly relieve symptoms
those with mild and early symptoms. Recording the median latency for a few months and reduce the need for surgery, but a significant
at short distances over the course of the median nerve from palm to number of patients will ultimately need surgical treatment (Atroshi
wrist and/or comparing this latency with the latency for the ulnar or et al., 2013). Oral steroids are also effective but are associated with side
radial nerve at the same distance (internal comparison nerve conduc- effects. Severe sensory loss, thenar atrophy, and active denervation
tion studies) increase the sensitivity of these nerve conduction studies on needle EMG of thenar muscles suggest the need for surgical carpal
(Basiri and Katirji, 2015; Stevens, 1997; Table 106.4). tunnel release. Open surgical sectioning of the volar carpal ligament
Mild CTS must be distinguished from proximal median neuropa- or fiberoptic techniques are often successful, with more than 90% of
thies, upper brachial plexopathy, C6 or C7 radiculopathies, and poly- patients having prompt resolution of pain and paresthesias (Louie
neuropathy involving the hands. Occasionally, a transient ischemic et al., 2013; Mirza and King, 1996). Improvement in distal latencies
attack may mimic the symptoms of CTS. may lag behind the relief of symptoms. Comparing with preoperative
Ultrasound is increasingly used in the diagnosis of CTS. Thickening values, nerve conduction studies demonstrate improvement in those
of the median nerve, best expressed as an increase in the CSA of the with moderate abnormalities preoperatively, whereas patients with
median nerve at the carpal tunnel inlet (more than 13 mm; normal severe or no abnormalities on baseline nerve conduction studies have
<10–13 mm), or flattening of the nerve at the level of the hamate are poorer results (Bland, 2001). A correlation between patients seeking
the best diagnostic criteria (Fig. 106.7) (Cartwright et al., 2012; Tai workers’ compensation who hire attorneys and poorer operative out-
et al., 2012). The majority of studies have found that the diagnostic comes has also been reported (Katz et al., 2001a). Older individuals
utility of ultrasound and EDX studies are equal (Mondelli et al., 2008; may not improve as much as younger patients (Porter et al., 2002), and
Viser et al., 2008). MRI is most useful when a space-occupying lesion, factors such as poor mental health, significant alcohol consumption,
such as ganglion, hemangioma, or bony deformity, is suspected in longer disease duration, and male gender also portend a poorer out-
patients with CTS. come. Rarely, symptoms persist after operation. Poor surgical results
In cases with only mild sensory symptoms, treatment with splints in usually are associated with incomplete sectioning of the transverse lig-
neutral position, nonsteroidal antiinflammatory drugs (NSAIDs), and ament, surgical damage of the palmar cutaneous branch of the median
local corticosteroid injection often suffice (Padua et al., 2016). Local nerve by an improperly placed skin incision, scarring within the carpal
corticosteroid injection is slightly better than splinting (Chesterton tunnel, or an incorrect preoperative diagnosis. Surgical re-exploration
may be required in certain cases with poor response to the initial oper- Median nerve entrapment at the ligament of Struthers.
ation (Steyers, 2002). An often bilateral supracondylar spur of the humerus is present
Median nerve compressions at the elbow in approximately 1% of normal individuals. This beadlike bony
Anterior interosseous nerve syndrome. Isolated acute or cartilaginous projection arises from the anteromedial surface
involvement of the anterior interosseous nerve is often a presentation of the humerus, located about 5 cm above the medial epicondyle.
of neuralgic amyotrophy (idiopathic brachial plexus neuropathy, A fibrous band, the ligament of Struthers, extends from this spur
Parsonage-Turner syndrome) (England and Sumner, 1987; Katirji, to the medial epicondyle and may rarely compromise the median
1986). The majority of these lesions are fascicular lesions of the median nerve and the brachial artery above the elbow. Clinical symptoms
nerve in the arm involving the anterior interosseous nerve fascicle resemble the pronator teres syndrome, but sometimes the radial pulse
selectively (Pham et al., 2014). Fascicular torsion of the anterior diminishes when the forearm is fully extended in supination because
interosseous fascicle in the lower arm has also been advocated to be due of the concomitant entrapment of the brachial artery. Elbow extension
to the high mobility of the anterior interosseous nerve fascicles during causes aggravation of the pain. On needle EMG, there is sometimes
elbow flexion leading to torsion injury or inflammation/edema followed denervation in the abductor pollicis brevis, flexor pollicis longus,
by intraneural adhesions (Noda et al., 2017). In chronic and indolent pronator quadratus, and pronator teres. Involvement of the pronator
lesions, a restricted form of MMN with conduction block should be teres muscle theoretically allows differentiation of the ligament of
considered and a careful and detailed electrophysiological study may Struthers syndrome from the pronator teres syndrome. Treatment
reveal involvement of other nerves. The anterior interosseous nerve consists of surgical excision of the spur and ligament.
may be externally compressed following anterior elbow dislocations
or complex elbow fractures, or rarely by fibrous bands attached to the Ulnar Nerve
flexor digitorum superficialis muscle, an anomalous Gantzer muscle Applied anatomy. The ulnar nerve derives its fibers from the C8
which is an accessory portion of the flexor pollicis longus or the flexor and T1 roots via the lower trunk and originates from the medial cord
digitorum profundus (Caetano et al., 2018). of the brachial plexus, along with the medial brachial and antebrachial
Patients often complain of an acute or subacute onset of pain in cutaneous sensory nerves. The ulnar nerve gives no branches in the
the forearm or elbow. The patient is unable to flex the distal phalan- arm. At the elbow, the nerve becomes superficial and enters the ulnar
ges of the thumb and index finger, making it impossible to form a groove formed between the medial epicondyle and the olecranon
circle with those fingers (pinch or O sign). Sensory and motor nerve process. Normally, the ulnar nerve remains in the groove, but in some
conduction studies of the median nerve are usually normal. Needle individuals or when there is an unusual degree of physiological cubitus
EMG reveals denervation in muscles innervated by the anterior inter- valgus, the nerve may be unduly mobile, tending to slip forward
osseous nerve, including the flexor pollicis longus, pronator quadra- (sublux) over the medial epicondyle when the elbow is flexed. In a
tus, and flexor digitorum profundus muscles of the index and middle small number of individuals, a dense fibrotendinous band and/or an
fingers. Spontaneous recovery usually occurs within 3–12 months, accessory epitrochleoanconeus muscle may be present between the
and therefore surgery may not be necessary unless penetrating injury, medial epicondyle and the olecranon process. Slightly distal to the
fracture, or progressive deterioration and weakness are detected. groove in the proximal forearm, the ulnar nerve travels under the
Patients with torsion injury showed good recovery after interfascic- tendinous arch of the two heads of the flexor carpi ulnaris muscle,
ular neurolysis. known as the humeral-ulnar aponeurosis, which forms the entrance
Pronator teres syndrome. In the pronator teres syndrome, of the cubital tunnel. Muscular branches originate to the flexor carpi
the median nerve is compressed in the proximal forearm between ulnaris and the flexor digitorum profundus (ulnar part to the little and
the two heads of the pronator teres muscle, a fibrous arcade of the ring fingers). The ulnar nerve continues under the flexor carpi ulnaris
flexor digitorum superficialis muscle, or the lacertus fibrosus (a and then exits in the distal forearm between the deep fascia separating
thick fascial band extending from the biceps tendon to the forearm the flexor carpi ulnaris and flexor digitorum profundus. Some 5–8
fascia). This extremely rare and controversial entrapment may develop cm proximal to the wrist, the dorsal ulnar cutaneous sensory branch
in individuals engaged in repetitive pronating movements of the exits to innervate skin on the dorsal medial hand and the dorsal little
forearm. Patients usually experience a vague aching pain in the volar and ring fingers. The palmar cutaneous sensory branch originates
aspect of the elbow and forearm, beginning or worsening during at the level of the ulnar styloid to supply sensation to the proximal
activities involving grasping or pronation or both. There is also an medial palm. The ulnar nerve then enters the wrist through the Guyon
insidious onset of paresthesias and numbness of the palm of the hand, canal, which is formed between the pisiform bone and the hook of the
mimicking CTS but without the nocturnal symptoms. Resistance to hamate and is covered by the volar carpal ligament and the palmaris
pronation produces pain in the proximal forearm. The pronator brevis muscle. Within the Guyon canal, the ulnar nerve divides into
teres may be firm and tender on palpation, and the Tinel sign may be its terminal deep palmar and superficial ulnar branches. Because the
elicited over the median nerve in the region of the elbow. Weakness palmar cutaneous sensory and dorsal cutaneous sensory branches do
of median-innervated muscles such as the flexor pollicis longus, not pass through the Guyon canal, the deep palmar branch is purely
pronator quadratus, and abductor pollicis brevis (but not of pronator motor and supplies muscular innervation to the hypothenar muscles,
teres) is rarely demonstrated, in contrast to traumatic cases such as the palmar and dorsal interossei, the third and fourth lumbricals, and
following elbow dislocation, forearm fracture, or intracompartmental two muscles in the thenar eminence, the adductor pollicis, and the deep
hemorrhage. Nerve conduction studies in the median nerve are usually head of the flexor pollicis brevis.
normal and do not show the distal median motor and sensory latencies Ulnar nerve entrapment at the elbow. Ulnar mononeuropathy
at the wrist that accompany CTS. Needle EMG is also usually normal, is the second most common entrapment or compression
with no definite signs of denervation. Injection of corticosteroids into mononeuropathy, although it is considerably less common than CTS.
the pronator teres muscle, NSAIDs, and immobilization of the arm Compression of the ulnar nerve by a thickened, fibrotic flexor carpi
with the elbow flexed to 90 degrees and in mild pronation often provide ulnaris aponeurosis (humeral-ulnar aponeurosis) at the entrance of
relief of symptoms. Surgery is controversial but may be occasionally the elbow’s cubital tunnel is a common cause of ulnar neuropathy
necessary, though patients may gain only partial relief. (cubital tunnel syndrome). Patients with a subluxed ulnar nerve
are at high risk for compression at the elbow. Also, prolonged and Similarly, weakness of median and radial innervated C8 muscles such
frequent resting of the flexed elbow on a hard surface such as a desk as the flexor pollicis longus or the long finger extensors points to a
or armchair may result in external pressure to the nerve (ulnar groove plexopathy or radiculopathy.
syndrome). Occupations involving repeated flexion of the elbow may Compared to evaluating other entrapment neuropathies such as
on occasion cause symptoms of ulnar neuropathy. A flexed elbow CTS, the EDX studies used to confirm and localize ulnar nerve entrap-
position increases both the intraneural and extraneural pressure on ment at the elbow are more challenging. Localizing ulnar neuropathy
the nerve. The nerve at the site of repeated compression is associated at the elbow relies upon the demonstration of focal demyelination
with fibrous thickening, when a spindle-shaped swelling may be felt. across the elbow, namely slowed motor conduction velocity (>10–15
Other possible sources of injury of the ulnar nerve at the elbow include m/sec) or conduction block (localized reduction in CMAP amplitude
direct compression when the patient uses the arms to raise up in bed and area of >20%–30%) or both. Focal slowing or conduction block
following surgical operations (Stewart and Shantz, 2003) or after may be found in the elbow segment in more than 75% of cases (Azrieli
periods of prolonged unconsciousness. The ulnar nerve at the elbow et al., 2003). Performing an additional ulnar motor conduction study,
may be acutely injured as a result of fracture or dislocation involving recording the first dorsal interosseous muscle in addition to record-
the lower end of the humerus and the elbow joint. Occasionally, ing the abductor digiti minimi muscle, increases the yield of finding
however, the nerve becomes chronically compressed years after such focal slowing or conduction block. In the remaining patients, local-
an injury, which often has led to cubitus valgus deformity (“tardy ization becomes less precise because of predominant axonal loss. To
ulnar palsy”). The nerve may be damaged by osteophyte outgrowths provide the extra nerve length needed during elbow flexion, the ulnar
resulting from arthritis of the elbow joint, by a ganglion or lipoma, by nerve is anatomically redundant in the ulnar groove when the elbow is
a Charcot elbow, and by the epitrochleoanconeus muscle and/or its extended, and this can cause measurement errors. A flexed position of
dense fibrotendinous band. The ulnar nerve may also be involved in the elbow (70–90 degrees) is preferred to the extended position when
conditions that are known to increase the susceptibility of nerves to doing ulnar motor conduction studies to localize an ulnar lesion at the
compression, such as DM or HNPP. Ulnar neuropathy at the elbow elbow.
segment may also occur without any apparent cause. Reference values to determine absolute across-elbow ulnar motor
Ulnar nerve lesions at the elbow result in numbness and tingling of conduction velocity slowing or relative slowing in across-elbow versus
the little and ring fingers, with variable degrees of hand weakness. Less forearm conduction velocities have varied depending on study design
commonly, patients present with weakness and wasting with no clear and population studied. In addition, the optimal distance for measur-
sensory symptoms. There is also variable weakness of the flexor carpi ing ulnar motor NCV around the flexed elbow continues to be debated
ulnaris and the flexor digitorum profundus of the ring and little fingers between 6 and 10 cm (Logigian et al., 2014). To improve diagnostic
(ulnar part). Grip strength is reduced secondary to weakness of the accuracy and reduce false-positive and false-negative results, differ-
adductor pollicis, flexor pollicis brevis, and palmar and dorsal interos- ent diagnostic criteria are advocated for patients with different pre-
seous muscles. To compensate for adductor pollicis weakness during test probability of ulnar neuropathy across the elbow (Logigian et al.,
an attempt to pinch a piece of paper between the thumb and index 2014). Patients with high pre-test probability of ulnar neuropathy
fingers, the flexor pollicis longus, a median nerve-innervated mus- across the elbow (i.e., with typical clinical symptoms and signs) should
cle, becomes involuntarily active and flexes the distal phalanx of the have less stringent diagnostic criteria (for example >14 m/sec velocity
thumb (Froment sign). Weakness of the interossei muscles results in difference or <47 m/sec velocity), while those with low pre-test proba-
an inability to forcefully extend the interphalangeal joints, as is neces- bility of ulnar neuropathy across the elbow (i.e., with atypical or incon-
sary in finger-flicking movements. Prominent atrophy of hand muscles sistent clinical symptoms and signs) should have more strict diagnostic
ensues and is most noticeable at the first dorsal interosseous muscle. criteria (such as >23 m/sec velocity difference and <38 m/sec veloc-
Lumbrical weakness leads to clawing of the fourth and fifth fingers ity). Short-segment incremental studies (“inching”) by stimulating the
and flexion of the proximal and distal interphalangeal joints, with sec- ulnar nerve in successive 1- or 2-cm increments across the elbow, look-
ondary hyperextension of the metacarpophalangeal joints (benediction ing for either an abrupt drop in amplitude or increase in latency, are
posture or ulnar clawing). Weakness of the third palmar interosseous useful techniques that help to precisely localize the ulnar nerve lesion
muscle results in abduction of the little finger, which may get caught (Omejec and Podnar, 2015; Visser et al., 2005). Electrophysiological
when the patient tries to put the hand in a pocket (Wartenberg sign). In tests are helpful in differentiating between an ulnar neuropathy and a
chronic ulnar neuropathies, the weakness and atrophy of small mus- C8 nerve root or brachial plexus lesion. Ulnar sensory nerve conduc-
cles of the hand is always more severe than the weakness and atrophy tion sparing points to C8 radiculopathy and normal needle EMG of C8
of the forearm muscles. Sensory loss or hypoesthesia involves the fifth muscles innervated by the median nerve (e.g., abductor pollicis brevis,
finger, part of the fourth finger, and the hypothenar eminence and flexor pollicis longus) and radial nerve (e.g., extensor indicis proprius)
includes the dorsum of the hand but does not extend above the wrist help exclude a C8 root lesion or a lower brachial plexopathy.
level. Pain around the elbow and tenderness of the ulnar nerve with High-resolution ultrasonography at the elbow is also useful by
deep palpation is common, but distal hand or finger pain is rare. A accurately detecting enlargement of the ulnar nerve at the elbow
Tinel sign at the elbow may be elicited, but this sign as well as provoca- (Beekman et al., 2004). MRI of the elbow may reveal a space-occupying
tive tests (flexion compression test, palpating for local ulnar nerve ten- lesion or anomalous structures impinging on the nerve or demonstrate
derness and nerve thickening) have poor diagnostic values (Beekman nerve enlargement and increased signal intensity, even in the absence
et al., 2009). of localizing electrophysiological abnormalities (Vucic et al., 2006).
Ulnar nerve lesions at the elbow should be distinguished from ulnar Conservative treatment should be attempted in patients with mild
nerve lesions at the wrist, lower brachial plexus lesions (lower trunk or intermittent sensory symptoms or in those with symptoms brought
or medial cord), and C8 radiculopathy. Confirmed sensory loss that on by occupational causes. Avoidance of repetitive elbow flexion and
extends more than 3 cm above the wrist into the medial forearm and extension or direct pressure on the elbow may alleviate the symptoms.
arm, the territories of the medial brachial and antebrachial cutaneous Elbow protectors are helpful in patients with a history of excessive
nerves, is inconsistent with an ulnar neuropathy at the elbow and sug- elbow leaning. Conservative treatment should be continued for at least
gests a more proximal lesion of the lower plexus or C8 or T1 roots. 3 months before surgery is considered. Several surgical approaches to
an ulnar nerve lesion at the elbow are possible, each with its propo- Radial Nerve
nents and critics. Techniques include simple release of the flexor carpi Applied anatomy. The radial nerve is the largest nerve in the upper
ulnaris aponeurosis, anterior transposition of the nerve trunk, and extremity. In the arm, lying medial to the humerus, the radial nerve
resection of the medial epicondyle. The choice of procedure should innervates all three heads of the triceps muscle and the anconeus muscle.
be tailored to the specific lesion found at surgery and may be assisted The nerve passes obliquely behind the humerus and then through the
by short-segment incremental electrophysiological studies (“inch- spiral groove, a shallow groove formed deep to the lateral head of
ing”). Transposition of the nerve trunk carries a higher rate of com- the triceps muscle. Before entering the spiral groove in the midarm,
plications than ulnar neurolysis (Biggs and Curtis, 2006). Depending it gives three sensory branches: the posterior cutaneous nerve of the
on the type of surgery and the severity and duration of neuropathy, arm (which innervates a strip of skin overlying the triceps muscle), the
response to these procedures will vary. Only about 60% of patients, lower lateral cutaneous nerve of the arm (which innervates the lateral
especially those with symptoms of less than 1 year’s duration, bene- half of the arm), and the posterior cutaneous nerve of the forearm
fit from surgery; some experience worsening of symptoms. It appears (which innervates the skin of the extensor surface of the forearm). In
that those with more thickening of the nerve at the time of diagnosis the anterior compartment of the arm, the radial nerve, lying lateral
(as determined by sonography) have a more unfavorable outcome, to the humerus, innervates the brachioradialis and the extensor carpi
and those with electrophysiological signs of demyelination across the radialis longus. The nerve then passes anterior to the lateral epicondyle
elbow, specifically significantly greater than 50% conduction block, and innervates the extensor carpi radialis brevis and supinator. The
have a more favorable course (Beekman et al., 2004; Dunselman and “radial tunnel” is a space (not an anatomical tunnel) where the radial
Visser et al., 2008). nerve travels in the upper forearm from the humeroradial joint past
Ulnar nerve entrapment at the wrist. Distal entrapment of the supinator muscle. Within that space, the radial nerve divides into
the ulnar nerve at the wrist (Guyon canal) or hand is a relatively its terminal branches, the superficial radial and posterior interosseous
uncommon condition. Ulnar nerve entrapment in the Guyon canal nerves (PINs). The PIN, a terminal pure motor branch, passes under
occurs much less frequently than at the elbow. Aside from direct the proximal edge of the supinator muscle (arcade of Frohse) and
trauma and laceration, the most common cause is a ganglion cyst. travels in the forearm and innervates all the remaining wrist and finger
Other usual causes are chronic or repeated external pressure by hand extensors. The superficial radial nerve is a terminal pure sensory nerve
tools, bicycle handlebars, the handles of canes, or excessive push-ups. and innervates the skin of the proximal two-thirds of the extensor
Compression also may be caused by degenerative wrist joint changes, surfaces of the thumb, index, and middle fingers, and half of the ring
rheumatoid arthritis, or distal vascular anomalies. finger, along with the corresponding dorsum of the hand.
Ulnar nerve entrapment at the wrist may present with a confusing Radial nerve compression in the arm. Radial nerve compression in
array of sensory and motor symptoms or both, depending on which the arm often occurs at the spiral groove of the humerus during drunken
branches of the nerve are involved. Most cases of ulnar nerve entrap- sleep wherein the arm is draped over a chair (Saturday-night palsy)
ment at the Guyon canal, however, involve solely motor fibers and (Spinner et al., 2002). The radial nerve may also be injured following
present with painless unilateral hypothenar and interossei weakness or fractures of the humerus. Radial nerve lesions at the axilla are much less
atrophy. Because the palmar cutaneous and dorsal cutaneous branches common; they may result from misuse of crutches or from the weight
leave the ulnar nerve in the distal forearm and do not enter the Guyon of a sleeping partner’s head (honeymoon palsy) or follow shoulder joint
canal, sensation in the proximal hypothenar region and the dorsum replacement. The radial nerve is also often involved in isolation or in
of the little and ring fingers is not impaired in all cases of ulnar nerve combination with other single nerves in MMN with conduction block.
lesions at the wrist or hand. The sensory loss, if present, is confined In radial nerve lesions in the spiral groove or midarm, there is
to the palmar surface of the ulnar-innervated fingers (the little finger weakness of the brachioradialis, wrist, and finger extensors, while the
and usually the ulnar half of the ring finger) and the distal hypothe- triceps is spared. Sensory abnormalities may occur over the dorsum
nar region. Compression at the distal portion of the Guyon canal (also of the hand, thumb, index finger, and middle finger. In lesions at the
referred to as the pisohamate hiatus) results in selective involvement axilla, there is additional weakness of the triceps, and the sensory loss
of the deep motor branch, with interossei weakness and atrophy and may extend into the extensor surface of the forearm and lateral half of
complete or relative sparing of the hypothenar muscles as well as sen- the arm and over to the triceps owing to involvement of the posterior
sation (Katirji and Dokko, 1996). cutaneous nerve of the forearm and the lower lateral cutaneous and
The diagnosis is confirmed by EDX studies, often by demonstrating posterior cutaneous nerve of the arm.
low amplitude (with or without prolonged distal motor latencies) to The EDX studies are essential in confirming the site and extent of
the first dorsal interosseous or abductor digiti minimi muscles or both, the lesion, excluding other causes of wrist drop, and estimating sever-
along with denervation of the ulnar-innervated hand muscles that ity and prognosis. Low-amplitude or absent radial SNAP is common
parallels the clinical manifestations. Ulnar SNAP may or may not be except when the pathology at the spiral groove is purely demyelinating.
abnormal. These EDX studies are also important in excluding an ulnar Conduction block across the spiral groove is seen in segmental demye-
neuropathy at the elbow. Several features on the EDX examination are linating lesions, or the radial motor responses are low in amplitude in
inconsistent with an ulnar neuropathy at the wrist: low amplitude or axon-loss lesions. Mixed lesions are also common. Needle EMG reveals
absent dorsal ulnar SNAP, focal slowing or conduction block across denervation of all finger and wrist extensors, as well as the extensor carpi
the elbow, or denervation of the flexor carpi ulnaris or the flexor digi- radialis and the brachioradialis. The triceps and anconeus are spared in
torum profundus (ulnar portion). midarm lesions and denervated in axillary lesions. Ultrasonography is a
Plain radiograph of the wrist may reveal a fracture of the pisiform useful additional tool to electrodiagnosis for diagnosing radial neurop-
or hook of the hamate bone. Neuromuscular ultrasound or MRI is athy across the spiral groove. Enlarged radial nerve as determined by
extremely helpful and may demonstrate a structural lesion such as a CSA above at 5.75 mm2 is a highly specific finding (Song et al., 2018).
ganglion cyst. Sources of occupational or recreational trauma should As with other peripheral nerve lesions, the prognosis depends on
be eliminated. In patients with fractures, ganglia, or mass lesions, sur- the primary pathology. Radial nerve lesions due to demyelinative con-
gical intervention is necessary. The prognosis is usually good after sur- duction block, such as in most cases of Saturday-night palsy, usually
gical decompression with effective reinnervation. improve in 6–8 weeks. Axon-loss lesions such as those often associated
with humeral fracture, however, have a less favorable prognosis, with a the two muscles it innervates—the biceps brachii and brachialis. It
protracted course and often incomplete recovery. then terminates as a sensory nerve, the lateral antebrachial cutaneous
Posterior interosseous neuropathy. Lesions of the PIN are nerve, which innervates the lateral forearm to the base of thumb. This
uncommon and usually occur in association with trauma, fracture, nerve may be damaged with shoulder dislocations, following general
soft-tissue masses (e.g., lipomas, gangliomas), or exuberant synovium anesthesia, or with vigorous exercise such as weight lifting or repet-
motor neuropathy (i.e., rheumatoid arthritis). Occasionally, a PIN itive movements such as occur in carpet carriers, where the nerve is
lesion, in isolation or in combination with other single nerves is a repeatedly compressed by carrying carpets on the shoulder while held
manifestation of neuralgic amyotrophy, with acute arm pain followed in place by the arm (Sander et al., 1997). The musculocutaneous nerve
within a few days by weakness (Van Eijk et al., 2015). The clinical may also be involved in neuralgic amyotrophy (Parsonage-Turner syn-
manifestations of a PIN lesion are dropped fingers and inability to drome; Van Eijk et al., 2015). The differential diagnosis includes C5 or
extend them at the metacarpophalangeal joints. Radial deviation of the C6 radiculopathy, upper trunk or lateral cord brachial plexopathy, and
wrist on wrist extension is often pathognomonic and is due to weakness rupture of the biceps tendon.
of the extensor carpi ulnaris muscle with sparing of the extensor carpi Clinically, patients with musculocutaneous mononeuropathy pres-
radialis muscle, the latter innervated by the main trunk of the radial ent with weakness and atrophy of the biceps brachii and brachialis
nerve. EMG study confirms the diagnosis by demonstrating normal muscles, diminished biceps brachii reflex, and sensory loss over the
radial SNAP and denervation of the muscles supplied by the PIN, with lateral aspect of the forearm anteriorly. Nerve conduction studies show
sparing of more proximal radial-innervated muscles including the reduced musculocutaneous CMAP amplitude recording the biceps
brachioradialis, extensor carpi radialis, and triceps muscles. muscle and a low-amplitude or absent lateral antebrachial cutaneous
In rheumatoid arthritis, local injection of corticosteroids may be sensory response. Needle EMG demonstrates denervation limited to
helpful. If the syndrome is progressive, surgical exploration, includ- the biceps brachii and brachialis muscles, often sparing the coracobra-
ing synovectomy or decompression of the PIN, may become necessary chialis muscle.
(Shergill et al., 2001). Spontaneous recovery is the rule. Local corticosteroid injection
Radial tunnel syndrome. Patients with persistent tennis elbow may provide some relief of pain. Surgical decompression is contem-
(lateral epicondylitis) are sometimes given a diagnosis of radial tunnel plated if no improvement occurs.
syndrome, an extremely rare and highly controversial entrapment
of the radial nerve or its posterior interosseous branch within the Suprascapular Nerve
radial tunnel (Rosenbaum, 1999). The nerve appears most vulnerable The suprascapular nerve is a pure motor branch of the upper trunk
to entrapment at the level of the supinator muscle. These patients of the brachial plexus with innervation from the C5 and C6 roots. It
present with forearm pain and tenderness at the lateral epicondyle and then passes through the suprascapular notch, covered by the transverse
slightly distally into the forearm, with no associated muscle weakness scapular ligament, to innervate the supraspinatus muscle. It wraps
or sensory loss in the radial or PIN distribution. Pain is induced by around the spinoglenoid notch of the scapular spine and innervates the
extension of the middle finger or supination with the elbow extended. infraspinatus muscle. Entrapment at the suprascapular notch occurs
The EMG study, including radial nerve conduction studies recording after repetitive forward traction of the shoulders—a condition seen
the extensor digitorum communis and extensor indicis proprius, is in certain athletes, especially volleyball players. This nerve also may
almost always normal. Local steroid injection may temporarily relieve be involved in a restricted form of neuralgic amyotrophy (Parsonage-
symptoms. In patients with persistent pain, surgical division of the Turner syndrome, Van Eijk et al., 2015). Diffuse aching pain in the
supinator muscle has been advocated, with variable results. posterior aspect of the shoulder exacerbated by overhead activities is
Superficial radial sensory neuropathy (cheiralgia paresthetica). a cardinal symptom. The pain has an articular characteristic because
Cheiralgia paresthetica is a mononeuropathy of the superficial dorsal the acromioclavicular joint and surrounding structures are innervated
sensory branch of the radial nerve. It occurs as a result of trauma by the suprascapular nerve. Atrophy and weakness are confined to
from tight wristbands or handcuffs, or may result from intravenous the infraspinatus and supraspinatus muscles. Slow and steady abduc-
cannulation, fracture of the wrist, or wrist surgery (e.g., plating of forearm tion of the arm starting from a vertical position alongside the chest is
bones after fracture). The use of one-way (only tighten) ratcheting not possible with a severe lesion of the suprascapular nerve. Tendon
mechanism of handcuffs increases the risk of cheiralgia paresthetica ruptures of the rotator cuff have to be considered in the differential
(Grant and Cook, 2000). In up to 50% of nontraumatic cases, it is also diagnosis. EMG shows denervation restricted to the supraspinatus and
associated with de Quervain tenosynovitis, an inflammatory condition infraspinatus muscles. Local corticosteroid injection may give tempo-
of thumb extensor muscles, predominantly extensor pollicis brevis rary relief of pain, although surgery is sometimes required (Antoniou
(Lanzetta and Foucher, 1995). In de Quervain tenosynovitis, there is et al., 2001). In entrapment at the spinoglenoid notch, pain is usually
tenderness of the anatomical snuffbox and thumb extensor tendons absent, and there is atrophy, weakness, and denervation of the infra-
with forced ulnar deviation while holding the thumb wrapped in the spinatus muscle only.
palm (Finkelstien sign). Paresthesias and pain in the distribution of the
superficial sensory branch of the radial nerve characterize this benign Intercostobrachial Nerve
self-limiting condition. A small area of hypoesthesia in the dorsoradial The intercostobrachial nerve is a cutaneous sensory nerve derived
aspect of the hand is frequently identified. Nerve conduction study from the second and third thoracic nerve roots. It supplies the skin
often shows a low-amplitude or absent dorsal radial SNAP with normal on the medial surface of the upper arm and axilla, as well as the adja-
needle EMG including all radial innervated muscles. cent chest wall. It may be injured in a modified radical mastectomy
and other surgical procedures involving the axilla and lateral pectoral
Musculocutaneous Nerve region (Wallace et al., 1996).
The musculocutaneous nerve arises from the lateral cord of the bra-
chial plexus, with fibers originating from the C5 and C6 roots via the Double Crush Syndrome
upper trunk. The nerve innervates and penetrates the coracobrachialis When a sizable cohort of patients with EDX evidence of distal
muscle and courses down the anterior aspect of the upper arm between upper-limb entrapment neuropathies was found to have either
electrophysiological or radiological and clinical evidence of cervical during coma, anesthesia, or prolonged sitting on a hard surface (“toilet
radiculopathy, Upton and McComas proposed that focal compres- seat palsy”). Either or both divisions of the nerve may be compressed
sion of single nerve fibers proximally might so alter axoplasmic trans- by a Baker cyst in the popliteal fossa.
port as to render the distal nerve more susceptible to symptomatic A complete sciatic nerve lesion results in weakness of knee flexors
entrapment neuropathy (Upton and McComas, 1973). They termed and all muscles below the knee, as well as sensory loss of the entire
this the double crush syndrome. Although the concept of double crush foot and leg below the knee except for a region supplied by the saphe-
syndrome has since been invoked in a wide variety of entrapment nous nerve over the medial leg. The fibular division is more commonly
neuropathies, often as an explanation for failure or dissatisfaction involved than the tibial in proximal lesions of the sciatic nerve. Partial
with decompressive surgeries of the neck or limb or as a rationale sciatic nerve lesions often affect the fibular nerve more than the tibial
to decompress a nerve in multiple proximal-to-distal sites along its nerve and may mimic a more distal common fibular neuropathy. This
course, this phenomenon is of uncertain validity (Kane et al., 2015; is explained by the fewer fascicles with limited supportive tissue within
Wilbourn and Gilliatt, 1997). the fibular nerve, which is also taut and secured at the sciatic notch
and fibular neck. In such patients, evidence of denervation in the short
Mononeuropathies of the Lower Extremities head of the biceps femoris and tibialis posterior muscles and abnormal
Entrapment neuropathies of lower limbs are shown in Table 106.5. sural or medial plantar SNAPs help localize partial proximal sciatic
nerve lesions (Yuen and So, 1999). Occasionally, the common fibular
Sciatic Nerve nerve gets injured selectively (Katirji and Wilbourn, 1994). Young age,
Applied anatomy. The sciatic nerve is formed from nerve roots lack of severe initial weakness, and recordable distal motor or sensory
L4 through S3 and is composed of two distinct nerves, the common responses are predictors of favorable outcome (Cherian and Li, 2019;
peroneal (renamed the fibular nerve by the Federative Committee on Yuen and So, 1999).
Anatomical Terminology [FCAT], owing to confusion between the Piriformis syndrome. On rare occasions, the piriformis muscle
terms peroneal and perineal) and tibial nerves, which share a common may entrap the sciatic nerve trunk as it passes through or over the
sheath from the pelvis to the popliteal fossa. Usually the sciatic nerve piriformis muscle. Since the term was coined in 1947 by Robinson,
emerges from the pelvis by passing beneath the piriformis muscle, the piriformis syndrome has been subject to controversy (Fishman and
but sometimes the fibular division only passes through or above the Schaeffer, 2003; Stewart, 2003). The syndrome fell out of fashion with
piriformis muscle. The sciatic nerve innervates all the hamstring the advancement of radiological techniques (myelography, CT, MRI)
muscles via the tibial nerve except the short head of the biceps femoris, that often demonstrate that most patients with sciatica have nerve root
which is innervated by the common fibular nerve. The common fibular compression and occasionally lesions of the sacral plexus or sciatic
and tibial nerves separate completely in the upper popliteal fossa or nerve at other locations.
slightly above. The typical patient with piriformis syndrome has a history of
Sciatic neuropathy at the sciatic notch. The sciatic nerve is buttock trauma and experiences maximal buttock pain during pro-
occasionally vulnerable to entrapment as it crosses over the sciatic longed sitting (e.g., driving, biking), bending at the waist, or activity
notch leaving the pelvis. Most sciatic nerve lesions are complications that requires hip adduction and internal rotation (e.g., cross-country
of hip replacement surgery (Cherian and Li, 2019; Plewnia et al., skiing) (Kirschner et al., 2009). The neurological and EDX examina-
1999). Traumatic lesions include bullet and stab wounds, fractures, tions are usually normal. A bedside test maneuver in which the hip is
dislocations, hematomas in the posterior thigh compartment, and placed passively in adduction, internal rotation, and flexion of the hip
misplaced intramuscular injections. Recurrent sciatic mononeuropathy (AIF maneuver) may reproduce the pain and is considered diagnostic.
may be caused by endometriosis involving the nerve at the sciatic notch. Imaging is usually normal but occasionally shows hypertrophy of the
Direct compression of the sciatic nerve is rare but occasionally occurs piriformis muscle or abnormal vessels or bands in the region of the
TABLE 106.5 Entrapment/Compressive Neuropathies of Lower Limbs

Nerve Site of Compression Predisposing Factors Major Clinical Features
Sciatic Sciatic notch Endometriosis, intramuscular injections Pain down thigh, flail foot, absent ankle jerk
Hip Fracture, dislocations Pain down thigh, flail foot, absent ankle jerk
Piriformis muscle Remote fall on buttock Pain on sitting only, no weakness
Popliteal fossa Popliteal Baker cyst Normal hamstrings
Fibular (Peroneal) Fibular neck Weight loss, leg crossing, squatting, intraop- Foot drop, weak ankle eversion, sensory loss in
erative compression, intraneural ganglion dorsum of foot
Anterior compartment Muscle edema Severe pain. foot drop
Tibial Medial malleolus (tarsal tunnel Ankle fracture, tenosynovitis, high heel Sensory loss over sole of foot, Tinel sign at
syndrome) shoes flexor retinaculum
Femoral Inguinal ligament Lithotomy position Weak knee extension, absent knee jerk
Pelvis Intraoperative compression (retractor) Weak hip flexion and knee extension, absent
knee jerk
Lateral femoral cutaneous Inguinal ligament (meralgia paresthet- Weight gain, diabetes, pregnancy, tight Sensory loss in lateral thigh
ica) clothing, utility belts
Ilioinguinal Abdominal wall Trauma, surgical incision Direct hernia, sensory loss in the iliac crest,
crural area
Obturator Obturator canal Tumor, surgery, pelvic fracture Sensory loss in medial thigh, weak hip
adduction
piriformis muscle. MR neurography may show sciatic nerve hyperin- A common fibular nerve lesion leads to weakness of foot and
tensity at the sciatic notch, a more specific sign of nerve entrapment toe extension and foot eversion, with a foot drop and steppage gait.
(Filler et al., 2005). Treatment consists of exercises that include pro- Sensory impairment is found over the lateral aspect of the lower two-
longed stretching of the piriformis muscle by flexion, adduction, and thirds of the leg and the dorsum of the foot. Foot eversion and sensory
internal rotation of the hip. CT- or MRI-guided corticosteroid injec- loss may be spared (except for the first web space of the foot) when the
tion into the piriformis muscle may alleviate the symptoms; a posi- lesion is selective, involving the deep fibular nerve. Pain is rare except
tive response is used as a confirmatory test. Surgical sectioning of the with intraneural ganglia.
piriformis muscle is indicated in cases resistant to conservative ther- Fibular mononeuropathy is most often confused with other causes
apy. Although good outcome is expected in carefully selected patients of unilateral foot drop, including L5 radiculopathy, sciatic nerve
(Filler et al., 2005), severe postoperative sciatic nerve injury was lesions (especially when predominantly affecting the common fibular
recently reported as a serious complication (Justice et al., 2012). nerve), and lumbosacral plexopathy (particularly when involving the
lumbosacral trunk). A fibular nerve lesion must be differentiated from
Common Fibular (Peroneal) Nerve anterior tibial compartment syndrome, in which the deep fibular nerve
Applied anatomy. As noted earlier, the confusing similarity is compressed by muscle swelling within the anterior compartment
between peroneal and perineal led FCAT to rename the peroneal secondary to injury, heavy exercise, trauma, or ischemia. This results
nerve the fibular nerve. Soon after the sciatic nerve divides close to in an acute syndrome of severe lower leg pain, swelling, and weakness
the popliteal fossa, the common fibular nerve gives off the lateral of foot and toe extensors. The anterior tibial compartment must be
cutaneous nerve of the calf, which innervates the skin over the upper decompressed rapidly by fasciotomy to prevent irreversible nerve and
third of the lateral aspect of the leg, and the fibular communicating muscle damage.
nerve which joins the sural nerve. The common fibular nerve then EDX studies are useful for localizing lesions and may provide clues
winds around the fibular neck and passes through the origin of the to the underlying cause and a guide to prognosis. Although it is often
peroneus longus muscle (“fibular tunnel”). Near that point, the possible by nerve conduction studies to demonstrate focal conduction
common fibular nerve divides into its terminal branches, the deep block across the fibular head, contrary to common belief, the most fre-
and superficial fibular nerves. The deep fibular nerve traverses the quent pathophysiological process is axonal loss, regardless of the cause
lateral and then anterior leg compartments and innervates the tibialis (Katirji and Wilbourn, 1988). Axon-loss lesions reveal diffusely low
anterior, extensor hallucis longus, peroneus tertius, and extensor or absent fibular motor and sensory amplitudes. In contrast to ulnar
digitorum longus. It then divides close to the ankle joint to innervate lesions across the elbow and CTS, localized slowing in the region of the
the extensor digitorum brevis and the skin of the web space between fibular head is not common. Needle EMG demonstrates denervation
the first and second toes. The superficial fibular nerve innervates the in common fibular-innervated muscles but not in the short head of the
peroneus longus and brevis and the skin of the lower two-thirds of biceps femoris (innervated by the common fibular division of the sci-
the lateral aspect of the leg and the dorsum of the foot (except for the atic nerve in the thigh), in the L5 nerve root-innervated muscles, such
first web space). An accessory deep fibular nerve, seen in up to 28% as the tibialis posterior, flexor digitorum longus, tensor fascia lata and
of individuals, arises from the superficial fibular nerve, passes behind gluteus medius, or the low lumbar paraspinal muscles.
the lateral malleolus, and innervates the lateral part of the extensor Ultrasound and MRI are effective in visualizing intraneural ganglia
digitorum brevis. and other soft-tissue masses or tumors. Ultrasound is slightly more
Common fibular (peroneal) neuropathy at the fibular neck. accurate than MRI in compressive fibular neuropathies (Bignotti
Compression of the common fibular nerve is the most frequent et al., 2017). It shows thickened fibular nerve (cross-sectional area >8
compressive neuropathy in the lower extremity. This nerve is mm2) in about 70% of patients (Visser et al., 2013), and establishes
particularly vulnerable to direct pressure in the region of the fibular involvement of the anterior fascicles (corresponding to fibers for the
neck as it passes through the origin of the peroneus longus muscle. deep fibular nerve) in the majority of compressive fibular neuropathies
Intraoperative compression due to improper positioning or padding (Bignotti et al., 2016).
during anesthesia is the leading cause of acute common fibular The prognosis is uniformly good in cases of acute demyelinating
neuropathy at the fibular neck (Katirji and Wilbourn, 1988). Weight lesions, whereas recovery is delayed in those with axonal lesions and
loss, habitual leg crossing, or unrecognized pressure on the nerve in stretch injuries. The distal fibular motor amplitude recording tibialis
hospitalized critically ill, debilitated, or unconscious patients may also anterior serves as an accurate estimate of the extent of axonal loss and
be responsible for this nerve injury (Aprile et al., 2005; Katirji, 1999). a good prognostic indicator of foot drop. Hence, fibular nerve stud-
Devices that may compress the fibular nerve include casts, orthoses, ies should be performed bilaterally and compared. Bracing with a
pneumatic compression, antithrombotic stockings, bandages, and custom-made plastic ankle-foot orthosis is necessary to improve the
straps. Fibular nerve stretch injury may result from an acute forceful gait in the presence of severe foot drop. The few patients who do not
foot inversion or prolonged squatting (strawberry pickers palsy). Blunt improve spontaneously after 3 months, or those who have pain or a
trauma (e.g., post fibular fracture, knee dislocation) and open injury slowly progressive fibular nerve lesion, may require MRI studies and
(e.g., lacerations) account for a significant number of cases. Postpartum surgical exploration (Kim and Kline, 1996).
peroneal neuropathy may be due to stirrups compression, prolonged
squatting, or direct hand compression. Fibular nerve injury is also a Tibial Nerve
known complication of knee surgery, including arthroscopic surgery Applied anatomy. The tibial nerve innervates all the hamstring
and lateral meniscus repair. Up to half of patients without a clear cause muscles except the short head of the biceps femoris. It then separates
of fibular mononeuropathy across the fibular head have intraneural from the common fibular nerve, usually in the upper popliteal fossa, and
ganglia (Young et al., 2009). These are formed when disruption of the gives off the sural sensory nerve, which is often joined by a branch from
capsule of the superior tibiofibular joint results in dissection of synovial the common fibular nerve, the sural communicating nerve, to innervate
fluid along the articular branch of the fibular nerve into the tibialis the skin over the lateral aspect of the lower leg and foot, including the
anterior motor branch (Hebert-Blouin et al., 2010). Other mass lesions little toe. In the upper calf, the tibial nerve passes underneath the soleus
such as osteochondromas or schwannomas are much less common. muscle and innervates the gastrocnemius, soleus, tibialis posterior,
flexor digitorum profundus, and flexor hallucis longus. At the ankle, procedures, the femoral nerve becomes compressed between the lateral
the tibial nerve passes under the laciniate ligament, which covers the blade of the retractor and the pelvic wall. Risk factors include the use of
tarsal tunnel through which the nerve passes together with the tendons self-retaining retractors, a thin body habitus, and transverse abdominal
of the tibialis posterior, flexor digitorum longus, and flexor hallucis incision (Chan and Manetta, 2002). Acute retroperitoneal hematoma
longus muscles and the tibial artery and veins. is often iatrogenic following anticoagulant therapy, pelvic operations,
Tarsal tunnel syndrome. Entrapment of the tibial nerve occurs or femoral vessel catheterization such as for cardiac catheterization. At
behind and immediately below the medial malleolus. Burning pain is the inguinal ligament, the femoral nerve may become kinked during
experienced in the toes and the sole of the foot. If the calcaneal sensory lithotomy positioning, particularly when the leg is held in extreme hip
branches are involved, pain and numbness also involve the heel. flexion and external rotation, used during vaginal delivery, vaginal
Examination usually reveals plantar sensory impairment and wasting of hysterectomy, prostatectomy, and laparoscopy. Total hip replacement,
the intrinsic foot muscles. Percussion at the site of nerve compression or particularly surgical revisions and complicated reconstructions, may
eversion of the foot often elicit pain and paresthesias. EDX study results result in femoral nerve injury.
should confirm entrapment of the tibial nerve at the tarsal tunnel by Femoral nerve injury due to spontaneous retroperitoneal hema-
demonstrating slowing of motor fibers to the abductor hallucis and/or toma may occur in hemophiliacs, patients with blood dyscrasias, or
abductor digiti minimi muscles, as well as involvement of the medial following a ruptured abdominal aortic aneurysm. Pelvic lymphade-
and/or lateral plantar mixed potentials fibers, with sparing of the sural nopathy, primary malignancy of the colon or rectum, and neurofi-
nerve sensory action potential. Unfortunately, medial and/or lateral bromas or schwannomas are rare causes of femoral neuropathies. Hip
plantar mixed (or sensory) potentials are technically very difficult hyperextension, such as in dancers or during Yoga exercise, may also
and may be unelicitable in normal subjects with plantar calluses, foot cause a femoral stretch injury.
edema, previous surgical procedures in the foot, or in adults over the Femoral nerve lesions manifest with acute thigh weakness and
age of 45. Needle EMG shows denervation of the abductor hallucis anterior thigh and medial leg numbness. Thigh weakness often leads
and/or abductor digiti minimi muscles and normal S1-innervated and to falls. Pain is usually absent except in cases due to retroperitoneal
proximal muscles such as the gastrocnemius, soleus, biceps femoris, hematomas. On examination, there is weakness of knee extension,
and gluteus maximus muscles. The majority of suspected cases of tarsal with absent or depressed knee jerk. Thigh adduction is normal. Hip
tunnel syndrome, particularly when symptoms are bilateral, turn out flexion is usually weak when the lesion is within the pelvis, although it
to have generalized peripheral neuropathy, S1 radiculopathy, or non- may be difficult to assess hip flexion in the setting of severe quadriceps
neurological foot pain such as plantar fasciitis, stress fracture, arthritis, weakness.
or bursitis. Ultrasound plays an important role in identifying the cause Needle EMG reveals denervation of the quadriceps muscle. The ili-
(Samarawickrama et al., 2016). This is particularly useful in elderly or acus muscle is often normal in inguinal lesions but shows denervation
patients with foot edema, calluses, or previous surgery as EDX studies in femoral nerve lesions in the pelvis. Needle EMG of the thigh adduc-
may be difficult to perform or interpret. tor muscles, innervated by the L2, L3, L4 roots via the obturator nerve,
Local injection with corticosteroids underneath the laciniate liga- helps distinguish femoral nerve lesions from upper lumbar radiculop-
ment may temporarily relieve symptoms. Surgical decompression is athy or plexopathy. Nerve conduction studies have prognostic value,
needed for permanent results in those rare cases in which objective since the amplitude and area of the femoral CMAP is a very good
evidence of this syndrome exists. quantitative measure of motor axonal loss (Kuntzer et al., 1997). CT
or MRI of the pelvis are urgently indicated in patients with suspected
Sural Nerve retroperitoneal hematoma or pelvic mass lesion.
Although the vast majority of sural nerve lesions are iatrogenic as the Apart from patients with confirmed retroperitoneal hematoma
result of diagnostic sural nerve biopsy or sural nerve harvesting for who may require emergent drainage, most other femoral nerve lesions
nerve grafts, mononeuropathy of the sural nerve has been reported are treated conservatively. A knee or knee-ankle-foot orthosis is help-
with a number of other conditions including lower-limb vein-strip- ful for patients with unilateral severe weakness of the quadriceps and
ping surgery, ankle liposuction, Baker cyst or ankle joint surgery, local will assist in walking and prevent falls. Prevention of femoral nerve
trauma such as with tightly laced high-topped footwear such as ski injury is of paramount importance. The surgeon should limit hip
boots or ice skates, and rarely as the initial presentation of vasculitic flexion, abduction, and external rotation during lithotomy position-
mononeuritis multiplex (Li and Lederman, 2014; Stickler et al., 2006; ing, particularly when “candy cane” stirrups are used. The incidence
Thammongkolchai and Katirji, 2017). of femoral nerve lesions after pelvic and gynecological operations is
significantly reduced when self-retractors are avoided; the retracting
Femoral Nerve blades should also cradle the rectus muscle without compressing the
Applied anatomy. The femoral nerve is formed in the pelvis from psoas muscle (Chan and Manetta, 2002).
the posterior divisions of the ventral rami of L2, L3, and L4 spinal
roots, where it innervates the psoas muscle. It then passes within the Saphenous Nerve
iliacus compartment and innervates the iliacus muscle via a motor Saphenous nerve lesions may follow stripping of a long saphenous var-
branch that originates 4–5 cm before the nerve crosses underneath the icose vein, harvesting the vein for a coronary artery bypass, or surgical
inguinal ligament. In the anterior thigh, the femoral nerve innervates and arthroscopic operations on the knee. Entrapment of the saphe-
the quadriceps and sartorius muscles and the skin of the anterior thigh nous nerve is rare and may occur as it exits the subsartorial (adductor
and gives off the saphenous sensory nerve, which innervates the skin of or Hunter) canal or by pes anserine bursitis. Patients with saphenous
the medial surface of the knee and medial leg. mononeuropathy have sensory loss or hyperesthesia of the medial leg
Femoral nerve lesions. The majority of femoral nerve lesions that may extend into the medial arch of the foot.
are iatrogenic (Al-Hakim and Katirji, 1993). Pelvic lesions follow Saphenous nerve lesions should be differentiated from L4 radicu-
a variety of gastrointestinal, vascular, urological, or gynecological lopathy, lumbar plexopathy, and femoral mononeuropathy. In addi-
operations such as abdominal hysterectomy, radical prostatectomy, tion to the clinical examination, EDX studies can confirm that the
renal transplantation, and abdominal aortic repair. During these quadriceps, iliacus, and thigh adductors are normal in patients with
saphenous nerve lesions. Saphenous SNAP is often unilaterally absent to have hip-flexor weakness as a false localizing sign. Although this phe-
or low in amplitude, but this response is difficult to elicit, particularly nomenon may be explained by pain, it is more likely due to mechanical
in elderly or obese patients. Saphenous nerve lesions improve sponta- disadvantage of the hip flexors in the presence of weak thigh adduc-
neously with time; decompression underneath the subsartorial canal is tors. CT or MRI scanning of the pelvis is helpful in finding primary
occasionally performed. or metastatic pelvic tumors. EMG testing is essential for diagnosis by
detecting selective denervation of the thigh adductor muscles, with
Other Lower-Extremity Mononeuropathies normal quadriceps and iliacus muscles, thus excluding other causes of
Lateral femoral cutaneous nerve entrapment (meralgia hip weakness including femoral nerve lesions, upper lumbar (L2, L3,
paresthetica). The lateral femoral cutaneous nerve, which is a pure or L4) radiculopathy or plexopathy, and diabetic amyotrophy (diabetic
sensory nerve, passes medial to the anterior superior iliac spine under proximal neuropathy or radiculoplexopathy) (Sorenson et al., 2002).
the inguinal ligament to enter the thigh under the fascia lata that it This entrapment neuropathy is treated conservatively, which often
penetrates to supply the skin of the anterolateral part of the thigh. The provides good results, especially in those with acute onset of symp-
site of entrapment is usually at the level of the inguinal ligament. Rarely, toms. If such treatment fails or if symptoms progress to involve other
the nerve may be affected in its proximal segment by retroperitoneal nerves in the region, a careful search for occult pelvic or retroperito-
tumors or be injured during appendectomy. The disorder occurs in neal malignancy must be pursued.
about 4 per 10,000 individuals. It is most often seen in association
with obesity, diabetes, and advancing age (Parisi et al., 2011). It is a Migrant Sensory Neuritis of Wartenberg
common entrapment neuropathy during pregnancy, particularly the In this rarely reported but not uncommon condition, a pure and relaps-
third trimester, and usually recovers after delivery. It may occur with ing-remitting sensory mononeuritis multiplex is associated with loss of
ascites, or in other conditions that increase intraabdominal pressure. sensation and pain in the distribution of the affected nerves. The onset is
Direct compression by a belt, corset, beeper, or cellular phone; fracture usually sudden, and pain is precipitated by movements and (especially)
of the anterior portion of the ilium; or pelvic tilt causing undue stresses stretching of the affected limbs. Many different cutaneous nerves may
on the abdominal musculature are other causes. be involved. Commonly involved nerves include the superficial and
Patients develop numbness, painful burning, and itching over the deep peroneal sensory nerves, the median and ulnar digital nerves, the
anterolateral thigh. Pressure at the inguinal ligament medial to the femoral and saphenous nerves, and the radial sensory nerve (Nicolle
anterior superior iliac spine may elicit referred pain and dysesthesias. et al., 2001). Motor nerve fibers are not affected. Laboratory tests fail
Some patients report relief of pain when assuming a supine position. to detect any underlying cause, but on occasion a sural nerve biopsy
Lateral femoral cutaneous nerve SNAP is technically difficult to demonstrates inflammatory changes or a vasculitis, with patchy loss of
measure and may be absent in healthy subjects, particularly women and nerve fibers and evidence of axonal degeneration suggestive of an isch-
obese individuals. Asymmetrical low-amplitude or absent potential on emic process. Rarely, immunoglobulin (Ig) G deposits are also observed
the symptomatic side is a confirmatory finding. Electrophysiological around blood vessels. The pain and areas of sensory loss often recover
studies of the femoral nerve and quadriceps femoris and iliacus over weeks to months, but the improvement may be partial. Symptoms
muscles are normal, which helps exclude lumbar radiculopathy and may recur at the same or other sites. The discrete areas of sensory defi-
plexopathy. A local anesthetic nerve block may have diagnostic value cit and nerve irritation in several cutaneous nerves should indicate the
(Haim et al., 2006). Treatment consists of symptomatic measures such proper diagnosis. The differential diagnosis should always include con-
as rest, analgesics, and weight loss. Postural abnormalities should be ditions like DM, leprosy, vasculitis, sarcoidosis, sensory perineuritis,
corrected. Neurolysis is rarely beneficial. and rarely HNPP (Nicolle et al., 2001; Zifko and Hahn, 1997).
Ilioinguinal neuropathy. The ilioinguinal nerve is analogous to
an intercostal nerve. Muscle branches innervate the lower portion of Localized Perineurial Hypertrophic Mononeuropathy
the transverse abdominal and internal oblique muscles. The cutaneous A slowly progressive painless mononeuropathy that cannot be localized
sensory nerve supplies the skin over the inguinal ligament and the base of to entrapment sites and is caused by a focal fusiform enlargement of
the scrotum or labia. As the nerve takes a zigzag course, passing through the affected nerve, termed localized hypertrophic neuropathy or perineu-
the transverse abdominal and internal oblique muscles, it is subject to rioma, is an uncommon condition affecting young adults (Simmons
mechanical compression such as with a direct inguinal hernia. Trauma, et al., 1999). Although any nerve may be involved, it often occurs in
surgical procedures, scar tissue, and increased abdominal muscle tone the radial, posterior interosseous, tibial, and sciatic nerves. The fusi-
caused by abnormal posture are frequently responsible. Pain is referred form enlargement is mainly composed of “onion bulblike whorls”
to the groin, and weakness of the lower abdominal wall may result in formed by layers of perineurial cells. The lamellae of the whorls stain
the formation of an asymmetrical bulging of the lower abdominal wall. for epithelial membrane antigen. The cause of the perineurial cell pro-
Conservative treatment includes rest and NSAIDs. Neurolysis may liferation is unknown. It typically results in painless, slowly progressive
be required in refractory cases when a mechanical lesion is suspected. weakness and atrophy in the distribution of the affected nerve. Sensory
Obturator neuropathy. The obturator nerve is vulnerable to symptoms are minor, although sensory nerve fibers are obviously
entrapment as it passes through the obturator canal (e.g., by an involved. EDX study shows an axonal mononeuropathy and help in
obturator hernia or osteitis pubis). An obturator neuropathy is most the precise localization of the focal nerve lesion. MRI shows a focal
often associated with pelvic malignancies (prostate, cervical, or uterine enlargement of the affected nerve, increased signal on T2-weighted
cancers). It can also be seen with trauma and synovial cyst of the hip images, and enhancement with gadolinium.
or as a surgical complication, especially with extensive retroperitoneal Surgical exploration and a fascicular biopsy by a surgeon experi-
surgeries or laparoscopic pelvic lymphadenectomies and during total enced in peripheral nerve microsurgery may confirm the diagnosis and
hip replacement. exclude malignant peripheral nerve sheath tumors, which are difficult
Entrapment produces radiating pain from the groin down the inner to exclude without biopsy. Surgical resection of the involved nerve seg-
aspect of the thigh, often difficult to distinguish from the pain of a ment with graft repair has been proposed, but because of the benign
recent procedure or trauma. There is weakness of hip adduction and nature of the “tumor” and its very slow progression, the involved nerve
sensory impairment in the upper medial thigh. Many patients appear should be preserved if it has even partial function.
a great variability in clinical expression exists among affected kin in

HEREDITARY NEUROPATHIES
the dominant disorders, a recessive inheritance can only be accepted
The hereditary neuropathies constitute a complex heterogeneous group if the clinical and electrophysiological examinations of both parents
of diseases that usually share the clinical features of insidious onset and have proved to be normal. Even when the cause is nonparental, most
indolent course over years to decades. The number of hereditary dis- of these patients phenotypically resemble CMT1.
orders for which a metabolic or molecular defect is known is rapidly The majority of CMT neuropathies are demyelinating, although
increasing, allowing a more accurate classification. For those inherited up to one-third are primary axonal disorders. Clinical studies com-
neuropathies for which the underlying genetic abnormality has yet to bined with electrophysiological studies of a large number of families
be identified, the classification still depends on the clinical phenotype, allowed a simple separation of CMT into two main groups: (1) the
mode of inheritance, and class of neurons predominantly affected. demyelinating form, or CMT1 (sometimes known as hereditary motor
Major advances in understanding the molecular basis of inherited and sensory neuropathy [HMSN-I]), in which there are marked reduc-
neuropathies have come from identifying chromosomal loci or caus- tions in motor NCVs and nerve biopsy findings of demyelination and
ative genes for a given disease phenotype, leading to identification of onion bulb formation; and (2) the axonal form, or CMT2 (HMSN-II),
an ever-increasing number of genes coding for a specific gene prod- in which motor NCVs are normal or near normal, and nerve biopsy
uct essential to myelin or axonal function (Bassam, 2014; Berger et al., reveals axonal loss without prominent demyelination (Harding, 1995).
2002; Fridman and Reilly, 2015; Kamholz et al., 2000; Scherer, 2006). A more severe phenotype of severe demyelinating polyneuropathy with
Hereditary neuropathies are common disorders, accounting for onset occurring in early childhood and very slow conduction velocities
nearly 40% of chronic polyneuropathies, and as many as 50% of previ- (<10 m/sec in forearm) is referred to as Dejerine-Sottas disease (DSD).
ously unidentified peripheral polyneuropathies. Their inherited nature DSD, formerly CMT3, may no longer be a useful designation because
may go unrecognized in a surprisingly large percentage of patients it is genetically heterogeneous, caused by different structural myelin
(Klein, 2007). Eliciting historical evidence of long-standing neuro- protein and transcription factor gene mutations. A CMT phenotype
muscular symptoms; obtaining detailed family histories; looking for without sensory involvement on either clinical or electrophysiologi-
skeletal abnormalities such as hammer toes, high arches, or scoliosis; cal examination has been classified as hereditary motor neuropathy or
performing neurological and electrophysiological evaluations in rela- hereditary distal spinal muscular atrophy.
tives of patients; and, more importantly, testing for confirmed genes More recent discoveries and phenotype-genotype correlations have
are essential in identifying a previously unsuspected inherited neurop- identified patients with CMT and intermediate conduction velocities
athy. Because of the paucity of positive symptoms, patients may not with X-linked inheritance (CMTX), thus revising the electrophysio-
volunteer information about their own or relatives’ conditions. For logical classification of patients with suspected CMT. These are now
example, paresthesias are spontaneously reported three times more divided into at least four groups based on forearm (ulnar or median)
commonly in acquired than in inherited neuropathies. Even in the face motor conduction velocities: Group 1 are patients with velocities ranging
of a truly negative family history, the possibility of an inherited neu- from 15 to 35 m/sec, with the majority diagnosed as CMT1 (mostly
ropathy cannot be dismissed. Such a situation may arise in cases of CMT1A); Group 2 are patients with normal or near-normal veloc-
early death of one or both parents, few blood relatives, or autosomal ities (>45 m/sec), with most patients diagnosed as CMT2; Group 3
recessive (AR) disease. Also, available diagnostic deoxyribonucleic acid are patients with intermediate velocities (35–45 m/sec), diagnosed
(DNA) testing has shown that about a third of isolated cases of inher- as CMTX, but also sometimes CMT1; and Group 4 are patients with
ited neuropathies may arise from de novo gene mutations (Boerkoel extremely slow velocities (<15 m/sec), many presenting in early child-
et al., 2002). It is advisable to consider the possibility of an inherited hood as DSD phenotype and others presenting in adolescence or early
neuropathy in any patient with a chronic polyneuropathy that remains adulthood as CMT1 phenotype.
cryptogenic or refractory to treatment. The classification of CMT remains fluid and continues to change
as experts alter and revise these designations based on new molecu-
Charcot-Marie-Tooth Disease (Hereditary Motor and lar findings. The classification of CMT subtypes based on alphabet
Sensory Neuropathy) has become unwieldy as the number of genes and mutations have
The syndrome of peroneal muscular atrophy, or CMT disease, was increased steadily; most neurologists, including specialists in neuro-
first described in 1886 by Charcot and Marie in Paris and Tooth in muscular medicine and neurogenetics, do not memorize this nomen-
London (Charcot and Marie, 1886; Tooth, 1886). CMT disease is the clature. In addition, recent studies have confirmed that the same gene
most common inherited neuropathy, with an estimated prevalence of defect may manifest as different phenotypes. For example, mutations
1 per 2500 individuals (Martyn and Hughes, 1997). in MPZ causes AD demyelinating CMT1B as well AD axonal varieties
Major advances have been made in recent years in the molecular (CMT2I/J). A recent proposal is to abandon the cumbersome numer-
genetics of CMT disease (Bennett and Chance, 2001; Berger et al., ical designation of CMT subtypes and precisely identify the disorder
2002; Kamholz et al., 2000). Mutations in more than 80 genes cause by using the mode of inheritance (AD, AR, X), electrophysiological
CMT (Inherited Neuropathy Variant Browser: http://hihg.med.miami. hallmark (De, Ax, In), and name of the gene (Magy et al., 2018; Mathis
edu/neuropathybrowser). These mutations in CMT affect proteins et al., 2015). For example CMT1A would be named as AD-CMTDe-
involved in Schwann cell membrane structure (PMP22, MPZ, Cx32) PMP22dup (i.e., AD CMT, demyelinating due to PMP22 duplication).
mitochondrial movement (MFN2), signal transduction (GDAP1), cell Similarly, CMT2A would be AD-CMTAx-MFN2 (AD CMT, axo-
cycle (MTMR2), cytoskeleton (NEFL, INF2, gigaxonin), transcription nal due to MFN2 mutation) and CMTX would be XL-CMTIn-GJB1
factors (EGR2), and protein degradation (LITAF/SIMPLE). (X-linked CMT, intermediate due to GJB1 mutation).
CMT may be classified by mode of inheritance (autosomal domi-
nant [AD], X-linked [XL], and AR), electrophysiological studies, chro- Charcot-Marie-Tooth Disease Type 1
mosomal locus, or causative genes (Table 106.6). CMT1 and the vast In CMT1, symptoms often begin during the first or second decade of
majority of subtypes of CMT2 display AD inheritance. A minority of life. It is characterized by slowly progressive weakness, muscular wast-
cases occur sporadically or in siblings only and have therefore been ing, and sensory impairment predominantly involving the distal legs.
attributed to AR inheritance or to de novo gene mutations. Because Foot deformities and difficulties in running or walking resulting from
TABLE 106.6 Molecular Genetic Classification of Charcot-Marie-Tooth Disease and Related

Disorders.
Disorder Locus Gene Mechanism Testing Available
CMT1
CMT1A 17p11.2 PMP22 Duplication > pm Yes
CMT1B 1q22-q23 MPZ Pm Yes
CMT1C 16p13.1 LITAF Pm Yes
CMT1D 10q21 EGR2 Pm Yes
CMT1E 17p11.2 PMP22 Pm Yes
CMT1F 8p21 NEFL Pm Yes
CMTX
CMTX1 Xq13.1 GJB1 (Cx32) Pm Yes
CMTX4 Xq24 AIFM1 Pm Yes
CMTX5 Xq22.3 PRPS1 Pm Yes
CMTX6 Xq22.11 PDK3 Pm Yes
CMT2
CMT2A2 1p36.22 MFN2 Pm Yes
CMT2A1 1p36.22 KIFBβ Pm —
CMT2B 3q21.3 RAB7 Pm Yes
CMT2B1 1q22 LMNA Pm Yes
CMT2B2 19q13.33 MED25 Pm Yes
CMT2C 12q24 TRPV4 Pm Yes
CMT2D 7p15 GARS Pm Yes
CMT2E 8p21 NEFL Pm Yes
CMT2F 7q11-21 HSPB1 Pm Yes
CMT2I 1q23.3 MPZ Pm Yes
CMT2J 1q23.3 MPZ Pm Yes
CMT2K 8q21.11 GDAP1 Pm Yes
HNPP
HNPP 17p11.2 PMP22 Deletion > pm Yes
DSD Phenotype
DSD-A 17p11.2 PMP22 Pm Yes
DSD-B 1q22-q23 MPZ Pm Yes
DSD-C 10q21-q22 EGR2 Pm Yes
AR CMT (CMT4)
CMT4A 8q21 GDAP1 Pm Yes
CMT4B1 11q22 MTMR2 Pm —
CMT4B2 11p15.4 SBF2 Pm Yes
CMT4C 5q23-q33 SH3TC2 Pm Yes
CMT4D 8q24 NDRG1 Pm Yes
CMT4E 10q21-q22 EGR2 Pm Yes
CMT4F 19q13 Periaxin Pm Yes
CMT4G 10q23 HK1 Pm —
CMT4H 12q11.1-q13.11 FGD4 Pm —
CMT4J 6q21 FIGURE4 Pm Yes
AIFM1, Apoptosis-inducing factor, mitochondria-associated, 1; AR, autosomal recessive; CMT, Charcot-Marie-Tooth disease; CMTX, X-linked CMT;
Cx32, connexin-32; DSD, Dejerine-Sottas disease; EGR2, early growth response 2 gene; FGD4, FYVE, RhoGEF, and PH domain-containing protein
4; FIGURE4, factor-induced gene 4 protein (polyphosphoinositide phosphatase); GARS, glycyl tRNA synthetase; GDAP1, ganglioside-induced dif-
ferentiation-associated protein 1; HK1, hexokinase 1; HNPP, hereditary neuropathy with liability to pressure palsies; HSPB1, HSPB8, heat shock
proteins; KIF1Bβ, microtube motor KIF1Bβ; LITAF, lipopolysaccharide-induced tumor necrosis factor-α factor; LMNA, Lamin A/C; Med25, Mediator
complex subunit 25; MFN2, Mitofusin 2; MPZ, myelin protein zero gene; MTMR2, myotubularin-related protein 2; NDRG1, N-myc downstream reg-
ulated gene 1; NEFL, neurofilament light chain gene; PDK3, pyruvate dehydrogenase kinase, isoenzyme 3; pm, point mutations; PMP22, peripheral
myelin protein-22; PRPS1, phosphoribosylpyrophosphate synthetase 1; RAB7, RAS associated protein 7; SH3TC2, SH3 domain and tetratricopeptide
repeats-containing protein 2.
Fig. 106.8 Leg atrophy, pes cavus, and enlarged great auricular nerve (arrow) are evident in a patient with
Charcot-Marie-Tooth type 1 disease.
symmetrical weakness and wasting in the intrinsic foot, peroneal, and Uniform conduction slowing is often used to differentiate CMT1 from
anterior tibial muscles are often present. In two-thirds of patients, the acquired demyelinating neuropathies. Uniform slowing along the entire
upper limbs are involved later in life. Inspection reveals pes cavus and length of nerves and among neighboring nerves suggests an inherited
hammer toes in nearly 75% of adult patients, mild kyphosis in approx- myelinopathy affecting conduction in all nerves and nerve segments in
imately 10%, and palpably enlarged hypertrophic peripheral nerves the upper extremities or lower extremities to the same degree. In con-
in 25% of patients (Fig. 106.8). The foot deformities occur because trast, acquired demyelinating neuropathies result in multifocal or non-
of long-term muscular weakness and imbalance between the intrin- uniform conduction slowing together with excessive temporal dispersions
sic extensor and long extensor muscles of the feet and toes (a similar and conduction blocks. Uniform conduction slowing is found in CMT1A
process causes clawing of the fingers in more advanced cases). Absent with PMP22 duplication or point mutations; CMT1B with MPZ point
ankle reflexes are universal and frequently associated with absent or mutations; DSD phenotype, including PMP22, MPZ, and EGR2 gene
reduced knee and upper limb reflexes. Some degree of distal sensory mutations; as well as metachromatic leukodystrophy (MLD); Cockayne
impairment (diminished vibration sense and light touch in the feet disease; and globoid cell (Krabbe) leukodystrophy (Lewis et al., 2000).
and hands) is usually discovered by examination but rarely gives rise Neuromuscular ultrasound in adults and children with CMT1 displays
to positive sensory symptoms. Occasionally, patients have an essential significantly larger nerve CSA compared with control (Zaidman et al.,
or postural upper-limb tremor. Such cases have been referred to as 2013). Nerve enlargement is commonly diffuse and more pronounced
Roussy-Lévy syndrome, but current evidence suggests that this is not a than in acquired demyelinating polyneuropathies (such as CIDP and
separate clinical or genetic entity. MMN), where the enlargement is often regional. In children with CMT1A,
Severity of neuropathy in affected family members varies consider- the CSA correlates with neurological disability and the expected increase
ably. Approximately 10% of patients with slowed NCVs may remain in nerve CSA with age is disproportionately greater in CMT1A, suggesting
asymptomatic. In women with CMT1, the disease may exacerbate ongoing nerve hypertrophy throughout childhood (Yiu et al., 2015).
during pregnancy. Such worsening is temporary in about a third of Routine hematological and biochemical studies are normal. CSF
patients but becomes progressive in the remainder. Slow deterioration is also normal, which helps differentiate the condition from chronic
in strength and decline in axonal function continues throughout adult- inflammatory demyelinating polyneuropathy (CIDP), in which the CSF
hood, although much of this deterioration likely represents the effects protein is usually elevated. Sural nerve biopsy typically shows the changes
of aging superimposed on decreased reserves (Verhamme et al., 2009). of a hypertrophic neuropathy, characterized by onion bulb formation,
SNAPs are usually absent with surface recordings. Motor nerve increased frequency of fibers with demyelinated and remyelinated seg-
conduction studies show uniform slowing to less than 75% of the ments, an increase in endoneurial area, and loss of large myelinated fibers
lower limits of normal in all nerves. Motor conduction velocities of (Fig. 106.9). Gene mutations, predominantly affecting genes for myelin
upper-limb nerves prove more useful than studies of lower-extremity and Schwann cell proteins, have been recognized that account for more
nerves because distal denervation in the feet is often severe and some- than three-quarters of families with CMT1 (Fig. 106.10). CMT1A is the
times complete. A motor conduction velocity below 35 m/sec in the most common CMT subtype, accounting for 70%–80% of CMT1 cases
forearm segment of the median or ulnar nerves is a proposed cutoff and more than 50% of all CMT cases. The disease is caused by duplica-
value to distinguish CMT1 from CMT2 and CMTX. Although this tion of a 01.5-Mb fragment in the short arm of chromosome 17p11.2-12
cutoff is useful, it can be misleading if applied too rigidly. The conduc- harboring peripheral myelin protein 22 (PMP22). Rarely, the disease is
tion slowing evolves over the first 5 years of age and does not change caused by PMP22 point mutation. PMP22 is a membrane glycoprotein
appreciably afterward. Neurological deficits correlate with reductions found in the compact portion of the peripheral myelin sheath. The pre-
in CMAP and SNAP amplitudes rather than conduction velocity, indi- cise function of PMP22 in normal nerve remains unknown. Deletion
cating that clinical weakness results from loss of axons. of the same 1.5-megabase region on chromosome 17p11.2 results in a
EGR2
LITAF
NCV
decreased Node of Myelin NCV
Ranvier normal
CMT1
HNPP
CMTX Axon CMT2
DSD
CMT4 KIF1B
Cx32
NF-L
Basal PMP22 P0 Periaxin
MPZ
lamina
A C
B P0 PMP22 Cx32
Fig. 106.10 A, Charcot-Marie-Tooth disease (CMT) and related disor-
ders: CMT1, CMT with X-linked inheritance (CMTX), hereditary neurop-
athy with liability to pressure palsies (HNPP), Dejerine-Sottas disease
(DSD), and most of CMT4 are inherited disorders of myelin. CMT2 is a
primary axonal disorder. Alterations in dosage of peripheral myelin pro-
tein 22 (PMP22) gene account for the majority of patients with CMT1A
and HNPP. B, Point mutations of these genes (connexin-32 [Cx32],
myelin protein zero [MPZ, P0], PMP22, EGR2, periaxin) result in CMTX,
CMT1B, CMT1A, DSD, and CMT4. Mutations of the LITAF gene result
in CMT1C. C, Point mutations of the KIF1B and NF-L genes and spe-
cific MPZ missense mutations result in CMT2. NCV, Nerve conduction
B velocity. (Adapted with permission from Lupski, J.R., 1998. Molecular
Fig. 106.9 Charcot-Marie-Tooth Type 1 Disease. A, Semi-thin trans- genetics of peripheral neuropathies. In: Martin, J.D. (Ed.), Molecular
verse section of sural nerve showing numerous onion bulbs. (Toluidine Neurology. Scientific American, New York. All rights reserved.)
blue; bar = 20 μm.) B, Electron micrograph of an onion bulb forma-
tion; two small myelinated fibers are surrounded by multiple layers of
Schwann cell processes. (Bar = 0.5 μm.) chromosome 16p13-12 expressed on Schwann cells. This gene encodes
a lysosomal protein that may play a role in protein degradation path-
ways (Street et al., 2003). Affected individuals in these families mani-
single copy of the normal PMP22 gene, a finding observed in 85% of fest characteristic CMT1 symptoms.
patients with HNPP. The CMT1A duplication or HNPP deletion is CMT1D is mapped to chromosome 10q21-q22 and is due to
caused by reciprocal recombination events that occur in male germ cell mutation of the early growth response 2 gene (EGR2) which encodes
meiosis. The PMP22 duplication or deletion can be detected in blood a zinc-finger transcription factor expressed in myelinating Schwann
samples using pulse-field electrophoresis followed by hybridization with cells that regulates the expression of myelin proteins including PMP22,
specific CMT1A duplication junction fragments or cytogenetic testing P0, Cx32, and periaxin (Kamholz et al., 2000). EGR2 gene missense
with a PMP22 probe by fluorescence in situ hybridization. mutations have also been reported in patients with DSD, or congen-
CMT1B is clinically indistinguishable from CMT1A but it only ital hypomyelination neuropathy (Timmerman et al., 1999; Warner
accounts for 4% to 5% of CMT1 cases. It is caused by mutations in the et al., 1998). Respiratory compromise and cranial nerve dysfunction
myelin protein zero (P0; gene symbol, MPZ) gene, mapped to chromo- are commonly associated with EGR2 mutations (Szigeti et al., 2007).
some 1q22-23. MPZ is the major peripheral myelin glycoprotein and Other rare CMT1 subtypes include CMT1E and CMT1F.
is thought to function as an adhesion molecule in the formation and
compaction of peripheral myelin. It is a member of the immunoglobulin Charcot-Marie-Tooth Disease Type 2
superfamily, with distinct extracellular transmembrane and intracellular CMT2 constitutes about one-third of all AD CMT disease. It is associ-
domains. Mutations in the gene encoding for MPZ have also been asso- ated with mutations in genes affecting intracellular processes such as
ciated with DSD, and congenital hypomyelination neuropathy. Different axonal transport, membrane trafficking, and translation (see Chapter
MPZ mutations result in divergent morphological effects on myelin 48). Clinical symptoms begin later than in CMT1, most commonly in
sheaths, consisting of uncompacting of myelin or focal myelin foldings the second decade, but may be delayed until middle age or beyond.
(Gabreëls-Festen et al., 1996). Motor conduction block was reported Foot and spinal deformities tend to be less prominent than in CMT1.
rarely in CMT1B patients with specific MPZ mutations (Street et al., The clinical features closely resemble those of CMT1 but differ in
2002). Specific MPZ missense mutations have also been reported with a that peripheral nerves are not enlarged, and upper limb involvement,
CMT2 phenotype, showing only mild slowing of NCVs (Marrosu et al., tremor, and diffuse areflexia occur less frequently. However, in indi-
1998). The Thr124 Met mutations in the MPZ gene have been detected vidual cases, it is often impossible to determine the type of CMT dis-
in several families with a distinct CMT2 phenotype (CMT2J) character- ease on the basis of clinical manifestation alone. Approximately 20% of
ized by late onset, marked sensory loss, and sometimes deafness, chronic affected individuals are asymptomatic.
cough, and pupillary abnormalities (De Jonghe et al., 1999). CMT2A is the most common CMT2 subtype and accounts for
CMT1C is caused by a mutation in lipopolysaccharide-induced 30% of CMT2 cases (see Table 106.6). CMT2A2, which is responsi-
tumor necrosis factor-alpha (LITAF/SIMPLE) gene, mapped to ble for most CMT2 families, shares clinical features of weakness and
atrophy with other CMT variants, but has an earlier onset and is more channels that facilitate transfer of ions and small molecules between
severe, often resulting in earlier disability and wheelchair dependence. Schwann cells and axons. More than 200 different mutations in Cx32
It may also be associated with optic atrophy. It is caused by muta- have been identified in CMTX1 families. Genotype-phenotype correla-
tions in the mitofusin 2 (MFN2) gene, with a locus on chromosome tions among patients with Cx32 mutations suggest that most missense
1p36.22. MFN2 protein is a mitochondrial fusion protein ubiquitously mutations result in a mild clinical phenotype, whereas nonsense and
expressed in many tissues including peripheral nerves. CMT2A1, frameshift mutations produce more severe phenotypes (Ionasescu et al.,
linked to chromosome 1p36.22, is caused by a mutation in kinesin pro- 1996a).
tein involved in axonal transport of synaptic vesicles (Saito et al., 1997; Cx32 is expressed in Schwann cells and oligodendrocytes, regions of
Zhao et al., 2001). In CMT2B, which is linked to chromosome 3q13- noncompact myelin (incisures and paranodes), as well as other non-neu-
22, there is prominent sensory loss with foot ulcerations (De Jonghe ral cells. Some mutations of Cx32 have been reported to be associated
et al., 1997). A mutation in the RAB7 gene, which encodes a small with central nervous system (CNS) involvement with white-matter
guanosine triphosphatase (GTPase) late endosomal protein, has been MRI and MR spectroscopy abnormalities, abnormal brainstem auditory
found to be causative (Verhoeven et al., 2003). This form of CMT is evoked potentials, and deafness (Murru et al., 2006). An interesting phe-
clinically very similar to hereditary sensory neuropathy type 1 (HSN1) nomenon of transient and acute ataxia, dysarthria, and weakness occur-
but lacks spontaneous lancinating pain. CMT2B1 and CMT2B2 are ring after visiting high altitudes and associated with CNS white-matter
AR disorders, caused by mutation in the lamin A/C gene on chromo- MRI abnormalities has been described in patients with two mutations:
some 1q22, and mediator of RNA polymerase II transcription, subunit R142W and C168Y (Paulson et al., 2002). This suggests that CMTX1
25 gene (MED25) on chromosome 19q13.33, respectively. Another patients should be cautioned about travel to high-altitude locations. It
distinct subgroup of severely affected patients, designated CMT2C has been proposed that Cx32 mutations may cause these abnormalities
(mapped to chromosome 12q24), develop vocal cord, intercostal, by reducing the number of functional gap junctions between oligoden-
and diaphragmatic muscle weakness (Klein et al., 2003). Because of drocytes and astrocytes, making them more susceptible to changes in
respiratory failure, the life expectancy of these patients is shortened. intercellular ions and small-molecule exchange that occur in situations
CMT2D, mapped to chromosome 7p14, is characterized by weakness of metabolic stress (e.g., high altitude or physical activity).
and atrophy that is more severe in the hands than in the feet (Ionasescu Men with CMTX1 show significant slowing in NCV, and brainstem
et al., 1996b). In CMT2E, some patients within the same kindred and auditory evoked responses are often abnormal. A picture of both axo-
with an otherwise typical CMT2 phenotype may exhibit slowed motor nal loss and demyelination is revealed on nerve biopsy. There is debate
nerve conduction that is much below the forearm cutoff value of 38 m/ as to whether CMTX1 should be classified as a primary axonal or
sec and a more severe clinical phenotype. This form of CMT is caused demyelinating disorder (Birouk et al., 1998). However, careful studies
by mutations in genes that encode neurofilament light (NEFL) sub- of individual patients suggest nonuniform conduction slowing consis-
unit, and patients may have axonal swelling (giant axons) and signif- tent with demyelination (Gutierrez et al., 2000; Lewis, 2000). NCVs in
icant secondary demyelination on sural nerve biopsies (Fabrizi et al., males with CMTX1 with Cx32 mutations are often slow, usually in the
2006; Jordanova et al., 2003). CMT2F, caused by mutations in small intermediate, slowing between 35 and 45 m/sec. Conduction slowing
heat shock protein 27 (Hsp27), is characterized by later onset (35–60 in heterozygous women may be subtle and frequently is in the range
years), mild sensory impairment, and moderate to severely slowed found in patients with axonal polyneuropathies leading to a suspected
NCVs of lower limbs but normal or mildly reduced velocities in the diagnosis of CMT2. The absence of male-to-male transmission on fam-
upper limbs. Mutation in Hsp27 may impair formation of the stable ily history, the presence of mild to intermediate conduction velocities
neurofilament network that is essential for the maintenance of periph- (>42 m/sec) in female carriers, and delayed brainstem auditory evoked
eral nerves. CMT2G has the same gene locus as CMT4H (see later dis- response latencies in affected men is highly suggestive of CMTX1 and
cussion on type 4 disease) on chromosome 12q12-q13.3, with the age Cx32 mutations (Nicholson et al., 1998). Much less common X-linked
onset from 9 to 76 years. CMT2I and CMT2J are designated as CMT2 CMT subtypes have been described (see Table 106.6)
with MPZ (myelin protein zero) gene mutations. CMT2J is associated
with pupillary abnormalities (Adie pupil) and hearing loss. Dejerine-Sottas Disease (Charcot-Marie-Tooth Disease with
Motor NCV may be normal or mildly reduced. SNAPs are either Dejerine-Sottas Phenotype)
absent or reduced in amplitude. Sural nerve biopsy specimens show DSD, previously designated as CMT3, is an uncommon progressive
preferential loss of large myelinated fibers, without significant demy- hypertrophic neuropathy with onset in childhood. Although originally
elination; there may be clusters of regenerating myelinated fibers, a the disorder was thought to be AR, most cases are sporadic and in some
hallmark of axonal regeneration. instances have been shown to result from a de novo dominant muta-
tion. The majority of patients have mutations that are common in
X-Linked Charcot-Marie-Tooth Disease other types of CMT, including PMP22 duplication or point mutation,
X-linked Charcot-Marie-Tooth disease (CMTX) is phenotypically MPZ mutation, or EGR2 mutation.
similar to CMT1. CMTX1 is caused by many mutations in gap junc- Motor development is delayed; proximal weakness, global areflexia,
tion protein B1 (GJB1), the gene that encodes connexin 32 (Cx32), on enlarged peripheral nerves, and severe disability are the rule. Motor
chromosome Xq13.1. Affected male subjects tend to be more severely conduction velocities are markedly slowed, often to less than 10–15 m/
affected, and females with the gene mutation are asymptomatic or may sec in the forearms. Temporal dispersion and amplitude reduction on
have a mild neuropathy. CMTX1 should be considered in any patient proximal stimulation may be found in such cases, owing to high electrical
whose family history does not exhibit a male-to-male transmission. stimulation thresholds in hypertrophic nerves. CSF protein is frequently
CMTX1 accounts for 7%–16% of all forms of CMT, making it the sec- increased. Pathologically, pronounced onion bulb changes are associated
ond most common form of CMT (following CMT1A). with hypomyelination and loss of myelinated fibers. Defective myelination
The connexins are a family of highly related genes encoding a group is confirmed by an increased axon-to-fiber diameter ratio. Cases of con-
of channel-forming proteins. Cx32 is a gap junction protein found in genital hypomyelination neuropathy probably represent a variant of DSD
noncompacted paranodal loops and Schmidt-Lanterman incisures of at the far end of a spectrum of defective myelination. DSD is genetically
Schwann cell cytoplasm, which is encoded by a four-exon gene located heterogeneous and is caused by different structural myelin protein and
on chromosome Xq. As a gap junction protein, Cx32 forms small transcription factor gene mutations (see Chapter 48).
TABLE 106.7 Selected Charcot-Marie-Tooth Phenotypes and Molecular Diagnostic Testing

Test CMT1 HNPP CMTX CMT2 DSD/CHN
PMP22 dup/del FISH X, duplication X, deletion — — X, duplication
DNA sequencing:
Cx32 X X
PMP22 X X
MPZ X X
EGR2 X
Periaxin X
NEFL X
CMT1, Charcot-Marie-Tooth disease type 1; CMTX, X-linked CMT; Cx32, connexin-32, DSD/CHN, Dejerine-Sottas syndrome/congenital hypomyelin-
ation neuropathy; EGR2, early growth response 2 gene; FISH, fluorescence in situ hybridization; HNPP, hereditary neuropathy with liability to pres-
sure palsies; MPZ, myelin protein zero; NEFL, neurofilament light chain gene; PMP22 dup/del, peripheral myelin protein 22 duplication or deletion is
detected by pulse field gel electrophoresis or cytogenetic testing with FISH.
Charcot-Marie-Tooth Disease Type 4 and 45 m/sec. These forms have been classified separately as domi-
The majority of Charcot-Marie-Tooth disease type 4 (CMT4) patients nant intermediate CMT (DI-CMT) and include types A, B, C, and D.
have AR inheritance. They are less common, accounting for less than DI-CMTA maps to chromosome 10q24-25, but its gene defect has not
10% of all CMT cases. They are characterized by onset in early child- been discovered. DI-CMTB is caused by mutations in the dynamin
hood and progressive weakness leading to inability to walk in ado- 2 (DNM2) gene and maps to chromosome 19p12-13. This typically
lescence. Both demyelinating and axonal types have been identified presents as a classic mild to moderately severe CMT phenotype. Some
(Dubourg et al., 2006). Common to all the demyelinating subgroups families with this variety have developed neutropenia and early cata-
is a disturbance in normal myelination of the axons; clinical and elec- racts (Claeys et al., 2009). A mutation in tyrosyl-tRNA (transfer ribo-
trophysiological features are similar in several of these subtypes with nucleic acid) synthetase has been found to be the cause of DI-CMTC,
severe forms of CMT1 or DSD. Conduction velocities are slowed (20– which maps to chromosome 1p34-35 and typically displays a mild,
30 m/sec). CSF protein is normal. Nerve biopsy shows loss of myelin- very slowly progressive course (Jordanova et al., 2006). DI-CMTD
ated fibers, hypomyelination, and onion bulbs. maps to chromosome 1q22 MPZ gene mutations.
CMT4 consists of several subgroups (see Table 106.6). Each sub- A number of families with CMT exhibit additional features such as
group is rare and tends to be more common in certain inbred popula- optic atrophy, pigmentary retinal degeneration, deafness, and spastic
tions. CMT4A is the most common and accounts for 25%–30% of all paraparesis. Cardiac involvement is encountered in occasional patients,
AR cases. The disease has been mapped to chromosome 8q13 because but prospective family studies find no association between cardiomyopa-
of ganglioside-induced differentiation-associated protein 1 (GDAP1) thy and CMT disease. A syndrome of CIDP responding to prednisone and
mutations, the most common cause of CMT4, and may result in demy- immunosuppression has been reported in patients with inherited CMT
elinating as well as axonal phenotypes (Nelis et al., 2002). CMT4B1 is disease due to MPZ mutation (Watanabe et al., 2002), providing evidence
mapped to chromosome 11q21 caused by myotubularin-related pro- that nongenetic factors may play a role in clinical expression of the mutant
tein 2 (MTMR2) mutations, with findings of redundant loops of focally gene. It has been suggested that any patient with a hereditary neuropathy
folded myelin (Houlden et al., 2001b), while CMT4B2 is mapped to who suffers a recent rapid deterioration should be considered as having a
chromosome 11p15.4 caused by set-binding factor-2 gene (SBF2) secondary CIDP and be treated with immunosuppressants such as corti-
mutations. In both, irregular folding and redundancy of loops of costeroids or high-dose intravenous immunoglobulin (IVIG).
myelin are evident on nerve biopsies. Children affected with CMT4B2
also exhibit congenital glaucoma, leading to loss of vision. CMT4C, Practical Molecular Diagnostic Testing for Patients with
characterized by frequent and severe scoliosis, is linked to chromo- Charcot-Marie-Tooth Disease and Related Disorders
some 5q31-q33 and is caused by SH3TC2 gene mutation (Azzedine Molecular diagnostic testing should be considered in CMT and related
et al., 2006). CMT4D has onset in childhood but may progress into the peripheral neuropathies. Commercial reference laboratories can detect
fifth decade of life. It is associated with dysmorphic features and hear- point mutations or PMP22 duplication/deletion by DNA sequencing
ing loss. CMT4E is a form of congenital hypomyelinating neuropa- of PMP22, Cx32, MPZ, EGR2, periaxin, GDAP1, and NEFL, among
thy, often diagnosed as DSD, associated with mutations in PMP22 and others, in samples of peripheral blood (Table 107.7). It is, however,
ERG2 (early growth response) genes. The phenotypic presentation of advisable to use the clinical and EDX findings supplemented by a
CMT4F is also severe, similar to that for DSD phenotype, but the muta- detailed family history and plan a logical approach to obtaining DNA
tions occur in the periaxin gene, which produces a membrane-associ- studies. An all-inclusive “battery” of available genetic tests of CMT
ated protein solely expressed in myelinating Schwann cells. Periaxin disease is tempting but interpretation of results may be more difficult
is a cytoskeleton-associated protein that links the cytoskeleton of the because of frequent detection of genes with variants of unknown sig-
Schwann cell with the basal lamina, a necessary function to stabilize nificance. Population studies confirmed that CMT1A (PMP22 dupli-
the mature myelin sheath (Takashima et al., 2002). CMT4H is similar cation or PMP22 deletion), CMT1X (Cx32 mutation), CMT1B (MPZ
to CMT2G in terms of genetic locus but is more severe clinically, with mutation), and CMT2A (MFN2 mutation) account for about 65%–
an onset in early childhood and prominent nerve hypomyelination. 70% of all CMT cases (Bassam, 2014; Boerkoel et al., 2002).
• In families with at least two generations with the disease, known
Complex Forms of Charcot-Marie-Tooth Disease male-to-male transmission, and uniform conduction slowing
Some dominant forms of CMT have displayed features intermediate (<35 m/sec if forearm), CMT1A should be considered first and the
between CMT1 and CMT2, with conduction velocities between 35 PMP22 duplication test should be obtained.
• I f normal, PMP22 sequencing should be done. of isolated mononeuropathies, typically affecting, in order of decreasing
• If normal, CMT1B should be excluded by obtaining MPZ DNA frequency, the fibular nerve, ulnar nerve, brachial plexus, radial nerve,
sequencing. and median nerves. Painless brachial plexopathy is seen in up to a third
• Patients who have neither the PMP22 duplication nor male-to- of patients. Most HNPP patients experience the initial episode in the
male transmission should be screened for CMTX1 by looking for second or third decade of life. Attacks usually are provoked by minor
Cx32 mutations. compression, slight traction, or other trivial trauma. Most episodes are of
• For patients displaying an axonal pattern, the MFN2 mutation sudden onset, painless, and usually followed by complete recovery within
should be investigated first, as this is the most common type of days or weeks. Less-common presentations include transient position-
CMT2 (England et al., 2009a). ally induced sensory symptoms, progressive mononeuropathy, chronic
• Given the high spontaneous mutation rate, the diagnosis of CMT1A sensory polyneuropathy, mild CMT phenotype with pes cavus, and a dif-
should be considered even in the absence of a positive family his- fuse chronic sensorimotor neuropathy resembling CIDP (Mouton et al.,
tory. 1999). About 15% of mutation carriers remain asymptomatic.
• The PMP22 duplication test followed by DNA sequencing of Nerve conduction studies in patients with HNPP associated with
PMP22, MPZ, EGR2, and periaxin should be considered in child- PMP22 deletion typically demonstrate a characteristic pattern of
hood cases with severe demyelinating neuropathy suggestive of prolonged distal motor latencies with only mild slowing in forearm
DSD or congenital hypomyelination neuropathy. segments of median and ulnar nerves, focal slowing and conduction
• Because of the severe reactions to vincristine and other chemo- blocks of median, ulnar, and fibular nerves at compression sites, and
therapeutic neurotoxic drugs in CMT patients, before initiating diffuse reduction of SNAP amplitudes (Dubourg et al., 2000; Mouton
cancer chemotherapy it is best to rule out CMT1A in any patient et al., 1999). The median forearm motor NCV is typically above 38
with either unexplained chronic neuropathy or a family history of m/sec, but sensory studies demonstrate velocities in the demyelinat-
neuropathy (Graf et al., 1996). ing range and reduced or absent SNAPs. The sural SNAP is absent or
abnormal in more than 90% of patients, while the tibial motor nerve is
Treatment and Management slowed in about 60% of the patients. The most common focal entrap-
The rates of progression of CMT1 and CMT2 are slow, disability occurs ment neuropathy at compressive sites are the ulnar nerve at the elbow
relatively late, and lifespan may be normal. Management is mainly symp- and median nerve at the wrist, each occurring in more than three-
tomatic. Patients should be instructed in proper foot care and advised fourths of patients, followed by the fibular nerve at the fibular head,
to wear broad, well-fitting shoes. Insoles may be used to distribute body seen in one-third of the patients (Takahashi et al., 2017). Prolonged
weight more evenly in patients with a foot deformity. Ankle-foot braces median distal motor latencies and abnormal sensory conduction stud-
or orthopedic procedures are indicated to correct severe foot drop. ies are frequently found in asymptomatic carriers (Infante et al., 2001).
Patients should be warned to avoid neurotoxic drugs because of greater Sural nerve biopsy specimens demonstrate focal sausage-like thicken-
susceptibility to agents such as vincristine. Issues like genetic counseling, ings of myelin, termed tomacula (Fig. 106.11), segmental demyelination,
family planning, prenatal diagnosis, and psychological concerns must be and axonal loss. Linkage studies show a 1.5-megabase deletion of chro-
carefully approached, preferably by a multidisciplinary team including mosome 17p11.2-12 that includes the PMP22 gene and corresponds to
a genetic counselor. Recent studies suggest that CMT is associated with the duplicated region in CMT1A in 85% of affected patients with HNPP.
higher risk for complication during delivery (Hoff et al., 2005). Also, The remaining patients have a variety of mutations in PMP22 that lead
during pregnancy the symptoms of CMT may worsen. to frameshift or nonsense mutations causing functional changes in the
Despite astonishing advances in the molecular genetics of CMT, there protein (Lenssen et al., 1998; van de Wetering et al., 2002). Exactly how
is still no effective treatment available for any form of the disease. Rats the deletion of PMP22 causes HNPP remains unclear, though loss of
overexpressing PMP22 worsen with progesterone administration. This function of the PMP22 protein is the likely explanation for HNPP,
has led to proposed use of progesterone antagonists for CMT1A, though and a toxic gain of function in CMT1A (Katona et al., 2009; Li et al.,
potentially unacceptable side effects have prevented such trials. The same 2004). Molecular diagnosis of the 17p11.2 deletion has replaced nerve
animal model showed a convincing clinical and pathological improvement biopsy for the diagnosis of HNPP. Testing should be considered regard-
following administration of ascorbic acid (vitamin C), a known promoter less of family history in any patient presenting with painless multiple
of myelination. Though pharmacological treatment trials in CMT are rare, mononeuropathies, brachial plexopathy, or recurrent demyelinating
this discovery prompted a multicenter double-blind placebo-controlled neuropathy (Tyson et al., 1996). The primary treatment strategy in
study on the use of ascorbic acid at 1 or 3 g/day in CMT1A. Ascorbic acid HNPP is to prevent nerve injury by avoiding pressure damage.
was found to be well tolerated, but no significant benefit was demonstrated
in the CMT neuropathy score at 12 months, concluding vitamin C does Hereditary Neuralgic Amyotrophy
not improve the course of CMT1A in adults or children (Gess et al., 2015; Recurrent brachial plexopathy, often preceded by severe ipsilateral limb
Micallef et al., 2009). The possibly beneficial role of neurotrophins, par- pain, is the hallmark of hereditary neuralgic amyotrophy, an AD disorder.
ticularly neurotrophin 3 (NT3), in CMT1A and nerve regeneration has Most patients recover over weeks to a few months, with accumulating
recently been demonstrated in a small pilot study (Sahenk et al., 2005). evidence of residual neurological deficit over time. Patients also have dys-
Treating cells with curcumin, derived from the curry spice turmeric, morphic features, including hypotelorism, epicanthal folds, microstomia,
releases the MPZ mutants from the endoplasmic reticulum into the cyto- and dysmorphic ears. The disorder maps to chromosome 17q25 and is
plasm, thus reducing the number of apoptotic cells and becoming a poten- associated with mutations in the SEPT9 gene (Kuhlenbäumer et al., 2005).
tial treatment for CMT1B (Khajavi et al., 2005). Some CMT2 patients with Other hereditary neuropathies, including GAN, hereditary sensory
MPZ mutations may respond to corticosteroids (Donaghy et al., 2000). and autonomic neuropathy (HSAN), neuropathy associated with spi-
nocerebellar, primary erythromelalgia, familial amyloid polyneuropathy
Hereditary Neuropathy with Liability to Pressure Palsies (FAP), porphyric neuropathy, Fabry disease, leukodystrophies with neu-
HNPP is an AD disorder of peripheral nerves leading to increased suscep- ropathy, Refsum disease, Tangier disease, Bassen-Kornzweig syndrome,
tibility to mechanical traction or compression. It occurs with an estimated and mitochondrial cytopathies and polyneuropathy are discussed in the
prevalence of 16 per 100,000 population. Patients have recurrent episodes online version of this chapter, available at http://www.experconsult.com.
CHAPTER 106 Disorders of Peripheral Nerves 1880.e1
Giant Axonal Neuropathy features but without significant motor involvement (Verhoeven et al.,
GAN is a rare AR multisystemic neurodegenerative disorder of 2006). Currently these neuropathies are divided into five main groups
intermediate filaments affecting the peripheral and CNS. GAN based on the inheritance, clinical features, and type of sensory neurons
presents as a slowly progressive axonal sensorimotor neuropathy involved (eTable 106.8). Compared with CMT, HSANs are distinctly
in early childhood and leads to death by late adolescence. Most rare. Molecular genetic studies have identified seven disease-causing
affected children have tightly curled hair and distal leg weakness. gene mutations in these disorders. More genetic discoveries are likely
Some develop a peculiar gait disturbance with a tendency to walk forthcoming; a study of 100 patients with familial HSAN and isolated
on the inner edges of the feet With disease progression, evidence patients diagnosed with HSAN found that only 14% of the isolated
of CNS involvement occurs, including optic atrophy, nystag- cases and 31% of the familial cases were found to have mutations in the
mus, cerebellar ataxia, upper motor neuron signs and intellectual known causative genes (Rotthier et al., 2009). The pronounced sen-
decline, and abnormal visual, auditory, and somatosensory evoked sory loss in HSAN predisposes these patients to unnoticed recurrent
potentials. MRI of the brain demonstrates cerebellar and cere- trauma, leading to neuropathic (Charcot) joints, nonhealing ulcers,
bral white-matter abnormalities. Nerve conduction studies show infections, and osteomyelitis resulting in acral mutilations (acrodys-
reduced CMAP and SNAP amplitudes with normal to only slightly trophic neuropathy). These complications are preventable by careful
reduced conduction velocities. Sural nerve biopsy demonstrates the avoidance of trauma to the insensitive extremities.
pathognomonic changes of large focal axonal swellings that contain
densely packed disorganized neurofilaments (eFig. 106.12). Axonal Hereditary Sensory and Autonomic Neuropathy Type I
function and axoplasmic transport are impaired. The disease locus HSAN type I is an AD disorder and the most common hereditary sen-
was mapped to chromosome 16q24. GAN is caused by mutations sory neuropathy (Houlden et al., 2006). Symptoms begin in the sec-
of the GAN gene, which encodes a novel protein called gigaxonin ond to fourth decade with sensory loss and subsequent tissue injury
(Bomont et al., 2000; Kuhlenbäumer et al., 2002). Gigaxonin is a mainly affecting the feet and legs. Sensory loss initially affects pain and
ubiquitously expressed cytoskeletal protein and a member of the temperature perception more than touch-pressure sensation, but it
BTB/kelsch superfamily, which is involved in diverse cellular func- involves all modalities as the disease progresses. Autonomic involve-
tions and may be important in the cross-linking of intermediate ments are limited to hypohidrosis. Patients present with calluses on the
filaments (Herrmann and Griffin, 2002). soles, painless stress fractures of the feet, neuropathic foot and ankle
joints, and recurrent plantar ulcers. If ulcers are neglected and become
Hereditary Sensory and Autonomic Neuropathy infected, severe acromutilation may result (acrodystrophic neuropa-
HSANs are a clinically and genetically heterogeneous group of neurop- thy). Lancinating or shooting pains are often prominent and are con-
athies characterized by prominent sensory loss and variable autonomic sidered the hallmark feature of HSAN-I. Distal muscle weakness and
wasting are present in advanced cases. Such motor involvement, albeit
without the lancinating pain, may create diagnostic confusion with
CMT2B with dense sensory loss (linked to chromosome 3q13) or with
certain axonal MPZ gene mutations. Variable neural hearing loss or
rarely spastic paraparesis may be seen in HSAN-I. Some families pres-
ent with burning feet or neurogenic arthropathy, suggesting clinical as
well as genetic heterogeneity both within and between families with
HSAN-I (Dyck et al., 2000a; Houlden et al., 2006).
SNAP amplitudes are reduced late in the disease. Motor conduc-
tion velocities remain normal, but CMAP amplitudes are reduced
in advanced cases. Sural nerve biopsy confirms a severe loss of small
myelinated axons and, to a lesser degree, of unmyelinated and large
myelinated fibers (eFig. 106.13). Pathological evidence of regenerative
activity is usually minimal. HSAN-I has been mapped to chromosome
eFig. 16.12 Giant Axonal Neuropathy. Electron micrograph of a giant 9q22.1-22.3. Mutations in the SPTLC1 gene encoding a subunit of
axon filled with neurofilaments and with an attenuated myelin sheath. serine palmitoyltransferase are identified in 90% of patients (Dawkins
(Bar = 1 μm.) et al., 2001). These mutations result in increased de novo ceramide
eTABLE 106.8 Hereditary Sensory and Autonomic Neuropathies

Disease Inheritance Locus Gene Clinical Features
HSAN I (HSN I) AD 9q22 SPTLC1* Small > large MF sensory loss, distal weakness, onset in second to fourth
decade
HSAN II AR WNK1/HSN2 Pansensory loss in infancy
HSAN III (FD) AR 9q31 IKBKAP* Sensory loss, autonomic dysregulation, absent tears, fungiform tongue papillae
HSAN IV AR 1q21 NTRK1/NGF receptor Insensitivity to pain, anhidrosis at birth, mental retardation, nl SNAPs
HSAN V AR NGFB NTRK1/NGF Insensitivity to pain at birth, nl SNAPs, no mental disability, absent small MF
*Molecular gene testing is clinically available.
AD, Autosomal dominant; AR, autosomal recessive; FD, familial dysautonomia; HSAN, hereditary sensory and autonomic neuropathies; IKBKAP, the
protein encoded by IKBKAP gene is a member of the human elongator complex; MF, myelinated fibers; NGFB, nerve growth factor beta; nl SNAP,
normal sensory nerve action potential; NTRK1/NGF, NTRK1 encodes for the high-affinity NGF (nerve growth factor) receptor; SPTLC1, SPTLC1
encodes serine palmitoyltransferase long chain 1; WNK1/HSN2, HSN2 is a nervous system-specific exon of the with no lysine(K)-1 gene.
3000
II1 II1
2000
Control
1000
MF number/1 µm of diameter/mm2
4000
Control
3000
2000
UF number/mm2
1000
eFig. 106.13 Semi-thin transverse section of sural nerve from a patient 0 0
with hereditary sensory and autonomic neuropathy type I. Note loss of 0 4 8 12 0 0.5 1.0 1.5
large and small myelinated fibers. (Toluidine blue; bar = 50 μm.) 3000
II4 II4
synthesis. Since ceramide plays a role in the regulation of programmed

cell death, the neuronal degeneration in HSAN-I may be caused by
ceramide-induced apoptosis. Molecular genetic testing for HSAN-I is 2000
clinically available. Families without linkage to chromosome 9q22 have
Control
been described, suggesting genetic heterogeneity (Auer-Grumbach
et al., 2000). A subtype, HSAN-IB, is associated with paroxysmal
cough, cough syncope, and gastroesophageal reflux (Spring et al., 1000
2005). Additional features include hoarseness of voice and hearing 4000
3000 Control
deficit; motor involvement, acral mutilations and ulceration are usu-
ally absent. The association of cough and gastroesophageal reflux is 2000
1000
not unique to HSAN-IB, as it has also been associated with CMT2 with
0 0
MPZ mutation.
0 4 8 12 0 0.5 1.0 1.5
Myelinated fiber Unmyelinated fiber
Hereditary Sensory and Autonomic Neuropathy Type II diameter (µm) diameter (µm)
HSAN-II is recessively inherited and rarely begins later than infancy. eFig. 106.14 Sural nerve fiber size-frequency histograms of myelinated
fibers (MF; left) and unmyelinated fibers (UF; right) of two affected sib-
All sensory modalities of distal upper and lower limbs and, to a lesser
lings with hereditary sensory and autonomic neuropathy type II (green
extent, of trunk and face are affected. The hands, feet, lips, and tongue bars) and control nerve (white bars). In the patients, the number of
are at risk for mutilation because of generalized sensory loss and myelinated fibers was less than 500/mm2 and that of the unmyelinated
insensitivity to pain. Autonomic symptoms are minimal, and men- fibers less than 10,000/mm2.
tal development is normal. There is loss of tendon reflexes. Rarely,
associations with spastic paraplegia, retinitis pigmentosa, mild motor
weakness, or neurotrophic keratitis have been described. The clinical stimuli provoke episodic hypertension, profuse sweating, and marked
course is slowly progressive, with progressive axonal loss. SNAPs are skin blotching caused by defective autonomic control. Hypotonia in
absent. Sural nerve biopsy specimens show almost complete absence of infancy contributes to delayed motor milestones. Later in childhood,
myelinated fibers and reduced unmyelinated fiber populations (eFig. hyporeflexia, insensitivity to pain, gait ataxia, stunted growth, and
106.14). Mutations in the HSN2 nervous-system-specific exon of the scoliosis become apparent. Defective lacrimation (absence of overflow
with-no-lysine(K)-1 (WNK1) gene on chromosome 12q13.33 cause tears with crying), absence of fungiform papillae of the tongue giving it
HSAN-II (Shekarabi et al., 2008). All mutations result in a truncation a smooth appearance, and pupillary hypersensitivity to parasympath-
of the HSN2 protein, with the protein loss or inactivation (or both) omimetic agents are telltale signs. Patients with FD are susceptible to
causing the peripheral neuropathy. The exact function of HSN2 pro- periodic episodes of paroxysmal hypertension, tachycardia, excessive
tein remains unknown, but it may play a role in the development or sweating, and vomiting, often termed dysautonomic crises. These epi-
maintenance of sensory neurons or accompanying Schwann cells. sodes are caused by uncontrolled catecholamine releases and occur
in 40% of patients, usually in response to stress, either emotional or
physical. They are also at risk to develop profound hypoxemia and
Hereditary Sensory and Autonomic Neuropathy Type III tachypnea following anesthesia or with high-altitude travel as a result
(Familial Dysautonomia, Riley-Day Syndrome) of diminished respiratory response to hypercapnia and hypoxia. In
HSAN-III, or familial dysautonomia (FD) or Riley-Day syndrome, older patients, clinical manifestations of orthostatic hypotension may
is an AR inherited sensory neuropathy with prominent autonomic become apparent but because of adaptation of cerebrovascular auto-
manifestations particularly affecting children of Ashkenazi Jewish eth- regulation rarely lead to syncope. As affected children grow older, sex-
nicity. Symptoms begin at birth and include poor sucking, uncoordi- ual maturation is delayed, but normal pregnancies have occurred and
nated swallowing due to esophageal dysmotility, episodes of vomiting, male patients have fathered children.
recurrent pulmonary infections largely due to oropharyngeal incoor- The number of neurons in the sympathetic, parasympathetic, and
dination, attacks of fever, and cardiovascular instability. Emotional spinal ganglia is reduced. Peripheral blood vessels also demonstrate lack
of autonomic nerve terminals. A marked reduction in the density of ulcers develop, weight bearing should be discontinued until the ulcers
unmyelinated axons and small myelinated fibers is seen in sural nerve heal. Infusion of pamidronate, a bisphosphonate, has been suggested
biopsy specimens, even in the youngest patients. Recent studies have to be helpful in the management of Charcot neurogenic arthropathy.
confirmed that FD is a disorder of afferent nerve function, with relative Treatments for patients with AF are also limited, and mainly pre-
sparing of the efferent motor neurons. This is confirmed by selective ventive and symptomatic. They include managing dysphagia, protect-
failure of baroreceptor afferent reflex and impaired brainstem reflexes ing airway passages, prompt treatment of aspiration pneumonia, and
involving the trigeminal nerves (Gutierrez et al., 2015; Norcliffe- using nighttime noninvasive ventilation for apneas and hypercapnia.
Kaufmann et al., 2010). On tilt-table study, there is a significant drop At present, no specific treatment effectively delays the progression
in blood pressure and heart rate. Plasma norepinephrine and vasopres- of any of the HSANs. Clinical trials of compounds that slow the pro-
sin levels do not increase with head-up tilt (Norcliffe-Kaufmann et al., gression of FD by increasing levels of ELP-1 (IKAP) are in progress.
2010). Motor NCVs are generally normal, whereas SNAP amplitudes
are frequently reduced. Linkage studies have mapped the gene locus Neuropathy Associated with Spinocerebellar Ataxias
to chromosome 9q31-q33. The disease is caused by a point mutation Friedreich ataxia is an AR neurodegenerative disease characterized by
in the IKBKAP gene that affects the splicing of the elongator-1 pro- degeneration of large sensory neurons and spinocerebellar tracts, car-
tein (ELP-1, also known as IKAP), an essential protein of the human diomyopathy, and increased incidence of diabetes (see Chapter 96).
elongation complex. The major FD mutation is a splice mutation Even in the early stages of the disease, examination reveals lower-limb
that results in aberrant tissue-specific messenger (m) RNA splicing areflexia and impaired joint position and vibration sense, with pre-
(Slaugenhaupt and Gusella, 2002). The elongator complex is thought served pain and temperature sensation. Pes cavus and hammer toes
to be involved in the regulation of cell-surface transport of exocytosis, occur in approximately 90% of cases.
and its impairment results in the dysregulation of neural endocytosis. SNAPs are invariably reduced in amplitudes or absent. However,
FD is a potentially life-threatening disorder with a high mortality motor nerve conduction studies are normal or slightly reduced. A
rate due to aspiration pneumonia or autonomic crises. Improved sup- selective loss of large myelinated fibers occurs in the sural nerve.
portive treatment has extended the survival of patients into adulthood. Friedreich ataxia is the result of a large GAA triplet repeat expansion
There is a greater than 50% probability for infants with FD to reach 30 on chromosome 9q13-q21.1, leading to loss of frataxin expression (see
years of age (Gold-Von Simson and Axelrod, 2006). Chapter 96).
Peripheral nerve involvement in spinocerebellar ataxias (SCAs) is
Hereditary Sensory and Autonomic Neuropathy Type IV inconsistent. This is a mainly axonal sensorimotor peripheral polyneu-
HSAN-IV is a rare AR disorder characterized by congenital insensitiv- ropathy or pure sensory polyneuropathy. The prevalence of peripheral
ity to pain and thermal sensation as well as anhidrosis. This leads to neuropathy, based on nerve conduction studies, in SCA1, SCA2, and
repeated episodes of fever, thick and calloused skin, dystrophic nails, SCA3 ranges from 87% to 96% (Yadav et al., 2012). SCA4, SCA18, and
self-mutilating behavior, and mild mental retardation associated with SCA25 have also an associated peripheral polyneuropathy.
emotional lability and hyperactivity. Tendon reflexes, muscle strength,
and SNAPs are preserved, but sympathetic skin responses are absent. Primary Erythromelalgia
Biopsy of sensory nerves shows selective total or near-total loss of Inherited or primary erythromelalgia is a rare AD neuropathic con-
unmyelinated axons and small myelinated fibers. Confirmation of a dition with an incidence of 0.36–1.1 per 100,000 persons. The onset
neuropathic abnormality in cases of congenital indifference to pain of symptoms is often in the first decade of life. It is characterized by
without apparent neurological signs therefore depends on the mor- recurrent attacks of erythema and intense burning pain of the hands
phometric study of unmyelinated and myelinated fiber populations and feet in response to mild warmth or moderate exercise. To get
in nerve biopsy specimens, and is supported by quantitative sen- relief, patients often attempt to cool the affected areas. The most fre-
sory testing and lack of sweating by the QSART. Intradermal hista- quently affected areas are the feet, involved in 90%–100% of patients,
mine injection produces a wheal but no flare response. Skin biopsy followed by the hands in 25%–60%. The head and neck are rarely
has demonstrated a lack of intradermal nerve fibers and sweat glands involved, reported in 2%–15% of patients. These symptoms may
devoid of nerve fibers (Verzé et al., 2000). The gene locus for HSAN-IV lead to significant disability. Patients may function normally between
maps to chromosome 1q21-22. Mutations in the NTRK1 (formerly episodes.
trkA) gene encoding the tyrosine kinase receptor for nerve growth Sensory and motor nerve conduction studies are normal in all
factor (NGF) have been described in patients with HSAN-IV (Indo, patients, confirming the absence of large-fiber polyneuropathy.
2002). These findings indicate that the NGF-trkA system plays a crucial QSART and thermoregulatory sweat testing showed evidence of a
role in the development of unmyelinated nociceptive and sudomotor small-fiber neuropathy in about half of children (Cook-Norris et al.,
fibers. 2012). Mutations in the voltage-gated sodium channel Na(v)1.7,
Clinically similar cases with selective loss of only small myelinated encoded by the gene SCN9A, are responsible for this syndrome.
fibers have been designated HSAN type V. These patients do not have Na(v)1.7 is preferentially expressed in small dorsal-root ganglia neu-
mental retardation. Mutations in the NTRK1 gene have been found in rons. Gain-of-function mutations in Nav1.7 that enhance activation
some cases, suggesting that the two disorders may be allelic (Houlden and impair fast inactivation cause the sensation of pain (Choi et al.,
et al., 2001a). A related disorder with loss of deep pain perception 2006; Dib-Hajj et al., 2017; Han et al., 2012; Waxman, 2007). Other
but normal sweating has been linked to chromosome 1p13.2-p11.2, mutations in SCN9A that cause a loss of Na(v)1.7 function result in
encoding the NGFB gene (Minde et al., 2004). the opposing condition of “congenital inability to experience pain,”
emphasizing the importance of sodium channels in nociception (Cox
Treatment and Management et al., 2006). A third disorder has also been linked to Na(v)1.7: parox-
The prevention of stress fractures and plantar ulcers is of utmost impor- ysmal extreme pain disorder, which was formerly known as familial
tance in most patients with HSAN. This can be achieved by meticulous rectal pain syndrome (Fertleman et al., 2007). The linkage between pain
foot care, avoiding barefoot walking, daily inspection of feet and shoes, and temperature in erythromelalgia is in keeping with other diseases of
and proper skin care with moisturizing lotions. Whenever plantar sodium channels.
eTABLE 106.9 Familial Amyloid Neuropathies

Associated Organ
Type Aberrant Protein Decade of Onset Neuropathy Involvement
FAP I and II TTR Early onset: Third through fourth Length-dependent sensorimotor neu- Heart, eye
decade ropathy, life-threatening autonomic
Late onset: Sixth through eighth neuropathy, carpal tunnel syndrome
decade
FAP III Apolipoprotein A1 Third through fourth decade Sensorimotor neuropathy (not promi- Kidney, liver, gastrointesti-
nent) nal tract
FAP IV Gelsolin Third to fourth decade Cranial neuropathy Cornea (lattice dystrophy)
and skin (cutis laxa)
FAP, Familial amyloid polyneuropathy; TTR, transthyretin.
No treatment is consistently effective and has to be individualized. groups (Ando et al., 2005). The neuropathy begins insidiously in the
Sodium channel blockers such as lidocaine (gel, patch, or infusion), third and fourth decades with dissociated sensory impairment (loss
carbamazepine, and mexiletine are frequently used (Tang et al., 2015). of pain and thermal sense) in the lower extremities, often associated
Aspirin, tricyclic antidepressants (TCAs), and vasoactive drugs have with lancinating pain and paresthesias. Because of its similarity to other
been used with varying success. neuropathies, it may be difficult to diagnose this condition (Ikeda,
2007; Planté-Bordeneuve et al., 2007). Autonomic dysfunction com-
Familial Amyloid Polyneuropathy monly includes impotence, postural hypotension, bladder dysfunc-
FAP is a group of AD disorders characterized by the extracellular tion, distal anhidrosis, and abnormal pupils with scalloped margins.
deposition of amyloid proteins in peripheral nerves and other organs. Gastrointestinal symptoms characterized by constipation alternating
Amyloid is a fibrillar conformation of a protein characterized by (1) with diarrhea, delayed gastric emptying, and weight loss may be prom-
green birefringence of Congo red-stained sections viewed in polar- inent. Eventually panmodality sensory loss, distal wasting, weakness,
ized light, (2) the presence of nonbranched 10-nm amyloid fibrils and areflexia develop. Systemically, amyloid is deposited in the ocular
on electron microscopy, and (3) a β-pleated sheet structure on x-ray vitreous, heart, and kidneys. Cardiac manifestations include cardiac
diffraction. More than 20 different proteins are known to undergo hypertrophy, arrhythmias, ventricular blocks, or cardiomyopathy. The
conformational changes leading to the generation of amyloid depos- pattern of myocardial involvement varies according to specific TTR
its in tissues. These deposits may be widespread or restricted to cer- mutations. The disorder is relentlessly progressive. Untreated patients
tain organs (localized amyloidosis). The clinical presentation depends usually die, often of cardiac disease and less often from renal failure or
on the organs involved and the size of amyloid fibrils. In FAP, one of malnutrition 10–15 years after the onset (Coelho et al., 2018).
three aberrant proteins (transthyretin, apolipoprotein A1, or gelsolin EDX studies reveal a distal axonal neuropathy that affects sensory fibers
[Falk et al., 1997; Planté-Bordeneuve and Said, 2011]) may be found earlier and more prominently than motor fibers. Early changes include
in the peripheral nerves. The latter two are rare and restricted to a few low-amplitude or absent SNAPs, mild reduction in CMAP amplitudes,
families. In acquired primary systemic amyloidosis, polypeptides of and preserved motor conduction velocities. Evidence of denervation is
immunoglobulin light-chain origin are deposited in tissues as amy- found in distal leg muscles. Until specific biochemical and genetic stud-
loid, which leads to the term amyloid light (AL) amyloid (see Primary ies became available, the diagnosis was confirmed by the demonstration
Systemic Amyloidosis, later). of amyloid in tissue biopsy specimens. In early cases, sural nerve biopsy
The classification of FAP was traditionally based on clinical presen- specimens show a predominant loss of unmyelinated and small myelin-
tation. However, progress in understanding the protein composition ated fibers. Amyloid deposits of variable size are usually seen within the
and molecular genetics of these disorders justifies a different approach endoneurium or around vasa nervorum. Immunostaining with antibod-
(eTable 106.9). ies to TTR can identify the specific type of amyloid. Many but not all
mutations have evidence of myocardial infiltration on echocardiography.
Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP, The mechanisms of nerve fiber injury and their relationship to amyloid
Familial Amyloid Polyneuropathy Types I and II) deposits are incompletely understood. It has been proposed that the pref-
The majority of patients with FAP have mutations of the plasma pro- erential deposition of amyloid in sensory and autonomic ganglia inter-
tein TTR. This is a bifunctional transport protein for thyroxin and feres with or is toxic to neuronal function, leading to a length-dependent
retinol-binding protein. It is predominantly synthesized in the liver axonal degeneration. An alternative theory suggests that endoneurial
and choroid plexus and consists of a single polypeptide chain of 127 edema associated with amyloid deposition in blood vessels and the endo-
amino acid residues. The gene for TTR is located on chromosome neurium results in ischemic nerve fiber injury. However, this does not
18q11.2-q12.1. Most patients are heterozygous for TTR gene muta- explain the selective involvement of smaller nerve fibers.
tions (more than 90 described) that result in transcriptions of aberrant A more restricted form of the disease, referred to as FAP type II, has
proteins with predisposition toward amyloid formation and deposi- a later onset than FAP I in the sixth to eighth decade, may present with
tion in peripheral nerve, heart, kidney, eye, and (rarely) leptomeninges. CTS, and slowly progresses to peripheral polyneuropathy. Autonomic
TTR-FAP is rare, with endemic populations predominantly in manifestations are also less prominent. Vitreous opacities are common
Portugal, Sweden, Japan, and Brazil. TTR amyloidosis demonstrates two and cardiac involvement may develop. Surgical decompression of the
disparate clinical phenotypes. The original cases described by Andrade carpal tunnel provides symptomatic relief despite the fact the CTS is
in Portugal are referred to as FAP type I. Two other large foci of patients often more severe than in patients with idiopathic CTS. Demonstration
are found in Sweden and Japan. This is the most common form of FAP of amyloid infiltration of the flexor retinaculum obtained at surgery or
and has been observed in 30 different countries and in many ethnic in other tissues establishes the diagnosis.
More than 90 different amino acid substitutions of the TTR pro- any additional clinical characteristics of disease in a Nordic population
tein have been identified as causing the clinical TTR-FAP phenotypes. appeared to be of little value (Samuelsson et al., 2019).
Among these, substitution of valine by methionine at position 30 Initially, the diagnosis could be established by confirming the pres-
(Val30Met) is by far the most frequent; it is found in clusters in distinct ence of amyloid in nerve and muscle, rectal biopsies, a sample of sub-
areas of Portugal, Sweden, and Japan and accounts for 50% of muta- cutaneous abdominal fat, or any other tissues removed at the time of
tions worldwide. Other TTR variants, including isoleucine 33, alanine unrelated procedures. Sampling error, however, confounds these tests.
60, and tyrosine 77 substitutions, have similar features of generalized Nerve biopsies have shown 83% sensitivity, and salivary gland biopsies
polyneuropathy with varying degrees of autonomic involvement. A 67% (Planté-Bordeneuve et al., 2007). Immunostaining using specific
serine substitution at position 84 and histidine at position 58 are the antibodies against one of the three aberrant proteins may identify the
two TTR mutations seen most commonly in FAP-II. The age of onset responsible protein. In sporadic cases, the more common AL amyloi-
varies greatly with specific TTR mutations. Even in families with the dosis should be excluded by a search for clonal plasma cell dyscrasia
Val-30Met mutation, variation in age of onset is observed in different (see Primary Systemic Amyloidosis, later). If no evidence of plasma
geographic regions (Ikeda et al., 2002). Specific TTR mutations may cell dyscrasia exists, TTR can be identified by isoelectric focusing of the
produce unique phenotypes with predominantly cardiac or leptomen- serum, which separates variant and wild-type TTR.
ingeal amyloidosis (Hund et al., 2001). In highly suspected patients or after finding of a variant TTR in
tissue should prompt genetic testing. DNA isolated from periph-
Apolipoprotein A1 Amyloidosis (Familial Amyloid eral leukocytes or tissue can be amplified with the polymerase chain
Polyneuropathy Type III, Iowa, Van Allen) reaction (PCR) and specific oligonucleotide primers used to amplify
This is a rare form of familial amyloidosis, described first by Van Allen regions of the gene of interest, thereby demonstrating specific point
and colleagues in Iowa. The clinical manifestations of the type III variant mutations. DNA testing for the most common TTR mutations (Met-
have much in common with those of type I, except for a less promi- 30, lle-33, Ala-60, Tyr-77, and Ser-84) is available in reference labora-
nent length-dependent sensorimotor polyneuropathy and for early renal tories. A negative result, however, does not exclude a TTR mutation.
involvement and a high incidence of duodenal ulcers. Uremia is the most Mutation analysis of the entire TTR gene detects more than 99% of
common cause of death, typically occurring 12–15 years after the onset amyloidogenic mutations. Genetic testing has become the most reli-
of neuropathy. Sixteen mutations of apolipoprotein A1 are known to able form of testing for FAP and should be considered in appropri-
cause FAP. Those involving codons 1–75 more commonly cause hepatic ate patients with cryptogenic progressive axonal neuropathy affecting
and renal amyloidosis, while those involving codons 173–178 cause car- small-fiber nerves in a length-dependent fashion and the autonomic
diac, laryngeal, and cutaneous amyloidosis (Eriksson et al., 2009). nervous system.
Gelsolin Amyloidosis (Familial Amyloid Polyneuropathy Treatment

Type IV, Meretoja) The prognosis of untreated TTR amyloidosis varies with the specific
Gelsolin amyloidosis is an AD condition first described in Finland, but mutation, age of onset, and organ involvement. If untreated, the disease
subsequently isolated cases have also been reported elsewhere. Symptoms progresses rapidly in patients with TTR-FAP and the Val30Met muta-
begin in the third or fourth decade, with corneal clouding caused by a tion, leading to death, usually within the first decade after symptom
fine, strand-like network of amyloid filament deposits referred to as lat- onset (Coelho et al., 2018). Supportive measures are essential for both
tice corneal dystrophy. This is followed in the fifth decade by progres- the neuropathy and specific organ system involved, including cardiac
sive cranial neuropathies with prominent facial palsy and skin changes pacing, hemodialysis, parenteral nutrition, hydration, elastic stockings,
producing a typical baggy skin over the atrophic face (cutis laxa). Other and physical therapy. Symptomatic treatment includes the use of anti-
cranial nerves (VIII, XI, and XII) may be affected, and bulbar signs may convulsants or antidepressants for neuropathic pain, and midodrine,
develop, at times leading to aspiration, together with mild peripheral droxidopa and fludrocortisone for orthostatic hypotension.
neuropathy and CTS but without significant autonomic dysfunction. Because over 90% of TTR is synthesized in the liver, orthotopic
Gelsolin, the amyloid protein isolated from tissues of patients with liver transplantation has been considered as definite therapy for this
FAP type IV, is an actin-binding protein found in plasma, leukocytes, disorder. Transplantation results in rapid clearance of the variant TTR
and other cell types. Plasma gelsolin is largely derived from muscle. It from serum; it may halt progression of neurological deficits in patients
presumably functions as the clearing agent for actin by binding to it with mild neuropathy and stop the rate of axonal degeneration; auto-
in the plasma. The gelsolin gene maps to chromosome 9. Amino acid nomic dysfunction remains largely unchanged (Adams et al., 2000;
substitutions (asparagine or tyrosine at position 187) result in amy- Stangou and Hawkins, 2004). The reported 5-year survival rate after
loid-forming mutant gelsolin. The mutant plasma gelsolin is deposited liver transplantation in patients with Val30Met in Sweden is approx-
in the tissues, particularly nerves and skin. imately 92%, with many surviving more than 20 years (Yamamoto
et al., 2007). Overall, 60% stabilize, 20% improve, and 20% do poorly.
Diagnosis of Familial Amyloid Polyneuropathy Liver transplantation is recommended for patients who are younger
The diagnosis of FAP requires high index of suspicion. In patients pre- than 50 years, have mild neuropathy (walking unaided), and have no
senting with progressive symmetric peripheral polyneuropathy, the significant cardiac or renal involvement. In some cases of non-Val-
diagnosis of TTR-FAP should be seriously considered if the patient has 30Met mutation, despite liver transplantation, the amyloidogenic TTR
more than one of the following findings: (1) positive family history, continues to be deposited in the heart, vitreous, and peripheral nerves,
(2) early autonomic dysfunction (e.g., erectile dysfunction or postural which is thought to be due to wild-type TTR complexing with already
hypotension), (3) heart disease (e.g., myocardial hypertrophy, arrhyth- deposited mutant TTR (Liepnieks et al., 2010; Stangou et al., 1998).
mias, ventricular blocks, or cardiomyopathy), (4) bilateral CTS (espe- Combined liver and renal transplantation has been performed in a few
cially if also present in family members), (5) renal abnormalities (e.g., patients with severe renal involvement.
albuminuria or mild azotemia), or (6) vitreous opacities (Conceicao Dissociation of TTR tetramers is the rate-limiting step of amyloi-
et al., 2016). In contrast, screening for hereditary TTR-FAP in patients dogenesis in patients with TTR-FAP. Slowing TTR tetramer dissocia-
with idiopathic mixed sensorimotor or small-fiber neuropathy without tion appears to minimize clinical disease expression. TTR stabilization
includes using diflunisal, a NSAID, which prevents dissociation of the deaminase [PBGD]) in AIP, of protoporphinogen IX oxidase in varie-
TTR tetramer and amyloid fibril formation by binding to the thyroxine- gate porphyria, and of coproporphinogen oxidase in coproporphyria,
binding sites on TTR. A randomized, placebo-controlled trial of difl- all of which result in abnormalities of heme synthesis. Each abnormal-
unisal in patients with FAP showed a reduction in progression of neu- ity of enzyme activity provokes a compensatory overproduction of
ropathy in the diflunisal arm, with preservation of quality of life, after porphyrins and their precursors through the negative feedback regu-
2 years of treatment (Berk et al., 2013). This agent may worsen renal lation by heme of the first and rate-limiting enzyme of the heme bio-
function and cause volume overload in FAP patients who often have synthetic pathway, δ-aminolevulinic acid synthase (ALAS). A fourth
renal disease and cardiomyopathy. Tafamidis is a novel, small-mole- disorder, referred to as plumboporphyria, is inherited as an AR trait and
cule TTR stabilizer, reduces all-cause mortality and the decline in func- is caused by a deficiency of δ-aminolevulinic acid dehydratase (ALAD)
tional capacity and quality of life as compared with placebo (Maurer (eTable 106.10). More than 90 mutations in the PBGD gene have been
et al., 2018). Suppression of TTR expression is another treatment con- identified that decrease enzyme activity and cause AIP (Elder et al.,
cept by using small interfering RNA agents that bind to conserved 1997). These partial enzyme defects remain latent until precipitating
sequences on TTR messenger RNA (mRNA), leading to degradation factors trigger acute attacks. Precipitating factors include certain drugs,
of the mRNA. Patisiran has been shown, in a phase 3 trial, to reduce the menstrual cycle, alcohol, hormones, and fasting (either intentional
serum TTR levels in patients with FAP, and significantly improves gait or during an intercurrent illness). Precipitating factors induce hepatic
and modified neuropathy impairment score (Adams et al., 2018). Anti- δ-ALAS, the rate-limiting enzyme in heme biosynthesis, leading to the
sense oligonucleotides (ASOs) promote degradation of mRNA and overproduction and overexcretion of PBG and δ-ALA.
reduce TTR suppression. A phase 2/3 trial of IONIS-TTRx in patients
with FAP is ongoing. Finally, doxycycline, tauroursodeoxycholic acid, Clinical Features of the Acute Porphyric Attack
epigallocatechin-3-gallate (the predominant polyphenol in green tea), The neurological manifestations of all forms of the acute porphyrias are
and curcumin (the principal ingredient of turmeric) may be useful in identical. All clinical symptoms may be explained by the dysfunction of
TTR disruption and prevention of amyloid fibril aggregation. Larger the autonomic nervous system, peripheral nervous system (PNS), and
trials are needed to explore the efficacy of these treatments. CNS. Characteristically, porphyric attacks first occur during the second
In patients with non-Val30Met mutations, the prognosis is not as to fourth decades of life and are five times more common and severe in
good and progressive neuropathy and cardiomyopathy may continue women than men. The diagnosis is often delayed by a mean of 15 years
after liver transplantation. Combined liver and heart transplantation (Bonkovsky et al., 2014). Abdominal pain, neurological dysfunction, and
in one patient with the same mutation resulted in mild improvement psychiatric disturbances form the classic triad of AIP. The most frequent
of the peripheral neuropathy. Medical therapy with agents that inter- presenting symptom is recurrent abdominal pain, often with nausea,
fere with amyloid fibril formation and gene therapy are promising vomiting, and severe constipation. Many patients undergo appendecto-
future therapeutic strategies. mies and cholecystectomies prior to the diagnosis of porphyria. Anxiety
and depression are very common, occurring in at least half of patients.
Porphyric Neuropathy Abdominal symptoms may occur several days before overt neuro-
Acute hepatic porphyrias are a group of AD inherited metabolic dis- logical manifestations. The autonomic manifestations are prevalent and
orders that manifest as acute or subacute severe life-threatening motor include persistent tachycardia, labile hypertension, orthostatic hypo-
neuropathy, abdominal pain, autonomic dysfunction, and neuropsy- tension, and difficulty with micturition. Only a few patients progress
chiatric manifestations (Albers and Fink, 2004). Its gene is thought to to develop the more ominous motor neuropathy or CNS involvement,
be present in one in 80,000 people, although only one-third of affected including psychosis and seizures. Onset of the predominantly motor
persons ever manifest symptoms of the disease. The main forms of por- neuropathy is subacute, with generalized, proximal, or asymmetrical
phyria include acute intermittent porphyria (AIP), variegate porphyria, muscle weakness developing over days or weeks. The arms rather than
and hereditary coproporphyria. The basic defects are a 50% reduction the legs may be affected first, and proximal muscles as well as the radial
in hydroxymethylbilane synthase (also known as porphobilinogen nerves may be preferentially involved. Muscular activity before the onset
eTABLE 106.10 Porphyric Neuropathies

Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Plumboporphyria
Enzyme defect PBG deaminase Protoporphyrinogen oxidase Coproporphyrinogen oxidase ALA dehydratase
Inheritance AD AD AD AR
Chromosome 11q24 1q22 3q12 9q34
Photosensitive eruption None Present Present None
Porphyrin excretion:
Urine:
PBG +++ +++ +++ 0
ALA +++ +++ +++ +++
Uro + + + Negative
Copro Negative ++ +++ +
Feces:
Copro Negative + +++ Negative
Proto Negative +++ + +
+++, ++, +, Relative indication of quantity excreted.
AD, Autosomal dominant; ALA, aminolevulinic acid; AR, autosomal recessive; Copro, coproporphyrin; PBG, porphobilinogen; Proto, protoporphyrin;
Uro, uroporphyrin.
and hereditary tyrosinemia. CSF is normal. Hyponatremia related to

Clinical symptoms plus positive
Watson-Schwartz or Hoesch test inappropriate antidiuretic hormone release is common, possibly due
to hypothalamic pathology (Suarez et al., 1997).
At once
EDX studies in patients with porphyric neuropathy reveal low-am-
plitude CMAPs but normal or borderline-slow motor conduction
Elimination of inducing drugs and circumstances Typing of porphyria
400 g carbohydrates/day velocities. SNAPs are reduced in amplitude or are absent. EMG
obtained early in the course reveals poor recruitment of normal
1–2 days MUAPs. Denervation changes appear later, first in the paraspinal and
proximal muscles and subsequently in distal muscles. Patients with
Improved Not improved Family studies
chronic disorder will exhibit an axonal length-dependent, often asym-
metrical, polyneuropathy. Morphological study results support axonal
degeneration and preferential loss of large myelinated axons.
Continue Add hematin 4 mg/kg Prophylaxis
carbohydrates bid for 3 days Pathogenesis
prn
The mechanism of the neuronal axonal injury remains uncertain.
eFig. 106.15 Management of Acute Porphyric Attack. bid, Twice a The two leading hypotheses implicate neuronal heme deficiency with
day; prn, as needed. (Adapted from Bosch, E.P., Pierach, C.A., 1987. impaired energy metabolism or direct neurotoxicity of ALA and neu-
Acute hepatic porphyria. In: Johnson, R.T. (Ed.), Current Therapy in Neu- rotoxic porphyrins.
rologic Disease. Decker, Toronto.)
Treatment and Management
of symptoms may influence the pattern of weakness. Facial and bulbar The treatment of patients with acute hepatic porphyria involves three
weakness is common. In severe cases, flaccid quadriplegia with respira- important steps: (1) attempts to repress hepatic ALA activity, thereby
tory failure ensues. This picture may resemble GBS and, often only after reducing porphyrin production; (2) supportive care; and (3) preven-
a second attack of neuropathy is the diagnosis of porphyric neuropa- tion of attacks.
thy considered because of the infrequency of a repeated episode of GBS. The porphyric attack must be treated promptly, as outlined in eFig.
Rapidly progressive muscle wasting is a striking feature. Tendon reflexes 106.15. First, all offending drugs are removed, and any intercurrent infec-
are diminished or absent, but, paradoxically, ankle jerks may be retained. tion is treated. A high-carbohydrate diet orally or by nasogastric feeding
Sensory impairment may occur in a distal stocking-glove distribution or (at least 400 g daily or the equivalence of glucose or levulose infusions)
may affect the trunk and proximal limbs in an unusual bathing-suit pat- results in reduced porphyrin precursor production. Intravenous hema-
tern. In exceptional cases, a bilateral radial motor neuropathy without tin is the treatment of choice for acute attacks (Bonkovsky et al., 2014).
abdominal pain may be the only manifestation of AIP (King et al., 2002). Hematin (a hydroxide of heme) represses the activity of hepatic ALA and
The rate of improvement varies. Some patients rapidly recover, suggest- may restore cytochrome functions by replenishing an endogenous heme
ing a reversible acute toxic-metabolic neuronal injury. Those with fixed deficit. Hematin therapy at the recommended dose of six infusions of 4
weakness caused by axonal degeneration improve slowly (mean time mg/kg body weight at 12-hour intervals has resulted in consistent reduc-
to recovery is 10.6 months for proximal muscles and nearly twice as tion of porphyrin precursors in serum and urine and clinical improve-
long for distal muscles). The protean CNS manifestations during severe ment in more than 80% of attacks. The only placebo-controlled study
attacks include seizure, posterior reversible encephalopathy syndrome suggested a more modest clinical benefit of IV hematin. Early admin-
(PRES), confusion, delirium, and coma (Zheng et al., 2018). istration of hematin is advocated to correct the metabolic insult before
Patients with variegate porphyria and hereditary coproporphyria neuronal damage becomes irreversible.
develop cutaneous photosensitivity during adult life. The skin mani- Supportive treatment consists of the correction of fluid imbal-
festations consist of blisters, hyperpigmentation, hypertrichosis, and ance, close attention to respiratory function, and physical therapy.
increased skin fragility. AIP occurs in all ethnic groups but is most Supplemental vitamin B6 and beta-blockers for control of tachycar-
common in individuals of Scandinavian or English descent. Variegate dia may become necessary. Abdominal pain can often be controlled
porphyria is also common among South Africans of Afrikaans descent. with simple analgesics but may require narcotics. Sedation with chlor-
promazine is often helpful. The treatment of seizures poses a difficult
Laboratory Studies therapeutic problem because most anticonvulsants may exacerbate the
The biochemical hallmark of the porphyric attack is marked elevation disease. Intravenous diazepam and parenteral magnesium sulfate are
of PBG and ALA in blood and urine. Enzyme assays may mislead and both effective and safe for immediate seizure control. All at-risk rela-
should not be used in place of porphyrin analysis. Rapid screening tests tives should be screened for latent disease.
for urinary PBG (e.g., Watson-Schwartz and Hoesch tests) give positive Ideally, attacks should be prevented by avoiding drugs and situa-
test results during virtually all acute attacks and are useful in an emer- tions that induce them. Among the inducing drugs, barbiturates are
gency. A positive screening test result must be confirmed with quanti- the most common precipitants, followed by sulfonamides, analgesics,
tative determinations of urinary PBG and ALA. Levels of urinary ALA nonbarbiturate hypnotics, anticonvulsants, and female sex hormones.
and PBG may decrease rapidly after an attack of variegate porphyria or Intentional fasting and alcohol consumption should be avoided.
hereditary coproporphyria but remain elevated in AIP. Subsequently, Gonadotropin-releasing hormone agonists may benefit women with
stool assays for protoporphyrins and coproporphyrins are necessary to recurrent attacks related to the menstrual cycle. Prophylactic and
distinguish variegate porphyria and hereditary coproporphyria from repeated administration of intravenous hematin is of benefit to those
AIP. The diagnosis of ALAD-deficiency porphyria (ADP) is supported prone to recurrent attacks (Bonkovsky et al., 2014).
by increased urinary excretion of ALA without accompanying PBG ele-
vation. Certain medications and disorders other than porphyrias are Fabry Disease
associated with increased urinary porphyrins, including lead poison- Fabry disease (angiokeratoma corporis diffusum) is an X-linked lyso-
ing, liver disease, alcoholism, chronic renal failure during hemodialysis, somal storage disorder caused by a deficiency of the lysosomal enzyme
as an intravenous infusion. Minor reactions include flushing, chest

discomfort, skin rash pruritus, and nasal congestion. Approximately
1% of patients developed anaphylactic or severe allergic reactions
(angioedema, bronchospasm, hypotension, or generalized urticarial)
during infusions. Reactions have included localized dysphagia, rash,
dyspnea, flushing, chest discomfort, pruritus, and nasal congestion.
Most patients, particularly those exhibiting infusion reactions, should
be pretreated with antipyretics, antihistamines, and corticosteroids.
Renal transplantation may correct the biochemical defect, resulting in
relief from pain and partial restoration of sweating.
Leukodystrophies with Neuropathy

The leukodystrophies result from inherited abnormalities of myelin
metabolism that may affect both the CNS and PNS. Overall inci-
eFig. 106.16 Fabry Disease. Typical angiokeratomas are clustered dence of the leukodystrophies in the United States is 1 in 7663 live
over the lower part of the trunk. births (Bonkowsky et al., 2010). Peripheral nerve involvement is
seen in MLD, Krabbe disease, adrenomyeloneuropathy (AMN), and
α-galactosidase A, which results in the accumulation of the glycolipid Cockayne syndrome. Recognition of an associated neuropathy may
globotriaosylceramide (ceramide trihexoside) within vascular endothe- be helpful in the differential diagnosis of the underlying leukodys-
lial cells of the kidneys, heart, brain, and skin. Over time, progressive trophy. Missense mutations in proteolipid protein, a major protein
vascular disease leads to renal failure, cardiac disease, and strokes. Skin component of CNS myelin, cause a spectrum of X-linked CNS disor-
involvement gives rise to the typical angiokeratomas, which are dark red, ders without peripheral neuropathy, including Pelizaeus-Merzbacher
punctate telangiectasias found mainly over the lower part of the trunk, disease and hereditary spastic paraparesis. Proteolipid protein is also
buttocks, and scrotum (eFig. 106.16). A painful small-fiber neuropathy expressed in Schwann cells and compact peripheral myelin. Absence
develops in childhood or adolescence. In fact, any boy or young man of proteolipid protein expression caused by a frameshift mutation has
with severe painful sensory neuropathy should be suspected as having been reported to produce a demyelinating neuropathy with less severe
Fabry disease, and skin lesions should be carefully scrutinized because CNS manifestations (Gabern et al., 1997).
they are usually sparse and may be easily overlooked. Distal pares-
thesias and lancinating pain are intensified by exertion, fever, or hot Metachromatic Leukodystrophy
environments. Autonomic dysfunction includes diminished sweating, MLD is an AR disorder of sulfatide metabolism caused by deficiency of
impaired tear and saliva formation, and decreased intestinal motility. the lysosomal enzyme arylsulfatase A (ASA) and subsequent accumu-
Some patients have hearing loss (Barras and Maire, 2006; Vibert et al., lation of sulfatides in brain, peripheral nerves, and other tissues. The
2006). Except for impairment of temperature sensation, overt neuro- storage of sulfatides affects central and peripheral myelin, leading to
logical signs are absent. Female carriers often show clinical involve- progressive demyelination. The ASA gene is localized to chromosome
ment but rarely develop renal failure, which is characteristically seen 22q13, and, thus far, over 60 mutations have been identified. Some gene
in affected men. mutations have been correlated with different clinical phenotypes.
On nerve conduction studies, the conduction velocities are mildly Three main clinical forms have been divided by age of onset: late-in-
reduced in two-thirds of patients. Deposition of glycolipid in small neu- fantile (6 months–2 years), juvenile (3–16 years), and adult. Peripheral
rons of sensory and peripheral autonomic ganglia results in neuronal nerve involvement characterized by a progressive gait disorder, hypo-
degeneration and selective loss of small myelinated and unmyelinated tonia, and lower-limb areflexia is an early manifestation that fre-
fibers in sural nerve biopsy specimens. Ultrastructurally, perineurial, quently precedes CNS involvement in late-infantile and early-juvenile
endothelial, and perithelial cells contain characteristic lamellated gly- MLD. In contrast, behavioral abnormalities and progressive demen-
colipid inclusions. Leukocyte preparations or skin fibroblasts are used tia predominate over subtle neuropathic signs in adult-onset MLD. A
for the diagnostic α-galactosidase assay. Although screening for Fabry homozygous missense mutation has been described in an adult patient
disease was recommended for patients with small-fiber neuropathy of presenting with an isolated polyneuropathy without CNS involvement
unknown cause, studies of Nordic populations has recently shown that (Felice et al., 2000). Marked uniform slowing of nerve conduction is
screening for Fabry disease in patients with idiopathic small-fiber or seen in late-infantile and juvenile cases. Reduced NCVs and delayed
mixed neuropathy without any additional disease-specific symptoms visual and somatosensory evoked potential latencies are present in
is of little value in a clinical setting (Samuelsson et al., 2019). most adult cases. Extensive segmental demyelination and abnormally
Analgesics, phenytoin, or carbamazepine, along with avoidance of thin myelin sheaths are seen in nerve biopsy specimens of all MLD
aggravating factors, are effective for pain relief. Recombinant α-galac- variants, along with metachromatic inclusions within Schwann cells
tosidase-A replacement therapy with recombinant α-galactosidase A and macrophages. Peripheral nerve biopsy therefore offers a means of
(agalsidase beta) is safe and effective in the removal of microvascular confirming the diagnosis, although this is rarely needed now. The diag-
endothelial deposits of globotriacylceramide from target organs (Eng nosis of MLD is supported by MRI of the brain and confirmed by an
et al., 2001). Enzyme replacement therapy results in slowing the pro- increased urinary sulfatide excretion and abnormal ASA enzyme assays
gression of renal, cardiac, and cerebrovascular complications and death in leukocytes or fibroblasts.
(Banikazemi et al., 2007) and in improvement of autonomic function Bone marrow transplantation may increase brain levels of ASA suf-
(Ries et al., 2006). Agalsidase alfa has also been shown to be benefi- ficiently to stop disease progression.
cial in cardiac, renal, neuropathic pain, and quality-of-life measures
(Mehta et al., 2009). Enzyme therapy before irreversible end-organ Globoid Cell Leukodystrophy (Krabbe Disease)
damage may provide greater clinical benefit. The recommended dos- Globoid cell leukodystrophy, or Krabbe disease, is an AR disease caused
age of agalsidase beta is 1.0 mg/kg body weight infused every 2 weeks by an inherited deficiency of the lysosomal enzyme galactocerebroside
β-galactosidase. The gene for Krabbe disease has been localized to acid is derived exclusively from dietary sources, mainly chlorophyll,
chromosome 14q31. The disorder is characterized by extensive CNS dairy products, meats, and fish oils. Clinical onset spans from child-
and peripheral nerve demyelination and the presence of multinucle- hood to the third decade of life. The cardinal manifestations include
ated macrophages (globoid cells) in the cerebral white matter. The pigmentary retinal degeneration with night blindness or visual-field
classic presentation in early infancy consists of rapidly progressive constriction, chronic hypertrophic neuropathy, ataxia, and other cer-
deterioration in intellectual and motor development, accompanied ebellar signs such as nystagmus and intention tremor. Initially, the
by hypertonicity, opistotonic posture, optic atrophy, and seizures. In neuropathy affects the lower limbs with distal leg atrophy, weakness,
the late-onset form, peripheral neuropathy and spasticity may be the areflexia, large-fiber sensory impairment, and sometimes palpably
only manifestations. Peripheral nerve involvement is demonstrated by enlarged nerves. Weakness becomes generalized later in the illness. In
marked uniform slowing of motor conduction velocities. Segmental addition to pes cavus, overriding toes caused by symmetrically short
demyelination, together with ultrastructurally characteristic tubular or fourth metatarsals are a helpful sign for Refsum disease. Progressive
crystalloid inclusions within Schwann cells and macrophages, is seen sensorineural hearing loss, anosmia, cardiomyopathy, and ichthyosis
in the sural nerve. Hematopoietic stem cell transplantation provides a are common. The course may be either progressive or fluctuating with
source of the missing enzyme and can thereby prevent and reverse the exacerbations and remissions. Exacerbations are often precipitated by
CNS manifestations (Krivit et al., 1998). fasting, which mobilizes phytanic acid from endogenous fat stores.
Motor conduction velocities are markedly slowed, and SNAPs are
Adrenomyeloneuropathy reduced or absent. CSF protein is increased in the range of 100–700
AMN, the adult phenotype of adrenoleukodystrophy, is an X-linked mg/dL. Sural nerve biopsy reveals a hypertrophic neuropathy with
recessive disorder of fatty acid metabolism characterized by adrenal prominent onion bulb formation. The diagnosis is confirmed by ele-
insufficiency, progressive myelopathy, and peripheral neuropathy. vated serum levels of phytanic acid.
A defect in beta-oxidation of saturated very-long-chain fatty acids Chronic dietary treatment, by restricting the exogenous sources
(VLCFAs) in peroxisomes leads to the accumulation of tetracosanoic of phytanic acid (<10 mg/day) and its precursor phytol, results in
(C24:0) and hexacosanoic (C26:0) acid in tissues and body fluids in reduction of serum phytanic acid levels and clinical improvement.
affected patients. A significant increase of VLCFA levels in plasma, The diet should provide sufficient calories to avoid weight loss. Plasma
fibroblasts, or both allows reliable detection in patients and hetero- exchange has been used to lower toxic serum phytanic acid levels more
zygote female carriers. The defective gene (ABCD1) is located in the rapidly in critically ill patients. Docosahexaenoic acid has been found
region Xq28 and codes for a peroxisomal membrane protein referred to be deficient in peroxisomal disorders, but supplementation does
to as ALD protein that belongs to the ABC transporter protein family not lead to clinical improvement even though docosahexaenoic acid
(Moser, 1997). AMN manifests in the second to third decades with pro- plasma levels do increase (Parker et al., 2010).
gressive spastic paraparesis, distal muscle weakness, sensory loss, and
sphincter disturbances. Neurological features frequently are preceded Tangier Disease
by clinical or laboratory evidence of hypoadrenalism. Approximately Tangier disease is an AR disorder named after Tangier Island, Virginia, the
10% of patients have primary adrenal insufficiency without evidence origin of the first described cases. It is characterized by severe deficiency
of nervous system involvement. At least 20% of female carriers develop of plasma α- or high-density lipoproteins, resulting in the deposition of
spastic paraparesis similar to that in men, but less severe and later in cholesterol esters in many tissues, including the reticuloendothelial system
onset. and peripheral nerves. The accumulation of lipids leads to enlarged yel-
Electrophysiological studies are helpful in identifying peripheral low-orange tonsils, which may provide a clue to the diagnosis. In adoles-
nerve involvement that may escape clinical detection because of prom- cence or adult life, approximately half of affected patients develop one of
inent upper motor neuron signs. Nerve conduction studies demon- two distinct neuropathic syndromes. The first is a progressive symmetrical
strate a distal axonopathy with low CMAP amplitudes and mildly neuropathy with dissociated loss of pain and temperature sensation in the
reduced NCVs. Fewer than 10% of patients have significant nerve con- face, arms, and upper trunk, combined with faciobrachial muscle wasting
duction slowing suggestive of demyelination (van Geel et al., 1996). and weakness. These findings bear a superficial resemblance to syringomy-
Sural nerve biopsy shows loss of myelinated fibers, occasional small elia. The second syndrome consists of relapsing multifocal mononeuropa-
onion bulbs, and curvilinear lamellar lipid inclusions in Schwann cells. thies involving the cranial, trunk, or limb nerves.
Brain MRI study results are abnormal, demonstrating white-matter High-density lipoprotein and serum cholesterol are markedly
changes in roughly half of patients with AMN at some time in the reduced, whereas triglyceride concentrations are elevated. A neuro-
course of their disease. pathic disorder is confirmed by absent or low-amplitude SNAPs and
Dietary restriction of VLCFA combined with the administration reduced conduction velocities. Nerve biopsy specimens from patients
of oleic and erucic acids (Lorenzo oil) lower plasma levels of VLCFA with the multiple mononeuropathy variant have shown segmental
but have no effect in arresting the rate of neurological progression demyelination and remyelination. By contrast, small myelinated and
(van Geel et al., 1999). Adrenal insufficiency responds readily to cor- unmyelinated axons are preferentially lost in the syringomyelia-like
ticosteroid replacement. In contrast to the cerebral form, patients variant. Typically abundant lipid vacuoles in Schwann cells are present
with AMN are not considered suitable candidates for bone marrow in both. No specific treatment is known.
transplantation.
Abetalipoproteinemia (Bassen-Kornzweig Syndrome)
Phytanic Acid Storage Disease (Refsum Disease) Abetalipoproteinemia is a rare AR disorder of lipoprotein metab-
Refsum disease, heredopathia atactica polyneuritiformis, is a rare olism. The condition is associated with gene defects coding for the
AR disorder of phytanic acid metabolism. The gene defect has been microsomal triglyceride transfer protein, resulting in abnormal very-
localized to chromosome 10 and encodes the peroxisomal enzyme low-density lipoprotein secretion. Fat malabsorption is present from
phytanoyl-CoA-hydroxylase. The defect in the enzyme that initi- birth and results in a severe deficiency of the fat-soluble vitamins A,
ates the alpha-oxidation pathway of β-methyl-substituted fatty acids E, and K. Steatorrhea, hypocholesterolemia, and abnormally spiky red
leads to phytanic acid accumulation in serum and tissues. Phytanic cells (acanthocytes) are present from birth. Most untreated patients
develop retinitis pigmentosa, peripheral neuropathy, and spinocere- may contribute to the development and severity of neuropathy in
bellar degeneration during the first two decades of life. A progressive, MELAS. The neuropathy of MELAS appears to be more common
mainly large-fiber sensory neuropathy occurs, with gait ataxia, are- in men than women.
flexia, impaired proprioceptive sensation, and modest distal weakness; • The syndrome of mitochondrial neurogastrointestinal encephalopa-
the condition must be considered in the differential diagnosis of the thy (MNGIE) is a progressive AR metabolic disorder caused by thy-
SCAs. Patients have absence of serum β-lipoproteins and very low lev- midine phosphorylase enzyme deficiency due to loss-of-function
els of vitamin E. mutation in the thymidine phosphorylase gene. A mixed axonal and
Clinical manifestations of vitamin E deficiency can also be found demyelinating neuropathy may be present in some patients with
in familial vitamin E deficiency caused by mutations of the α-tocoph- MINGIE. At times, the neuropathy may follow a course mimicking
erol transfer protein gene. These gene mutations result in the failure CIDP (Bedlack et al., 2004). However, these patients often have no
to incorporate α-tocopherol in very-low-density lipoprotein in the proximal weakness, suffer from gastrointestinal dysfunction due
liver and lead to low vitamin E levels in the absence of malabsorption to intestinal pseudo-obstruction, may have CNS demyelination
(Martinello et al., 1998). or lactic acidosis, exhibit extraocular abnormalities, and show no
Dietary fat restriction and large oral doses of vitamin E (100 mg/kg/ response to immunomodulatory treatments. Measurement of thy-
day) can prevent the onset of symptoms or arrest progression of neu- midine level in the serum or activity of thymidine phosphorylase
rological complications in abetalipoproteinemia and familial vitamin in buffy coat supports the diagnosis. DNA sequencing will confirm
E deficiency. the diagnosis by demonstrating mutations in the thymidine phos-
phorylase gene. A presentation similar to CMT with distal mus-
Mitochondrial Cytopathies and Polyneuropathy cle atrophy and pes cavus has also been observed in patients with
Inborn errors of mitochondrial metabolism encompass a hetero- MNGIE (Said et al., 2005). The course of neuropathy in MNGIE,
geneous group of multisystemic disorders caused by mutations in however, may become rapid and pain may be prominent. The role
either mitochondrial or nuclear DNA. These mutations impair cel- of nutritional factors secondary to gastrointestinal dysmotility in
lular energy metabolism of virtually every organ, but in particular the development and intensity of the neuropathy in such patients
the CNS and muscles. Involvement of the PNS also occurs in sev- should not be ignored. Nerve biopsies performed in a few patients
eral mitochondrial cytopathies (Bouillot et al., 2002; Stickler et al., with MNGIE have shown variable abnormalities including reduc-
2006). Mitochondrial cytopathy remains an uncommon cause for tion in myelinated fiber density, demyelination and remyelination,
isolated and progressive neuropathy. However, mitochondrial myelin sheath irregularity, and a high proportion of fibers with
cytopathies should be considered in the differential diagnoses of axonal degeneration and axonal atrophy. Schwann cells, axons, and
any patient with a peripheral neuropathy and a multisystemic endothelial cells may contain abnormal mitochondria, including
condition paracrystalline inclusions. Recent reports suggest that allogenic
• In the syndrome of neuropathy, ataxia, and retinitis pigmentosa stem cell transplantation corrects biochemical derangements in the
(NARP) caused by a mutation of the ATP6 gene, an axonal neurop- blood of MNGIE patients, but its clinical efficacy remains unproven
athy predominates and may be the presenting feature. In fact, the (Hirano et al., 2006).
first case of an established mitochondrial cytopathy and neuropa- • A mixed demyelinating and axonal neuropathy is seen in MERRF
thy was described in this syndrome. (myoclonic epilepsy and ragged red fibers).
• In sensory ataxic neuropathy, dysarthria, and ophthalmoplegia • In another mitochondrial disorder commonly observed in chil-
(SANDO), a multiple mitochondrial depletion disorder, a severe dren, Leigh disease, a demyelinating-remyelinating neuropathy
sensory axonal neuropathy and ophthalmoplegia associated with and hypomyelination of nerves is observed. This is particularly
other features such as migraine, depression, and cyclooxygenase prominent when mutations occur in nuclear genes (e.g., SURF1
(COX)-deficient muscle fibers develops after age 30 (Fadic et al., and SCO2) encoding the assembly of complex IV of the respiratory
1997). Mutations in the nuclear DNA polymerase (POLG), crucial chain.
for mitochondrial DNA replication, result in epilepsy, ataxia, head- • Navajo neurohepatopathy, a unique AR, multisystemic, progressive
ache, myoclonus, late-onset ophthalmoplegia, and a sensorimotor syndrome prevalent in Navajo children of the southwest United
neuropathy (Tzoulis et al., 2006). States, is caused by a mutation in the mitochondrial MPV17 gene,
• A peripheral polyneuropathy, at times severe, is seen in MELAS which is believed to be involved in mitochondrial DNA mainte-
(mitochondrial encephalomyopathy, lactic acidosis, and stroke-like nance and in the regulation of oxidative phosphorylation (Karad-
episodes). The majority of patients (≈75%) have a predominantly imas et al., 2006). These children develop a severe sensorimotor
axonal neuropathy, half predominantly sensory; the remainder neuropathy associated with corneal ulcerations, acral mutilation,
have only electrophysiological abnormalities (Kaufmann et al., poor weight gain, short stature, sexual infantilism, serious systemic
2006). Endocrine involvement, especially of thyroid and pancreas, infections, and liver derangement, including Reye syndrome-like
is common, and impaired glucose metabolism and hypothyroidism episodes, leading to cirrhosis and hepatic failure.
B
Fig. 106.11 Single teased nerve fibers from a patient with hereditary liability to pressure palsies, showing
examples of focal sausage-shaped enlargements of the myelin sheath (large arrows) in two fibers (A, B).
Fiber A shows thinly remyelinated internodes. Successive nodes of Ranvier (thin arrows) can be followed
from left to right. (Bar = 100 μm.) (Reprinted with permission from Bosch, E.P., Chui, H.C., Martin, M.A.,
et al., 1980. Brachial plexus involvement in familial pressure-sensitive neuropathy: electrophysiological and
morphological findings. Ann Neurol 8, 620–624.)
INFLAMMATORY DEMYELINATING BOX 106.10 Diagnostic Criteria for

POLYRADICULONEUROPATHIES Guillain-Barré Syndrome
Inflammatory demyelinating polyradiculoneuropathies are acquired Features Required for Diagnosis
immunologically mediated polyneuropathies classified on the basis of Progressive weakness of both legs and arms
their clinical course into two major groups: (1) GBS, and (2) CIDP. Areflexia or hyporeflexia
In GBS, the maximal deficits develop over days or weeks (maximum
Clinical Features Supportive of Diagnosis
4 weeks), followed by a plateau phase and gradual recovery. Chronic
Progression over days to 4 weeks
forms pursue either a slowly progressive (2 months or more) or a
Relative symmetry of symptoms and signs
relapsing-remitting course.
Mild sensory symptoms or signs
Guillain-Barré Syndrome Bifacial palsies
Autonomic dysfunction
In 1916, Guillain, Barré, and Strohl emphasized the main clinical
Absence of fever at onset
features of GBS: motor weakness, areflexia, paresthesias with minor
Recovery beginning 2–4 weeks after progression ceases
sensory loss, and increased protein in CSF without pleocytosis (albu-
minocytological dissociation). Our current understanding of the pathol-
Laboratory Features Supportive of Diagnosis
ogy was greatly enhanced when multifocal inflammatory demyelination
Elevated cerebrospinal fluid protein with <10 cells/μL
of spinal roots and peripheral nerves was described. The frequent find-
Electrodiagnostic features of nerve conduction slowing or block
ing of motor conduction blocks and reduced conduction velocities
provided further electrophysiological confirmation of the widespread Adapted from Ashbury, A.K., Cornblath, D.R., 1990. Assessment of
demyelination. Improvement in modern critical care has dramatically current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol
changed outcomes in GBS, including a reduction in the mortality rate 27(Suppl), S21–S24.
from 33% before the introduction of positive-pressure ventilation to
the current rate of approximately 1%–5% (Alshekhlee et al., 2008a). presentation. This axonal subtype of GBS is called acute motor-sensory
The diagnosis of GBS depends on clinical criteria supported by axonal neuropathy (AMSAN) because of involvement of both motor
electrophysiological studies and CSF findings (Box 106.10). These and sensory fibers and is known for its severity and poor recovery. A
diagnostic criteria define acute inflammatory demyelinating polyneu- second, pure motor axonal subtype called acute motor axonal neuropa-
ropathy (AIDP), which is the most common form of GBS in Europe thy (AMAN) was first described in northern China, where it occurs in
and North America. However, in recent years, it has been recognized summer epidemics in children and young adults (Yuki and Hartung,
that GBS is a heterogeneous syndrome, and not all GBS cases are due 2012). The Miller-Fisher syndrome (MFS) variant accounts for 6% of
to acute demyelination and resemble experimental allergic neuritis. An total GBS cases in Western countries, whereas in Taiwan the propor-
axonal immune-mediated injury may also produce a similar clinical tion is as high as 18%, suggesting a geographical difference. Other
be related to either increased or decreased sympathetic-parasympa-

BOX 106.11 Classification of Guillain–
thetic activity, resulting in orthostatic hypotension, urinary retention,
Barré Syndrome Subtypes and Variants gastrointestinal atony, iridoplegia, episodic or sustained hypertension,
Common Subtypes sinus tachycardia, tachyarrhythmias, anhidrosis or episodic diaphoresis,
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acral vasoconstriction. Excessive vagal activity accounts for sudden
Acute motor axonal neuropathy (AMAN) episodes of bradycardia, heart block, and asystole. These “vagal spells”
Acute motor-sensory axonal neuropathy (AMSAN) may occur spontaneously or may be triggered by tracheal suctioning or
similar stimuli. Serious cardiac arrhythmias with hemodynamic insta-
Rare Variants bility tend to be more frequent in patients with severe quadriparesis and
Miller-Fisher syndrome respiratory failure. Autonomic dysfunction can result in electrocardio-
Ataxic variant (acute ataxic neuropathy) graphic (ECG) changes, including T-wave abnormalities, ST-segment
Pharyngeal-cervical-brachial variant depression, QRS widening, QT prolongation, and various forms of
Multiple cranial neuropathy variant heart block. It is important to note that some of the common medical
Facial diplegia with paresthesias complications, including pulmonary embolism, hypoxia, and pneumo-
Paraparetic variant nia, lead to similar symptoms (e.g., tachycardia) and must be excluded
Acute pandysautonomia before they can be attributed to autonomic dysfunction.
Guillain-Barré Syndrome Subtypes and Variants

Several variations from the typical presentation of GBS exist (see Box
rare variants of GBS include acute pandysautonomia, facial diplegia 106.11). Their link to GBS is supported by preceding infectious epi-
with paresthesias, and the pharyngeal-cervical-brachial variants (Box sodes, diminished reflexes, elevated CSF protein levels, and, in many
106.11). The classification of GBS subtypes and variants is based on of them, an acknowledged immune-mediated origin.
the clinical picture and electrophysiological and pathological findings A GBS subtype, AMAN was first reported in epidemic proportions
(Griffin et al., 1996). among children and young adults in northern China during summer
months; AMAN is now considered the most common GBS subtype in
Clinical Features Asia. Sporadic cases of AMAN presenting with acute flaccid paralysis
The classic form of GBS is a nonseasonal illness that affects persons of without clinical or electrophysiological involvement of sensory nerves
all ages, but males are more often affected than females (1.5:1). With the are reported from Europe and North America, often scattered within
virtual eradication of acute poliomyelitis, GBS has become the leading large series of patients with GBS. AMAN differs from GBS in electro-
cause of acute paralytic disease in Western countries. The mean annual physiological studies that demonstrate normal SNAPs and reduced
incidence is 1.8 per 100,000 population and has remained stable over the CMAP amplitudes with no signs of demyelination as supported by nor-
past three decades (Flachenecker, 2006). Incidence rates increase with age mal motor distal latencies and conduction velocities. Autopsy studies
from 0.8 in those younger than 18 years to 3.2 for those 60 years and older. of some cases have shown noninflammatory wallerian-like degenera-
Patients with classic GBS initially present with weakness with or tion of ventral roots and motor axons in mixed nerves. However, nerve
without paresthetic sensory symptoms, often worse in the hands and biopsy studies in others have shown intrusion of macrophages between
fingers. The fairly symmetrical weakness of the lower limbs ascends the axon and the surrounding myelin sheath, with relatively little axo-
proximally over hours to several days and may subsequently involve nal degeneration. Most patients with AMAN improve as rapidly as
arms, facial, and oropharyngeal muscles, and in severe cases, respira- patients with AIDP (Ho et al., 1997). The rapid clinical improvement
tory muscles. Less often, weakness may be descending and begin in the rates and the paucity of pathological findings in some fatal cases could
upper limbs or cranial innervated muscles. Its severity varies from mild, be explained either by conduction failure of motor axons at nodes of
in which patients are still capable of walking unassisted, to a nearly total Ranvier because of macrophage intrusion or by axonal degeneration of
quadriplegia. Hyporeflexia or areflexia are the invariable features of GBS motor nerve terminals as confirmed by motor point biopsy. Antecedent
but may be absent early in the course of the disease. Campylobacter jejuni infection is detected by using serological tests in
Cranial nerve involvement occurs in 45%–75% of cases in differ- 76% of AMAN patients from northern China. AMAN represents a very
ent series. Facial paresis, usually bilateral, is found in at least half of good example of molecular mimicry in which the immune system, in its
patients. Involvement of extraocular muscles and lower cranial nerves efforts to eradicate C. jejuni, elaborates antibodies against neural anti-
is seen less often. Occasional patients may develop facial myokymia. gens who share ganglioside-like epitopes with the lipopolysaccharides
Pseudotumor cerebri with papilledema occurs as a rare complication of the organism. These antibodies, mainly anti-GM1 or anti-GD1a
and is almost always due to chronically elevated intracranial pressure. antibodies, bind to the axolemma at the node of Ranvier, leading to
The proportion of patients developing respiratory failure and requir- membrane-attack complex formation and conduction failure.
ing assisted ventilation seems to increase with age and ranges from 9% A fulminant and less common subtype of GBS, AMSAN, carries a
to 30% in hospital-based series (Alshekhlee et al., 2008a). poor prognosis for recovery. All patients develop an acute and rapidly
Sensory loss is not a prominent feature and is frequently limited to dis- progressive course leading to a maximum deficit in less than 7 days,
tal impairment of vibration sense. Moderate to severe pain in the extrem- often profound quadriparesis with severe muscle wasting and requir-
ities, interscapular area, or back occurs in about 70% of patients during ing prolonged ventilatory support. EDX studies show markedly reduced
the acute phase of illness, and this may persist for a year in a third of those or absent CMAPs, without significant conduction slowing, and absent
affected (Ruts et al., 2010b). Dysesthetic pain, described as burning or tin- SNAPs. The subsequent appearance of abundant fibrillation potentials
gling of the limbs, or joint stiffness is less common (Moulin et al., 1997). on needle EMG, together with persistently inexcitable motor nerves and
Autonomic dysfunction of various degrees has been reported in 65% poor recovery are compatible with a primary axonopathy as the under-
of patients admitted to the hospital. Most of the clinically significant lying disease process. Extensive wallerian axonal degeneration without
autonomic dysfunction occurs within the first 2–4 weeks of the illness, significant inflammation or demyelination has been described in ventral
the peak period of paralysis. Its varied and complex manifestations may and dorsal roots and in peripheral nerves at autopsy (Griffin et al., 1996).
MFS, which accounts for about 5% of cases, is characterized by the Diagnostic Studies
triad of ophthalmoplegia, ataxia, and areflexia. Patients present with CSF examination and serial EDX studies are important ancillary stud-
diplopia followed by gait and limb ataxia. Ocular signs range from ies for confirming the diagnosis of GBS. Other laboratory studies are
complete ophthalmoplegia, including dilated and unreactive pupils, to of limited value. Mild transient elevations in liver enzymes without
external ophthalmoparesis with or without ptosis. Cranial nerves other obvious cause are found in about a third of patients. Hyponatremia
than ocular motor nerves may be affected. The ataxia is attributed to is seen most frequently in ventilated patients because of inappropriate
a peripheral mismatch between proprioceptive input from the muscle secretion of antidiuretic hormone. Deposition of immune complexes
spindles and the kinesthetic information from joint receptors. Motor may rarely lead to glomerulonephritis and result in microscopic hema-
strength is characteristically preserved, although overlap with typical turia and proteinuria.
GBS seems to occur when some patients progress to develop quad- In the first week of neurological symptoms, the CSF protein may be
riparesis. EDX studies demonstrate an axonal process affecting pre- normal in up to 50% of patients but then becomes elevated on subsequent
dominantly sensory nerve fibers, with no or only mild motor nerve examinations. In approximately 10% of cases, the CSF protein remains
conduction abnormalities. SNAP amplitudes are normal in half of the normal throughout the illness. Transient oligoclonal IgG bands and ele-
patients and reduced or absent with a sural sparing pattern in one-third vated myelin basic protein levels may be detected in the CSF of some
of patients (Lyu et al., 2013). Motor conduction studies, F-wave laten- patients. The increase in CSF protein and immunoglobulins is not usually
cies, and needle EMG are usually normal. Most patients have increased associated with a cellular response (albuminocytological dissociation). In
CSF protein without pleocytosis 1 week after the onset. Brain MRI is about 10% of patients, there is a slight lymphocytic pleocytosis greater
usually normal, though rarely the MRI may show brainstem lesions than 10 cells/mm. However, moderate CSF pleocytosis (usually >50 cells)
or gadolinium enhancement of ocular motor nerves. About 20% of is a distinctive feature of GBS associated with HIV or Lyme infections.
patients with MFS have followed C. jejuni infection and 8% followed The prompt diagnosis of GBS is warranted by the need to initiate
Haemophilus influenzae infection. Serum IgG antibodies to the gangli- early treatment. Hence, EDX studies are increasingly requested early
oside GQ1b are detected in acute-phase sera of 98% of patients with on when the diagnosis of GBS is considered. The EDX consultant is
MFS and in many patients with GBS with ophthalmoplegia and ataxia, often asked not only to exclude other diagnoses (e.g., botulism, myas-
especially in those with a preceding C. jejuni infection, suggesting that thenia gravis) but also to confirm the diagnosis of GBS. Frustration is
the antibodies are disease specific and related to the pathogenesis (Yuki frequently encountered within the first few weeks of illness, since nerve
and Koga, 2006). GQ1b is abundantly present in paranodal regions conduction studies may not be diagnostic early in the course of the
of ocular nerves, explaining the association between high titers of this disease. The EDX studies in patients with GBS assist in detecting the
antibody and ophthalmoplegia. Other antiganglioside antibodies such presence of multifocal demyelination, the hallmark of acquired demy-
as anti-GT1a, anti-GD3, and anti-GD1b have also been associated with elinating polyneuropathy; however, these EDX abnormalities repre-
MFS but with a lesser frequency. MFS has a favorable prognosis, with sent an evolving picture in GBS.
recovery after a mean of 10 weeks and a corresponding reduction in Abnormalities of EDX studies are found in approximately 90% of
the antibody titers. established GBS cases, sometimes during the course of illness. EDX
Acute pandysautonomia, considered to be another variant of GBS, is studies performed in patients enrolled in the North American GBS
rare and characterized by the rapid onset of combined sympathetic and study found abnormalities of distal motor latencies and F-wave laten-
parasympathetic failure without somatic sensory and motor involve- cies in about half of patients studied within 30 days of onset (Cornblath
ment. The deep tendon reflexes are usually lost during the course of et al., 1988). Partial motor conduction block (30%), slowing of motor
the illness. These patients develop severe orthostatic hypotension, heat conduction velocity (24%), and reduced distal CMAP amplitudes
intolerance, anhidrosis, dry eyes and mouth, fixed pupils, fixed heart (20%) were less frequent. However, some of these abnormalities are
rate, and disturbances of bowel and bladder function. About half of often nonspecific and do not distinguish acquired demyelination from
patients have autoantibodies to ganglionic acetylcholine receptors, axonal degeneration, which is characterized by reduced CMAP and
which may play a pathogenetic role by blocking cholinergic transmis- SNAP amplitudes.
sion in autonomic ganglia (Vernino et al., 2000). Ganglionic recep- The most common EDX abnormalities seen in the first 2 weeks
tor-blocking antibodies serve as serological markers of autoimmune of illness are absent H reflexes and absent, delayed, or impersistent F
autonomic neuropathies and are elevated in both acute pandysautono- waves, findings that are common in polyneuropathies but not specific
mia and paraneoplastic autonomic neuropathy. for the demyelinating types. Abnormal F waves in the presence of nor-
GBS may be strictly regional, as in the pharyngeal-cervical-brachial mal conduction velocities and distal latencies are more specific find-
variant. Patients present with rapid onset of symmetrical multiple cra- ings since they suggest proximal demyelination. Multiple or complex
nial nerve palsies (polyneuritis cranialis), most notably bilateral facial A (axon) waves, recorded from several nerves and sometimes replacing
palsy. Isolated facial diplegia with distal paresthesias may be a forme F waves, are also commonly associated with AIDP. Reduced ampli-
fruste of this variant of GBS (Susuki et al., 2009). tude or absent SNAPs in the upper extremity combined with normal
The existence of a sensory ataxic variant of GBS affecting mainly sural SNAPs (sural sparing pattern) are changes highly specific for the
sensory nerve fibers has long been suspected but rarely confirmed. diagnosis of AIDP and occur in about 50% of patients during the first
Such patients present with acute ataxia, sensory loss, areflexia, high 2 weeks of the illness (Albers and Kelly, 1989; Gordon and Wilbourn,
levels of CSF protein, and nerve conduction features of demyelination 2001). Sural sparing combined with abnormal F waves is highly spe-
(Oh et al., 2001). SNAPs are intact in 60% and reduced or absent in the cific (96% specific) for the diagnosis of AIDP, is present in about half
rest. Clinically, this variant is similar to the MFS, except for the lack of of the patients with AIDP and in about two-thirds of patients younger
ophthalmoplegia and reduced occurrence of elevated GQ1b antibodies than 60 years during the first 2 weeks of illness (Gordon and Wilbourn,
(65% vs. 98% in MFS). An acute and painful small-fiber neuropathy that 2001). A sensory ratio (sural + radial SNAPs/median + ulnar SNAPs)
is claimed to be another variant of GBS is reported to be responsive to is a good substitute for sural sparing pattern, particularly in elderly
corticosteroids, unlike the other variants (Dabby et al., 2006). It has patients who have absent sural SNAP or those with preexisting CTS. A
been suggested that GBS following cytomegalovirus (CMV) infection high ratio (>1) is fairly specific and distinguishes GBS from other axo-
is more likely to have prominent or predominant sensory involvement. nal polyneuropathies such as diabetic neuropathies. Conduction block
of motor axons, the electrophysiological correlate of clinical weakness, confirmatory sign of distal demyelination. Inability to distinguish
is recognized by a decrease of greater than 50% in CMAP amplitude demyelinating conduction block from reversible conduction failure and
from distal to proximal stimulation in the absence of temporal disper- axon-discontinuity conduction block has caused erroneous classifica-
sion. Conduction block at non-entrapment sites is highly specific for tion in up to one-third of GBS patients where the initial classification
demyelination, but it occurs only in 15%–30% of early GBS, depend- changed after serial recordings (Rajabally et al., 2015).
ing on the number of nerves and nerve segments studied. Patients The value of specific serological tests in the diagnosis of GBS is lim-
with weakness that is related primarily to conduction block tend to ited except in MFS and AMAN (Yuki and Hartung, 2012). There is no
have a faster and more complete recovery than those with diffusely specific ganglioside antibody that appears to be associated with AIDP.
low motor amplitudes. Prolonged distal motor latencies, reduction in Hence, these ganglioside antibodies are not clinically useful. However,
distal CMAP amplitudes, significant CMAP dispersion, and slowing elevated anti-GQ1b ganglioside antibodies are consistently found in
of motor conduction velocities are less common and tend to occur about 95%–98% of patients with MFS. Preceding C. jejuni infection
later in the course of the disease (Cleland et al., 2006; Cros and Triggs, has been linked to AMAN variant and high titers of anti-GM1, anti-
1996; Gordon and Wilbourn, 2001). Needle EMG is mostly comple- GD1b, anti-GD1a, and anti-GalNAc-GD1a ganglioside antibodies of
mentary in GBS, initially showing decreased motor unit recruitment. the IgG class (Jacobs et al., 1996). Serological tests for C. jejuni infection
Subsequently, if any amount of axonal degeneration occurs, fibrilla- are difficult both to perform and interpret. Other studies confirmed
tion potentials appear 2–4 weeks after onset. the presence of IgG antiglycolipid antibodies in 10%–40% of patients
In general, the EDX studies become more specific for multifocal with GBS but failed to show a correlation with C. jejuni infection (Ho
demyelination during the third and fourth weeks of illness (Albers et al., 1995). Elevated serum antibodies to Mycoplasma, CMV, or C.
and Kelly, 1989). In fact, about half of the patients have normal NCSs jejuni can pinpoint the preceding infection. Antigalactocerebroside
during the first 4 days of illness (except for absent H reflexes), while antibodies have been detected in patients with precedent Mycoplasma
only about 10% of them have normal studies by the first week of illness infection. Complement-fixing antibodies to peripheral nerve myelin
(Gordon and Wilbourn, 2001). Additionally, several EDX criteria have are present in most patients during the acute phase of GBS.
been advocated over the years, with sensitivities ranging from 20% to Imaging studies, more specifically MRI of the brain and spine, are
70% (Alam et al., 1998). In general, about two-thirds of patients fulfill most useful to exclude brainstem or spinal cord disease as a cause of the
the criteria for highly suggestive or definite AIDP in the first 2 weeks of weakness. MRI of the lumbar spine with gadolinium, however, may be
illness, with high specificity (95%–100%). EDX parameters are the most abnormal in GBS and may show nerve root enhancement of the cauda
reliable indicators of prognosis. Mean distal CMAP amplitude of less equina, particularly in children with GBS (Yikilmaz et al., 2010).
than 20% of the lower limit of normal (LLN) was associated with poor
outcome in the North American GBS study (Cornblath et al., 1988). Differential Diagnosis
However, low distal CMAPs may be due to distal demyelination with Care should be taken to distinguish GBS from other conditions leading
distal conduction block and often mimics axonal loss. Rapid recovery to subacute motor weakness (Box 106.12). Among the polyneurop-
of low distal CMAPs and SNAPs on sequential studies is a necessary athies with acute onset, acute porphyria, diphtheria, and occasional
BOX 106.12 Differential Diagnostic Considerations in Guillain-Barré Syndrome

Muscle Disorders •
Hypophosphatemia (parenteral hyperalimentation, phosphate-bindings
• Polymyositis antacids, acute alcohol intoxication, and severe respiratory alkalosis)
• Dermatomyositis
• Necrotizing autoimmune myopathy Peripheral Nerve and/Root Disorders
• Rhabdomyolysis (drugs, toxins, exercise, trauma, metabolic myopathies, • Guillain-Barré syndrome
etc.) • Acute intermittent porphyria
• Critical illness myopathy • Diphtheritic polyneuropathy
• Critical illness polyneuropathy
Muscle Membrane Disorders • Vasculitic neuropathy
• Familial periodic paralysis • Heavy metal acute poisoning (thallium, arsenic)
• Secondary hypokalemic paralysis (thyrotoxicosis, malabsorption, barium salt • Diffuse polyradiculopathy:
poisoning, or abuse of diuretics, laxatives, or licorice) • Infectious (Lyme, cytomegalovirus [CMV])
• Inflammatory (sarcoidosis)
Neuromuscular Junction Disorders • Neoplastic (solid tumors, lymphomas)
• Myasthenia gravis (myasthenic crisis)
• Botulism Anterior Horn Cell Disorders
• Drug-induced neuromuscular blockade • Acute poliomyelitis (wild-type polio viruses, West Nile virus, enteroviruses)
• Toxic:
• Organophosphate Spinal Cord Disorders
• Nerve gas • Transverse myelitis
• Tick • Cord compression (disc herniation, fracture/dislocation, epidural malignancy)
• Black widow spider • Cord infarction (anterior spinal artery syndrome)
• Snake venoms
• Metabolic: Brainstem Disorders
• Hypermagnesemia (toxemia of pregnancy treated with parenteral magne- • Central pontine myelinolysis
sium, magnesium-containing antacids, or cathartics) • Pontine infarct (basilar artery thrombosis)
toxic neuropathies (arsenic, thallium, buckthorn, acrylamide, organo- Approximately two-thirds of patients report a preceding event, most
phosphate compounds, and n-hexane) must be considered. Flaccid frequently an upper respiratory or gastrointestinal infection, surgery,
general weakness and failure to wean from the ventilator are common or immunization 1–4 weeks before the onset of neurological symptoms
features of critical illness polyneuropathy that develops in patients con- (Govoni and Granieri, 2001; Table 106.11). The agent responsible for
fined to the intensive care unit (ICU) with sepsis and multiorgan fail- the prodromal illness often remains unidentified. Specific infectious
ure. EDX features of an axonal neuropathy and normal CSF findings agents linked to GBS include CMV, Epstein-Barr virus, varicella-zoster
distinguish critical illness neuropathy from the classic form of GBS. virus (VZV), hepatitis A and B, HIV, Mycoplasma pneumoniae, and
A related syndrome, critical illness myopathy, follows the use of non- H. influenzae. Recent evidence from Colombia, French Polynesia, and
depolarizing neuromuscular blocking agents or IV corticosteroids Puerto Rico have shown that infection with Zika virus, a mosquito-
or both. Metabolic disturbances (severe hypophosphatemia, hypo- borne RNA Flavivirus, plays an important role in the development of
kalemia, or hypermagnesemia), rhabdomyolysis, and inflammatory GBS (Parra et al., 2016).
myopathies may result in rapidly progressive generalized weakness. The most common identifiable bacterial organism linked to GBS
Elevated creatine kinase (CK), abnormal serum electrolytes, and nee- and particularly its axonal forms is C. jejuni, a curved gram-negative
dle EMG help distinguish these disorders from GBS. Disorders of rod that is a common cause of bacterial enteritis worldwide. Evidence
neuromuscular transmission including myasthenic crisis, botulism, of C. jejuni infection from stool cultures or serological tests was found
and tick paralysis should also be considered. Myasthenic crisis is often in 26% of patients with GBS admitted to hospitals in the United
associated with CMAP decrement on slow-frequency repetitive nerve Kingdom, compared with 2% of case controls (Rees et al., 1995).
stimulation. Botulism develops after the consumption of contaminated Retrospective studies from the United States, Holland, Germany, and
foods, with ophthalmoparesis and facial and bulbar weakness. Nerve Australia report serological evidence of recent C. jejuni infection rang-
conduction studies reveal low-amplitude CMAPs, and high-frequency ing from 17% to 39% of patients with GBS. It should be noted that
repetitive nerve stimulation or maximal voluntary contraction leads to in the United States alone, an estimated 2.4 million cases of enteric
an incremental response that is typical of presynaptic neuromuscular infection with C. jejuni are reported per year, yet only about 2500 indi-
transmission defect. Acute brainstem infarct, spinal cord compression, viduals develop GBS. This suggests that host-related factors or certain
epidural abscess, and transverse myelitis may present diagnostic dif- polymorphisms of C. jejuni determine the development of GBS. C.
ficulties before upper motor neuron signs develop and before results jejuni infection may play an even greater role in northern China, where
of EDX and CSF studies become available. Among other signs, early the infection rates are 76% in patients with AMAN and 42% in patients
urinary retention and a sharply demarcated sensory level on the trunk with AIDP (Ho et al., 1995). Molecular mimicry between GM1 gangli-
suggest spinal cord disease and call for urgent spinal MRI. CSF pleocy- oside and C. jejuni lipo-oligosaccharide is established as the pathogenic
tosis (>50 cells per μL) casts doubt on the diagnosis of uncomplicated link for this association.
GBS and suggests inflammatory or neoplastic meningoradiculopathies Epidemiological data suggested a slight increase in cases of GBS fol-
such as secondary to Lyme disease, HIV infection, or CMV in AIDS. lowing the 1976 A/New Jersey influenza vaccine, although no excess risk
Poliomyelitis caused by the wild-type polio viruses may produce a rap- of developing GBS was seen with subsequent influenza vaccines. The
idly evolving asymmetrical weakness accompanied by fever and CSF most recent studies suggest an even further decline of reported cases of
pleocytosis. Poliomyelitis due to West Nile virus may lead to flaccid GBS after influenza vaccination from the low levels reported a decade
paralysis in up to 27% of patients with neurological complications. earlier, indicating that the risk of GBS after influenza vaccination now
stands at only one additional case per 2.5 million persons vaccinated
Pathology (Haber et al., 2004). A UK study also provides reassurance that the great
Classic pathological studies of AIDP have demonstrated endoneur- majority of sporadically occurring GBS is not associated with immuni-
ial perivascular mononuclear cell infiltration together with multifocal zation (Hughes et al., 2006b). For these reasons, prior GBS should not
demyelination. The peripheral nerves may be affected at all levels from preclude administration of influenza vaccines in high-risk individuals.
the roots to distal intramuscular motor nerve endings, although most Other vaccines (notably tetanus and diphtheria toxoids, rabies,
lesions usually occur on the ventral roots, proximal spinal nerves, and oral polio, and meningococcal conjugate vaccines); drugs including
lower cranial nerves. Intense inflammation may lead to axonal degener-
ation as a consequence of a toxic bystander effect. Ultrastructural stud- TABLE 106.11 Antecedent Events of
ies have shown that macrophages play a major role in demyelination
Guillain-Barré Syndrome
by stripping off myelin lamellae from the axon. The inflammatory infil-
trates consist mainly of class II-positive monocytes and macrophages, Antecedent Event Percentage
and T lymphocytes. The expression of class II antigen is increased in Respiratory illness 58
Schwann cells, raising the possibility that Schwann cells may present the Gastrointestinal illness 22
antigen to autoreactive T cells and activate the destruction of myelin. Respiratory and gastrointestinal illness 10
Pathological studies in patients with AMAN using electron microscopy Surgery 5
have demonstrated the presence of macrophages in the periaxonal space Vaccination 3
of myelinated internodes. Extensive primary wallerian-like degeneration Other 2
of motor and sensory roots and nerves without significant inflammation
or demyelination is found in cases of AMSAN. Serological Evidence of Specific Infectious Agents
Campylobacter jejuni
Pathogenesis Cytomegalovirus
The bulk of experimental and clinical evidence suggests that GBS is Human immunodeficiency virus
an organ-specific, immune-mediated disorder caused by a synergistic Epstein-Barr virus
interaction of cell-mediated and humoral immune responses against Mycoplasma pneumonia
peripheral nerve antigens that are still incompletely characterized Hepatitis A and B
(Kieseier et al., 2006a). Zika virus
streptokinase, suramin, gangliosides, and heroin; and Hymenoptera Infection

stings have been associated in a few cases. Several cases have occurred
in immunocompromised hosts with Hodgkin lymphoma or in phar-
macologically immunosuppressed patients after solid organ or bone Th*
marrow transplantation. IL-2 B
A preceding infection may trigger an autoimmune response AIDP
↑ E-selectin TNF-α
through “molecular mimicry,” in which the host generates an immune ↑ CAM IFN-γ
Increasing severity of immune attack

Blood–nerve
response against an infectious organism that shares epitopes with the Antimyelin
barrier (“leaky”)
host’s peripheral nerves. At the onset of disease, activated T cells play antibody
M*
a major role in opening the blood–nerve barrier to allow circulating
antibodies to gain access to peripheral nerve antigens. T-cell activation Proteases
C5b-9 TNF-α
markers (interleukin [IL]-6, IL-2, soluble IL-2 receptor, and interferon C C3d ? Glycolipid
γ [IFN-γ]) and tumor necrosis factor α (TNF-α), a proinflamma- M*
tory cytokine released by T cells and macrophages, particularly IL-23 M*
(Hu et al., 2006), are increased in patient serum. In addition, adhe- M*
sion molecules and matrix metalloproteinases are critically involved

Secondary axonal degeneration
in facilitating recruitment and transmigration of activated T cells and
monocytes through the blood–nerve barrier. Soluble E-selectin, an M*
M* M* M*
adhesion molecule produced by endothelial cells, and metalloprotein- M* M* M*
ases are increased in patients with GBS during the early stages of dis-
Fig. 106.17 Immune Injury to Nerve Fibers in Acute Inflammatory
ease. A cell-mediated immune reaction against myelin components is
Demyelinating Polyradiculoneuropathy (AIDP). Preceding infection may
supported by experimental allergic neuritis, the accepted animal model trigger formation of antimyelin autoantibodies and activated T-helper
for AIDP. Experimental allergic neuritis can be produced by active cells (Th*). Proinflammatory cytokines (tumor necrosis factor alpha [TNF-
immunization with whole peripheral nerve homogenate, myelin, or α], interferon gamma [INF-γ]), and upregulation of adhesion molecules
PNS-specific myelin basic protein P2, P0, or galactocerebroside. (E-selectin, intercellular adhesion molecule [ICAM]) facilitate breakdown
Several observations indicate that humoral factors also partici- of blood–nerve barrier to activated T cells, macrophages, and antimyelin
pate in the autoimmune attack on peripheral nerve myelin, axons, antibodies. Antimyelin antibodies react with epitopes on the abaxonal
and nerve terminals: (1) immunoglobulins and complement can be Schwann cell membrane, with consequent activation of complement.
demonstrated on myelinated fibers of affected patients by immu- Deposition of complement activation products (C3d) and membrane
nostaining; (2) MFS and AMAN are strongly associated with specific attack complex (C5b-9) on the outermost Schwann cell membrane leads
to vesicular myelin changes, followed by recruitment of macrophages
antiganglioside antibodies; (3) serum from MFS and AMAN patients
(M*) and progressive demyelination. Intense inflammation may lead to
contains IgG antibodies that block peripheral nerve transmission in a secondary axonal degeneration. B, B cell; IL-2, interleukin 2. (Adapted
mouse nerve-muscle preparation; (4) complement C1-fixing antipe- from Bosch, E.P., 1998. Guillain-Barré syndrome: an update of acute
ripheral nerve myelin antibody can be detected in the serum of patients immune-mediated polyradiculoneuropathies. Neurologist 4, 211–226.)
during the acute phase of GBS; (5) intraneural injection of GBS serum
into rat sciatic nerve results in secondary T-cell infiltration of the
injection site at the time of the appearance of the hind limb weakness; (Hafer-Macko et al., 1996; Fig. 106.18). These findings suggest that
and (6) plasmapheresis or immunoglobulin infusions result in clinical AMAN is caused by an antibody- and complement-mediated attack
improvement. on axolemmal epitopes of motor fibers. The most attractive candidate
Understanding of the immune mechanisms of GBS, including targets are GM1- and asialo-GM1-like gangliosides, which are present
AIDP and its axonal subtypes, was enhanced by the detailed immu- in nodal and internodal membranes of motor fibers. Certain C. jejuni
nohistochemical and ultrastructural studies of clinically well-defined strains associated with axonal GBS and MFS variants contain GM1-
autopsied cases from northern China. The earliest changes seen in like epitopes in their polysaccharide coats. Anti-GM1 and GQ1b anti-
AIDP within days of onset consisted of deposition of complement bodies that cross-react to these lipopolysaccharide epitopes are found
activation products and membrane attack complex on the outer- in a high proportion of patients with AMAN and MFS, respectively,
most Schwann cell surface, followed by vesicular myelin changes at as well as in some patients with AIDP. These observations have led
the outermost myelin lamellae, with subsequent recruitment of mac- to the concept of molecular mimicry in which epitopes of the infec-
rophages and progressive demyelination (Hafer-Macko et al., 1996). tious agent elicit antibodies that cross-react with shared epitopes on
Previously, the role of complement had been suggested by the finding axons. The nerve fibers thereby become the inadvertent targets of an
of increased levels of complement activation products in CSF and sol- immune response directed against an infectious organism. The anti-
uble terminal complement complexes in serum of patients with AIDP. ganglioside antibodies obtained from AMAN and MFS patients block
The immune attack in AIDP appears to begin with binding of auto- neuromuscular transmission in an in vitro nerve-muscle preparation.
antibodies to specific epitopes on the outermost Schwann cell mem- The blocking activity of these IgG antibodies can be neutralized by
brane, with consequent activation of complement (Fig. 106.17). The IVIG (Buchwald et al., 2002). Furthermore, rabbits immunized with
nature of the epitope in AIDP, although still uncertain, is likely to be GM1 develop AMAN, thereby fulfilling the postulates for confirming
a glycolipid. Pathological studies of early cases of AMAN found depo- an autoimmune pathogenesis (Sheikh and Griffin, 2001). AMSAN
sition of activated complement components and immunoglobulins may be caused by a more severe immune injury triggered by axonal
at the nodal axolemma. This was followed by disruption of the para epitopes because similar pathological changes affecting motor and sen-
nodal space, allowing the entry of complement and immunoglobulins sory fibers have been observed in cases of AMSAN. In addition to C.
along the axolemma, with subsequent recruitment of macrophages to jejuni and gangliosides, molecular mimicry for GBS is also shown with
affected nodes. Finally, macrophages were shown to invade the peri- for Mycoplasma pneumonia and galactocerebroside, and CMV infec-
axonal space, leading to wallerian-like degeneration of motor fibers tion and moesin (Sawai et al., 2014).
Infection
GM1 epitope
Th* B
AMAN
Blood–nerve barrier
(“leaky”)
Increasing severity of immune attack
Anti-GM1
M* antibody
GM1 GM1
epitope epitope
M* M* M* M*
M*
C3d C5b-9
Motor nerve
terminals
M* M* M* M*
M* M* M*
Motor-sensory axonal pattern
AMSAN
Fig. 106.18 Immune Injury to Nerve Fibers in Acute Motor Axonal Neuropathy (AMAN). Molecular mimicry
of GM1-like epitopes common to both lipopolysaccharide coats of certain Campylobacter jejuni strains and axonal
membranes may cause an autoimmune response. Activated complement components (C3d, C5b-9) and immu-
noglobulins are found at nodes of Ranvier and along axolemma of motor fibers. Macrophages (M*) are recruited
to targeted nodes and invade periaxonal space, leading to wallerian degeneration. Lack of blood–nerve barrier at
motor nerve terminals may make these distal axons vulnerable to circulating GM1 antibodies. AMSAN, Acute
motor sensory axonal neuropathy; B, B cell; Th*, activated T-helper cells. (Adapted from Bosch, E.P., 1998. Guillain-
Barré syndrome: an update of acute immune-mediated polyradiculoneuropathies. Neurologist 4, 211–226.)
Treatment from baseline, maximal inspiratory pressure less than 30 cm H2O,

General supportive management is the mainstay of treatment. and maximal expiratory respiratory pressure of less than 40 cm H2O
Patients with rapidly worsening acute GBS should be observed in the (Lawn et al., 2001). This so-called 20-30-40 rule allows patients at risk
hospital until the maximum extent of progression has been estab- to be identified and transferred to an ICU for even closer monitoring.
lished. The reduction in mortality to less than 5% reflects improve- In a series of 200 patients, short disease duration, inability to lift the
ments in modern critical care. The prevention of complications, of head from the bed, and a vital capacity of less than 60% predicted
which respiratory failure and autonomic dysfunction are the most the need for mechanical ventilation in 85% of patients with all three
important, provides the best chance for a favorable outcome (Bosch, risk factors (Sharshar et al., 2003). Elective intubation for ventilatory
1998). Respiratory and bulbar function, ability to handle secretions, assistance should be performed when FVC falls below 12–15 mL/kg
heart rate, and blood pressure should be closely monitored during or below 18 mL/kg in patients with severe oropharyngeal weakness,
the progressive phase. Respiratory failure requiring mechanical ven- or when arterial PO2 values fall below 70 mm Hg with inspired room
tilation develops in up to 30% of patients with GBS. Predictors of air. When respiratory assistance is needed for longer than 2 weeks, a
future need for mechanical ventilation include rapid disease progres- tracheostomy should be performed.
sion (onset to admission in <7 days), severity of limb weakness, pres- In the event of cardiac arrhythmias or marked fluctuations of blood
ence of facial weakness, and bulbar weakness (Walgaard et al., 2010). pressure, continuous ECG and blood pressure monitoring allow early
Hence, patients with one or more of these predictors, evidence of detection of life-threatening situations that require prompt treatment.
dysautonomia, or signs of respiratory insufficiency should be admit- Antihypertensive and vasoactive drugs must be used with extreme
ted to the ICU for closer observation. Signs of impending respiratory caution in the presence of autonomic instability. Tracheal suction-
failure include deterioration in forced vital capacity (FVC), declining ing may trigger sudden episodes of hypotension or bradyarrhythmia.
maximal respiratory pressures, and hypoxemia caused by atelectasis. Back and radicular pain often respond to NSAIDs. At times, oral or
Initially it may be necessary to monitor FVC and negative inspira- parenteral opioids are required for adequate pain control. Increased
tory pressure every 4–6 hours while the patient is awake. Patients metabolic requirements together with negative caloric intake caused
should be monitored by pulse oximetry, especially at night, for the by impaired swallowing may lead to a state of relative starvation in
early detection of oxygen desaturation. Serial measures of decline severely affected patients. Nutritional requirements should be met by
in respiratory function that could predict future respiratory fail- providing a high-caloric protein diet or by beginning enteral feedings
ure include vital capacity of less than 20 mL/kg or a decline by 30% as early as possible.
Subcutaneous heparin or low-molecular-weight heparin together Anti-idiotypical antibodies supplied by IVIG that have the poten-
with calf compression devices should be ordered routinely in immobi- tial to bind and neutralize pathogenetic antibodies are the proposed
lized patients to lower the risks of venous thrombosis and pulmonary mode of action. Minor side effects such as headaches, myalgias and
embolism. Infections of the lung and urinary tract develop in almost arthralgias, flulike symptoms, fever, and vasomotor reactions are
half of patients with GBS in the ICU. Prevention and prompt treat- observed when infusion flow rates are excessive. More serious com-
ment of nosocomial infections are important aspects of care. Chest plications such as anaphylaxis in IgA-deficient individuals (1 per 1000
physical therapy and frequent oral suctioning aid in preventing atel- population, who develop anti-IgA antibodies after the first course of
ectasis in patients with impaired cough and sigh. Skilled nursing care IgA-containing IVIG infusions), aseptic meningitis, congestive heart
with regular turning and attention to skin, eyes, mouth, bowel, and failure, thrombotic complications (venous thrombosis and cerebral
bladder are essential. Exposure keratitis is avoided in cases of facial and myocardial infarctions), and transient renal failure, have been
diplegia by using artificial tears and by taping the eyelids closed at reported (Brannagan, 2002). The rate of vascular complications, par-
night. Pressure-induced ulnar or fibular nerve palsies are prevented ticularly cerebral and myocardial infarctions, is higher in patients with
by proper positioning and padding. Physical therapy is started early vascular risk factors treated with a more rapid infusion rate. To pre-
because it helps prevent contractures, joint immobilization, and vent headache and possibly aseptic meningitis, patients should be pre-
venous stasis. Psychological support and constant reassurance about treated with oral acetaminophen, 500–1000 g, or ibuprofen, 800 mg, a
the potential for recovery are important for the morale of patients and few hours before each infusion; the dose can be repeated 6 hours later
family members. In the recovery phase, skilled physical therapy and if headache develops. IVIG has become the preferred treatment for
rehabilitation hasten recovery. acute GBS in US hospitals, probably because of ease of administration
Among specific therapeutic interventions aimed at mitigating (Alshekhlee et al., 2008b; Fig. 106.19). For patients with hyperviscosity,
the harmful effects of the autoimmune reaction and autoantibodies, congestive heart failure, chronic renal failure (especially that due to
plasma exchange and high-dose IVIG infusions have been shown to diabetes), or congenital IgA deficiency, IVIG is contraindicated and
be equally effective. Six large randomized controlled trials involv- plasma exchange is preferred.
ing more than 600 patients have established the benefit of centrifu- The optimal effective dose of IVIG has not been well established.
gal plasma exchange in acute GBS by shortening the recovery time The IVIG dose used in the clinical trials and in practice was set arbi-
(Lehmann et al., 2006). Therapeutic plasma exchange is recom- trarily at a total of 2 g/kg divided in 5 days (0.4 g/kg/day) empirically
mended for patients with moderate to severe weakness (defined as based on clinical experience in patients with idiopathic thrombocy-
the ability to walk only with support or worse). Benefits are clearest topenic purpura. Six daily infusions of 0.4 g/kg were reported to be
when plasma exchange is begun within 2 weeks of onset. The effect superior to three daily infusions in patients who could not receive
of plasma exchange in mildly affected patients and the optimal num- plasma exchange (Raphael et al., 2001). GBS patients receiving the
ber of exchanges were investigated by the French Cooperative Group standard dose of IVIG (0.4 g/kg/day × 5 days) have a large variation
on Plasma Exchange (1997). Even mildly affected patients bene- of IgG levels measured 2 weeks after infusion, and those with a smaller
fited from two exchanges. Four exchanges were optimal for mod- increase in IgG level do worse, independent of other prognostic factors
erate and severe cases, and six exchanges did not have additional (Kuitwaard et al., 2009). It is not yet known whether the infusion of
benefit. The recommended plasmapheresis schedule entails a series additional IVIG to patients who show a small increase in IgG levels is
of four to five exchanges (40–50 mL/kg) with a continuous flow beneficial.
machine on alternate days, using saline and albumin as replacement With both plasma exchange and IVIG, one or more episodes of
fluid. A Cochrane review confirmed the value of plasma exchange deterioration following the initial improvement or stabilization after
over supportive therapy in hastening the recovery from GBS when treatment, described as “treatment-related fluctuations,” may be
started within 30 days after disease onset (Raphael et al., 2002). encountered in 10%–20% of patients. This may pose practical prob-
Plasmapheresis should be performed only in centers with experience lems both in terms of treatment and in differentiating these patients
in exchange techniques in critically ill patients. Most serious compli- from those who are developing a rapid-onset CIDP (Ruts et al., 2005).
cations are linked to venous access problems, including hematoma Additional rescue treatment with IVIG or plasma exchange in patients
formation at puncture sites, pneumothorax after insertion of central with poorly responsive or relapsing GBS may be useful (Alboudi et al.,
lines, and catheter-related septicemia. Septicemia, active bleeding, 2019); however, prospective randomized studies to either a second-line
and severe cardiovascular instability are contraindications for plas- treatment or supportive management are needed for patients who do
mapheresis. Filtration-based plasma exchange techniques, which use not respond or relapse after first-line treatment.
porous membranes for filtration, has similar safety and efficiency Corticosteroids are not recommended because two randomized
when compared to centrifugal plasma exchange. A single study com- controlled trials, one using conventional doses of prednisolone and
paring these two modalities in patients with GBS demonstrated a the other using high-dose IV methylprednisolone, have found no ben-
shorter time to onset of effect and greater change in disability with efit. The combination of IVIG with methylprednisolone failed to find
centrifugal plasma exchange. However, mortality and outcome after significant long-term advantage over IVIG alone in one trial. A recent
6 months were not different between the two therapeutic modalities Cochrane review confirms that corticosteroids do not produce signifi-
(Lyu et al., 2002). cant benefit or harm (Hughes et al., 2006c).
Three randomized trials comparing IVIG with plasma exchange
demonstrated the benefit of five daily infusions of immunoglob- Course and Prognosis
ulin (0.4 g/kg/day) given in the first 2 weeks of the disease (Plasma Approximately 15% of GBS patients have a mild condition, remain
Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group, ambulatory, and recover after a few weeks. Conversely, 5%–20% of
1997). Both treatment modalities were equally effective. There was no patients have a fulminant course and develop flaccid quadriplegia, ven-
advantage of using both together. These findings were confirmed by tilator dependence, and axonal degeneration, often within 2 days from
another Cochrane systematic review (Hughes et al., 2001b). In pediat- the onset of symptoms. The recovery is delayed and virtually always
ric patients with GBS, IVIG seems to be of similar efficacy as in adults incomplete and most have substantial residual motor deficits at 1-year
(Korinthenberg et al., 2005). follow-up. Patients with AMAN and electrophysiological evidence of
MANAGEMENT OF GBS
Fulfills clinical criteria
Normal: repeat in 1 wk
NCS and CSF exam
Consider other diagnostic possibilities
Abnormal: diagnosis confirmed
Monitor bulbar function, BP, FVC q4–6 h

Assess clinical severity FVC <12–15 mL/kg
Walks unassisted Walks with support or bedbound Mechanical ventilation
No
Symptoms <30 days
progression
a b
Conservative management IVIG Plasma exchange
Fig. 106.19 Decision-Making Pathway in Management of Guillain–Barré Syndrome. Both treatment

options, intravenous immunoglobulin (IVIG) (a) and plasma exchange (b), are equally efficacious. IVIG is pre-
ferred because of its ease of administration. BP, Blood pressure; CSF, cerebrospinal fluid; GBS, Guillain–
Barré syndrome; FVC, forced vital capacity; NCS, nerve conduction studies. (Adapted from Bosch, E.P.,
1998. Guillain-Barré syndrome: an update of acute immune-mediated polyradiculoneuropathies. Neurologist
4, 211–226.)
axonal failure have a prognosis which is comparable to patients’ AIDP. Patients with GBS should reach their maximum deficit within 4
This is explained by reversible conduction failure caused by tran- weeks of onset; if the disease progresses over a longer period of time,
sitory dysfunction at the node of Ranvier without secondary axonal CIDP should be considered. About 5% of patients initially diagnosed
degeneration. with GBS develop a more protracted course similar to CIDP: hence the
Because progressive axonal degeneration of nerve roots results term acute-onset CIDP (Odaka et al., 2003). Acute-onset CIDP should
in the disintegration of axonal membrane and release of axoskeletal be considered if GBS patients have one or more of these findings: (1)
proteins such as neurofilaments and tau proteins into the CSF, it has deteriorate after 8 weeks; (2) have more than two treatment-related
been suggested that higher levels of CSF neurofilaments and tau serve fluctuations, particularly when they occur beyond 1 month of the ill-
as predictors of worse motor and functional outcome (Jin et al., 2006; ness; (3) have prominent sensory symptoms or signs; (4) have multi-
Petzold et al., 2006). focal enlargement of peripheral nerves on ultrasound; or (5) develop
Up to 30% of patients with GBS develop respiratory insufficiency new prominent demyelinating features on follow-up EDX studies
requiring assisted ventilation, and between 2% and 5% die of compli- many months after the initial presentation (Anadani and Katirji, 2015;
cations (Alshekhlee et al., 2008a). After progression stops, patients enter Kerasnoudis et al., 2015; Ruts et al., 2010a). Recent studies have also
a plateau phase lasting 2–4 weeks or longer before recovery begins. suggested that nerve excitability techniques may be useful in distin-
Although most patients recover functionally, 20% still have residual guishing acute-onset CIDP from AIDP at the initial stage of disease
motor weakness 1 year later. Approximately 70% of patients complete (Sung et al., 2014).
their recovery in 12 months and 82% in 24 months. Up to 5% of patients
may have a recurrence following recovery. Predictors for poor recov-
ery (<20% probability of walking independently at 6 months) include Chronic Inflammatory Demyelinating
older age (>60 years), history of preceding diarrheal illness, recent CMV Polyradiculoneuropathy
infection, ventilatory support, rapid progression reaching maximum CIDP is a heterogeneous group of immune-mediated neuropathies
deficit in less than 7 days, hyponatremia, and low distal CMAP ampli- characterized by a relapsing-remitting or a chronically progressive
tudes (20% of LLN or less) or inexcitable nerves. The overall prognosis clinical course, typically exceeding 8 weeks, and demyelinating fea-
of GBS is also influenced by the patient’s age, the severity of illness at tures on EDX testing. Many similarities exist between CIDP and AIDP,
its peak, and whether immunomodulating therapies are initiated early. the most common acute form of GBS. Both disorders have similar
Complications such as acute hypoxic-ischemic encephalopathy and clinical features, involve the spinal roots and peripheral nerves, and
infectious episodes also probably worsen the prognosis. share the CSF albuminocytological dissociation and the pathological
abnormalities of multifocal inflammatory demyelination, with nerve nerves, papilledema, and facial or bulbar weakness. Rarely, respiratory
conduction features reflecting demyelination. An autoimmune basis failure requiring mechanical ventilation or autonomic dysfunction
is suspected for both disorders, although the supporting evidence may be seen. Massive nerve root enlargement, causing myelopathy
remains incomplete (Hughes et al., 2006a; Nobile-Orazio et al., 2014). or symptomatic lumbar stenosis, or vision loss due to progressive
The major differences between the two conditions are in the time pseudotumor cerebri are other unusual clinical features (Midroni and
course, prognosis, and their response to corticosteroids. CIDP has a Dyck, 1996). Occasionally, CIDP may be associated with a relapsing
more protracted clinical course, is rarely associated with preceding multifocal demyelinating CNS disorder resembling multiple sclerosis,
infections, has an association with human lymphocyte antigens, and with CNS demyelination confirmed by abnormal visual and somato-
responds to corticosteroid therapy. sensory evoked potentials and brain MRI (Falcone et al., 2006).
Two patterns of temporal evolution of CIDP can be seen. More than Chronic inflammatory demyelinating polyradiculoneuropathy
60% of patients show a continuous or stepwise progressive course over variants. CIDP has several atypical clinical variants with different
months to years, and one-third have a relapsing course with partial or distribution of weakness and sensory deficits. These atypical CIDP
complete recovery between recurrences, whereas acute-onset CIDP is variants constitute about 18%–20% of all CIDP patients (Donuddu
rare. The age of onset may influence the course of the disease. In one et al., 2019).
large series, the age of onset was younger (mean 29 years) in those who Some patients fulfilling the diagnostic criteria for CIDP have only
had a relapsing course than in those experiencing a chronic progressive distal limb involvement with symmetric, sensory, or sensorimotor symp-
course (mean 51 years). A history of preceding infection is found in toms and signs, often with sensory ataxia (distal acquired demyelinating
less than 10%. In contrast, pregnancy is associated with a significant symmetric neuropathy, or DADS variant). Electrophysiological studies
number of relapses, occurring mainly in the third trimester and the showed symmetrical and uniform slowing of distal latencies more than
immediate postpartum period. Human lymphocyte antigen-linked conduction velocities with rare conduction blocks. Nearly two-thirds of
genetic factors may influence susceptibility to CIDP. these patients have IgM monoclonal gammopathies, and though they
The prevalence of CIDP ranges from 1 to 9 per 100,000 of the have been reported to respond poorly to therapy, some patients respond
population depending on diagnostic criteria (Rajabally et al., 2009). favorably to IVIG or rituximab (Dalakas et al., 2009; Katz et al., 2000).
Although precise prevalence figures are not available for the United Multifocal distribution of weakness and sensory deficits are seen
States, CIDP represents 13%–20% of all initially undiagnosed neurop- in some patients. This multifocal form of CIDP, initially identified
athies referred to specialized neuromuscular centers. by Lewis and Sumner (hence the term Lewis-Sumner variant), is also
The substantial clinical, pathological, and electrophysiological vari- described by the acronym MADSAM (multifocal asymmetric demye-
ability of CIDP accounts for many of the diagnostic problems encoun- linating sensory and motor) neuropathy. Electrophysiological studies
tered in clinical practice, including the commonly observed under- or demonstrating focal conduction block or severe slowing of nerve con-
overdiagnosis of this condition. Inaccurate diagnosis may result in duction distinguish this multifocal demyelinating neuropathy from
months if not years of expensive, ineffective, and potentially harmful the vasculitic axon-loss multiple mononeuropathies. Unlike MMN,
treatments. Misdiagnosis of CIDP is increasingly occurring due to both patients with this multifocal variant of CIDP have clinical and electro-
clinical and EDX flaws. Erroneous diagnosis of CIDP is often due to physiological involvement of both motor and sensory nerves, increased
inclusion of extremely atypical forms, many patients with sensory symp- CSF protein, and a good response to corticosteroids.
toms only and reliance on wrong electrophysiological interpretation of Pure sensory and pure motor variants of CIDP are relatively com-
acquired demyelination such as absence of conduction block at non-en- mon. In both variants, motor conduction studies are abnormal despite
trapment sites, presence of mild amplitude-dependent slowing in axonal the absence of motor symptoms and signs in the sensory types.
polyneuropathies and diabetics, and slowing of conduction velocity at Selective involvement of sensory nerve roots, termed chronic immune
compression sites only (Allen and Lewis 2015; Allen et al., 2018). Other sensory polyradiculopathy (CISP), is likely another variant of CIDP. Such
sources of inaccuracies include subjective perception of treatment ben- patients present with a sensory ataxic syndrome with normal motor and
efit and presence of only mild or moderate elevation of CSF protein. sensory conduction studies. Sensory nerve root involvement is suggested
by abnormal somatosensory evoked responses, enlarged lumbar roots on
Clinical Features MRI, and elevated CSF protein. In selected cases, nerve root biopsy con-
CIDP is a lifelong disease that invariably causes some degree of disabil- firms segmental demyelination, onion bulbs, and endoneurial inflamma-
ity even with the most effective immunomodulating therapies (Lewis, tion (Sinnreich et al., 2004). These patients have a positive response to IVIG.
2007). It is seen at all ages, with the peak incidence in the fifth and Selective involvement of sensory and motor nerve roots, termed
sixth decades. The manifestations at onset are extremely variable. Most chronic immune sensorimotor polyradiculopathy (CISMP), is increas-
patients have symmetrical motor and sensory involvement, although ingly recognized (Thammongkolchai et al., 2019). This is considered
occasional cases with predominantly motor involvement may be seen a variant of CIDP and is responsive to IVIG. These patients have
(Mathey et al., 2015). To fulfill diagnostic criteria for CIDP, weakness both weakness and sensory symptoms with chronically progressive,
must be present for at least 2 months. Proximal limb weakness is almost stepwise, or recurrent symptoms. EDX studies show normal SNAPs
as severe as distal limb weakness, indicating a non-length-dependent and normal motor conduction studies (except for some reduction of
neuropathy. Muscle wasting is rarely pronounced. These signs provide CMAP amplitudes) without slowing or conduction blocks. The major-
helpful clinical clues to separate CIDP patients from those with axo- ity have abnormal F-waves and H-reflexes. Needle EMG is consistent
nal neuropathies. Both upper and lower limbs are affected, although with polyradiculopathy pattern with fibrillation potentials and large
the legs are often more severely involved. Generalized hyporeflexia or MUAPs with reduced recruitment involving multiple myotomes with
areflexia is the rule. Sensory symptoms in a stocking-glove distribu- or without involvement of the paraspinal muscles. CSF protein is ele-
tion (numbness or tingling) implicating large-fiber involvement occur vated and MRI often shows enhancing caudal and lumbosacral roots
frequently, whereas pain occurs less frequently. Children differ from in the majority of patients, confirming the inflammatory root pathol-
adults by having a more precipitous onset and more prominent gait ogy (Thammongkolchai et al., 2019). When regional and limited to the
abnormalities. Additional findings, listed in decreasing order of fre- lower extremities, this is sometimes referred to as chronic inflamma-
quency, are postural tremor of the hands, enlargement of peripheral tory lumbosacral polyradiculopathy (Caporale et al., 2011).
A syndrome characterized by chronic ataxic neuropathy and oph-

BOX 106.13 Diagnostic Criteria for
thalmoplegia is associated with disialosyl-ganglioside IgM antibodies and
cold agglutinins (known under the acronym CANOMAD) and is con-
Chronic Inflammatory Demyelinating
sidered a CIDP variant. The IgM protein has autoantibodies directed Polyradiculoneuropathy
against gangliosides, specifically to GD1b and GQ1b (Arbogast Mandatory Clinical Criteria
et al., 2007; Eurelings et al., 2001; Willison et al., 2001). Autopsies Progressive or relapsing muscle weakness for 2 months or longer
have shown dorsal root ganglionopathy with significant loss of dor- Symmetrical proximal and distal weakness in upper or lower extremities
sal root ganglion cells and dorsal column atrophy as well as clonal Hyporeflexia or areflexia
IgM anti-disialyl gangliosides secreting B lymphocytes within cranial
and peripheral nerves (McKelvie et al., 2013). Optimal treatment Mandatory Laboratory Criteria
for CANOMAD is not yet established. Plasma exchange followed Nerve conduction studies with features of demyelination (motor nerve conduc-
by rituximab or cyclophosphamide and IVIG may halt or improve tion <70% of lower limit of normal [LLN])
symptoms. Surgical correction of strabismus usually improves ocular Cerebrospinal fluid protein level >45 mg/dL, cell count <10/μL
motility and visual symptoms. Sural nerve biopsy with features of demyelination and remyelination including
It is important to remember that CIDP is a syndrome with many myelinated fiber loss and perivascular inflammation
underlying causes. Acquired demyelinating polyradiculoneuropathies
meeting the diagnostic criteria for CIDP may be associated with HIV-1 Mandatory Exclusion Criteria
infection, systemic lupus erythematosus (SLE), monoclonal gammop- Evidence of relevant systemic disease or toxic exposure
athy of undetermined significance (MGUS), chronic active hepatitis, Family history of neuropathy
and inflammatory bowel disease. Compared with idiopathic CIDP, Nerve biopsy findings incompatible with diagnosis
the patients with a monoclonal gammopathy tend to be older, have a
more protracted course but less severe functional impairment at pre- Diagnostic Categories
sentation, and respond less favorably to immunomodulatory therapy Definite: mandatory inclusion and exclusion criteria and all laboratory criteria
(Dalakas et al., 2009). Probable: mandatory inclusion and exclusion criteria and two of three labo-
Excluding patients with MGUS, CIDP has been reported in associ- ratory criteria
ation with hematological malignancies (including Waldenström mac- Possible: mandatory inclusion and exclusion criteria and one of three labora-
roglobulinemia [WM], multiple myeloma, POEMS syndrome, and tory criteria
Castleman disease) and lymphomas. Onset of CIDP frequently pre- Adapted from Cornblath, D.R., Asbury, A.K., Albers, J.W., et al., 1991.
ceded that of lymphoma. Occasional patients with malignant melanoma Research criteria for diagnosis of chronic inflammatory demyelinating
or after therapy by vaccination with melanoma lysates develop CIDP. polyneuropathy (CIDP). Neurology 41, 617–618.
The association between melanoma and CIDP might be explained by
molecular mimicry because both melanoma and Schwann cells are
derived from neural crest tissue and share common glycolipid antigens Laboratory Studies
(Weiss et al., 1998). The diagnosis of CIDP is supported by a laboratory profile including
CIDP may occasionally be drug induced. A demyelinating neu- EDX, CSF, and nerve biopsy findings (Box 106.13). A pattern of nerve
ropathy mimicking CIDP may follow treatment with tacrolimus, conduction changes strongly supports acquired multifocal and non-
a macrolide antibiotic with strong immunosuppressive properties. uniform demyelination. This includes (1) reduction in motor conduc-
Similarly, CIDP may be triggered by TNF-α antagonists, including tion velocities in at least two motor nerves (<80% of LLN if CMAP
etanercept, infliximab, and adalimumab (Alshekhlee et al., 2010). amplitude >80% of LLN, and <70% of LLN if CMAP amplitude <80%
The neuropathic manifestations in these patients may start as of LLN); (2) partial conduction block (proximal CMAP amplitude
early as 2 weeks after initiation of therapy or as late as 16 months. and area <50% of distal in long nerve segments, or proximal CMAP
Interferon-alpha treatment has been reported to induce CIDP and amplitude and area <20%–50% of distal in short nerve segments) or
Lewis-Sumner variant as well as AIDP, neuralgic amyotrophy, abnormal temporal dispersion in at least one motor nerve at non-en-
and cranial neuropathies (Supakornnumporn and Katirji, 2018). trapment sites; (3) prolonged distal latencies in at least two motor
Immune checkpoint–blocking antibodies are new immunotherapy nerves (>125% of upper limit of normal [ULN] if CMAP amplitude
tools that have shown remarkable benefit in the treatment of a range >80% of LLN, and >150% of ULN if CMAP amplitude <80% of LLN);
of cancer types, including melanoma, lung cancer, and urological and (4) absent F waves or prolonged F-wave latencies in at least two
malignancies. The majority of these agents, including ipilimumab motor nerves (>125% of ULN if CMAP amplitude >80% of LLN, and
(anti-CTL-4, cytotoxic T-lymphocyte antigen 4), nivolumab and >150% of ULN if CMAP amplitude <80% of LLN). At least three cri-
pembrolizumab (anti-PD-1, programmed cell death 1), and atezoli- teria are necessary to fulfill the diagnosis of CIDP.
zumab, avelumab, and durvalumab (anti-PD-L1, programmed cell Neuromuscular ultrasound of peripheral nerves in patients with
death ligand 1) have been reported to induce or worsen autoim- CIDP often shows multiple sites of nerve enlargement at non-en-
mune diseases including myasthenia gravis and myositis (Kolb et al., trapment sites, and increased intra- and inter-nerve size variabilities
2018). CIDP and AIDP have also been reported following the use of and increased nerve vascularization (Goedee et al., 2017; Padua et al.,
immune checkpoint–blocking antibodies (Supakornnumporn and 2014). Enlargements of proximal median nerve segments in the arms
Katirji, 2017, 2018). and any trunk of the brachial plexus is highly specific and sensitive
CIDP is claimed to be more than 10 times more frequent in patients findings in confirming CIDP and its variants, and reliably distinguish
with both insulin-dependent diabetes mellitus (IDDM) and noninsu- them from axonal neuropathies and motor neuron disease (Goedee
lin-dependent diabetes mellitus (NIDDM), and these patients respond et al., 2017).
to IVIG therapy (Sharma et al., 2002a). Appropriate laboratory studies CSF protein values in excess of 45 mg/dL are found in 95% of cases,
are necessary to separate these polyradiculoneuropathies from idio- and levels above 100 mg/dL are common. CSF pleocytosis is rare except
pathic CIDP without concurrent disease. in HIV-associated CIDP. MRI scanning may demonstrate gadolinium
A B
Fig. 106.20 A, T2-weighted postgadolinium sagittal lumbar magnetic resonance image showing diffuse
enlargement of cauda equina, with abnormal enhancement, in patient with chronic inflammatory demyelinat-
ing polyradiculoneuropathy. B, Hypertrophic nerve roots are best appreciated in parasagittal image.
enhancement of lumbar roots, providing radiological evidence of an using immunocytochemical markers. One study demonstrated epi-
abnormal blood-nerve barrier (Bertorini et al., 1995; Fig. 107.20). Blood neurial T cells in perivascular clusters and endoneurial infiltration of
cell counts, sedimentation rate, and biochemical screening tests are macrophages and T cells. Rarely is the biopsy entirely normal.
important to exclude systemic disorders. Serum and urine immunoelec-
trophoresis with immunofixation, a skeletal bone survey, or both are Treatment
required to look for the cause of an associated monoclonal gammopathy Corticosteroids, plasmapheresis, and immunoglobulin infusion are all
or underlying myeloma. Antimyelin antibodies directed against MPZ effective in CIDP and are the mainstays of treatment. About 50%–70%
(P0) have been found in a small proportion of patients (Yan et al., 2001). of patients respond to each of these treatments. Also, almost 50%
About 10% of patients with CIDP have antibodies against proof patients not responding to the first treatment respond to the sec-
teins of the node of Ranvier. Antibodies of the IgG4 isotype target ond therapy. The efficacy of these therapies was confirmed in recent
the paranodal proteins contactin-1 (CNTN1) and neurofascin-155 Cochrane Reviews and in consensus statements published by several
(NF155). This parallels the emerging evidence of nodo-paranodopa- neurological associations (Donofrio et al., 2009; Eftimov et al., 2009;
thy as a possible key pathophysiology in CIDP and immune-mediated Joint Task Force of the EFNS and the PNS, 2010; Mehndiratta and
neuropathies. These patients tend to have more severe, mostly motor, Hughes, 2002; Mehndiratta et al., 2004; Patwa et al., 2012).
polyneuropathy, with axonal loss and poor response to IVIG (Mathey Daily single-dose oral prednisone is started at 60–80 mg (1–1.5
et al., 2017; Querol and Illa, 2015). mg/kg for children). Improvement can be anticipated to start within
The changes in sural nerve biopsy specimens do not fully represent 2 months but may not be evident till 3–5 months (Van Schaik et al.,
the pathological process taking place in motor roots or more proximal 2010). Following improvement, the dose may be converted to an alter-
nerve segments. In one large series of biopsies, demyelinating features nate-day, single-dose schedule. The initial daily dose is tapered to alter-
were seen in only 48%; 21% had predominantly axonal changes, 13% nate-day prednisone by reducing the even-day dose by 10 mg/week;
had mixed demyelinating and axonal changes, and 18% were normal. high-dose alternate-day prednisone is maintained until a remission or
The value of nerve biopsy as a routine diagnostic tool for CIDP has plateau phase is achieved. More than 50% of patients reach this point
been questioned. A study conducted in 64 patients with CIDP used by 6 months. After attaining maximum benefit, a slow taper of predni-
multivariate logistic regression analysis of sural nerve biopsy findings sone (e.g., 10 mg/month followed by 5-mg decrements at doses below
and other clinical and laboratory criteria to assess the value of nerve 50 mg on alternate days) can then begin. The individual patient’s clin-
biopsy. Only high CSF protein (>100 mg/dL) and nerve conduction ical improvement and side-effect profile serve as guides to the rapidity
studies consistent with demyelination were strong predictors of CIDP, of the taper. Some patients are exquisitely sensitive to reduction in cor-
and an independent predictive value of the sural nerve biopsy could ticosteroid dosage, in which case this must be reduced slowly to avoid
not be demonstrated (Molenaar et al., 1998). Nevertheless, sural nerve producing a severe relapse. Patients may need alternate-day predni-
biopsy, when properly processed for semi-thin sections and teased sone (10–30 mg) for years to suppress disease activity. Side effects from
nerve fiber preparations, is helpful in supporting the diagnosis and prolonged oral prednisone use are significant. Osteoporosis causing
excluding other causes of neuropathy. Typically, moderate reduction vertebral compression fractures, obesity, diabetes, hypertension, and
in myelinated fibers, endoneurial and subperineurial edema, and seg- cataracts are the most common long-term complications. Patients
mental demyelination and remyelination are observed. Onion bulb should be followed for the development of cataracts, increased intra-
formations, a sign of repeated episodes of segmental demyelination ocular pressure, hypertension, truncal obesity, hyperglycemia, aseptic
and remyelination, may be absent or abundant depending on the chro- necrosis of bone, peptic ulcer disease, and susceptibility to infection.
nicity of the condition at the time of biopsy. Endoneurial and epineur- Precautions taken to diminish complications include a low-sodium
ial mononuclear inflammatory cells are a helpful diagnostic sign when (2 g/day) and low-carbohydrate diet and proton pump inhibitors for
present. The presence of inflammatory infiltrates can be highlighted all patients. Calcium and vitamin D supplements should be initiated
within a few months in an effort to limit osteoporosis, and bone den- controlled by reducing the rate of infusion (<200 mL/h) or by pre-
sity should be monitored. In patients with coexisting osteopenia or treatment with acetaminophen and ibuprofen (see previous discus-
osteoporosis, bisphosphonates or nasal calcitonin may be beneficial. sion). Diphenhydramine or intravenous corticosteroids or both may
Pulse corticosteroid treatment is a viable alternative treatment be used as premedications for allergic manifestations like hives, seen
since it may produce fewer side effects than long-term oral prednisone. in about 6% of patients. Aseptic meningitis is rare but could be severe.
High-dose intermittent IV or oral methylprednisolone has beneficial Thrombotic events including stroke, myocardial infarction, retinal
effects for initial and long-term therapy that are equal to those of oral vein occlusion, and deep vein thrombosis may occasionally occur in
prednisone and IVIG, and the side-effect profile and cost of treatment patients with cardiovascular risk factors and increased serum viscosity,
are less (Lopate et al., 2005; Muley et al., 2008). Pulse oral dexameth- particularly with infusion rates of greater than 0.4 g/kg/day. Patients
asone (40 mg/day × 4 days every 4 weeks) resulted in a similar remis- with preexisting renal disease, especially the elderly, and those with
sion rate and side effects as oral prednisone, but the patients improved DM and hypovolemia are at risk of developing worsening renal failure
twice as fast (Van Schaik et al., 2010). (Lozeron et al., 2016). This complication is often associated with IVIG
Three controlled studies have confirmed the benefit of therapeutic products containing high concentrations of sucrose. Close monitoring
plasma exchange for CIDP of both chronic progressive and relapsing of renal function, correction of hypovolemia, discontinuation of con-
course. Ten plasma exchanges performed over 4 weeks resulted in sub- comitant nephrotoxic drugs, and the use of products without sucrose
stantial but transient improvement in 80% of patients (Hahn et al., are measures to prevent renal tubular necrosis in patients with preex-
1996a). Improvement began within days of starting therapy, yet 70% of isting kidney disease. The serum IgA level may be determined before
responders relapsed within 14 days after plasma exchange was stopped. the first infusion because those with very low IgA levels may have aller-
The optimal schedule for plasma exchanges has not been established gic or anaphylactic reactions during later infusions; however, current
and probably varies from patient to patient. A common approach guidelines question the necessity of this precaution.
employs three exchanges (50 mL/kg) weekly for the first 2 weeks, fol- Comparison studies showed that the beneficial effect of IVIG is
lowed by one or two exchanges per week from the third through the equivalent to plasmapheresis. Both treatments were equally efficacious
sixth week. Then the treatment frequency is adjusted according to but short lived, and most patients required continued intermittent
clinical response. Plasma exchange can only be performed in medical treatment for sustained improvement. One trial compared IVIG (2 g/
centers with special expertise in apheresis and requires secure vascular kg given over 1 or 2 days) with oral prednisolone (60 mg for 2 weeks
access. Venous access problems may be overcome by placement of cen- followed by a taper over 4 weeks) in a crossover design. Both treat-
tral venous catheters, although this approach carries the risk of pneu- ments resulted in improvement after 2 and 6 weeks, although IVIG
mothorax, hematoma, brachial plexus injury, and serious infection. tended to be slightly superior to oral prednisolone (Hughes et al.,
Plasmapheresis may be difficult to maintain for months or years, and 2001a). A randomized controlled trial comparing the 6-month effi-
the majority of patients needing prolonged plasmapheresis require the cacy of IVIG to intravenous methylprednisolone showed that IVIG
addition of prednisone for lasting benefit and stabilization. was more frequently effective and better tolerated than steroids during
The benefit of IVIG as the initial treatment of CIDP were suggested the first 6 months of treatment. However, when effective, steroids
by several small studies (Fee and Fleming, 2003; Hahn et al., 1996b; were more likely to induce remission and less frequently associated
Mendell et al., 2001). Improvement was seen as early as the first week with deterioration after therapy discontinuation than IVIG (Nobile-
of treatment, whereas maximal benefit was reached after several infu- Orazio et al., 2012). Subcutaneous immunoglobulin (SCIG) provides
sions at 2–3 months (Latov et al., 2010). Those patients who respond to more even physiological IgG levels with less “drop off” period before
the initial series of infusions may need maintenance infusions every 3–8 next dose and less of a sharp peak in IgG levels after dose. It also has
weeks. A randomized double-blind, placebo-controlled, crossover inter- decreased severity and frequency of adverse headaches and nausea.
national trial (ICE study) used an initial IVIG dose of 2 g/kg followed by a Although SCIG may be more convenient for patients to administer at
maintenance dose of 1 g/kg every 3 weeks. The study included a 24-week home, it requires self-injection and has potential injection site reac-
placebo-controlled phase, a response-conditional crossover phase for tions. A recent randomized, double-blinded, placebo-controlled trial
patients who failed to improve, and a 24-week extension phase. The study confirmed that SCIG administered subcutaneously via infusion pump
showed that a statistically significant number of patients improved with at a weekly dose of 0.4 g/kg or 0.2 g/kg is effective as an alternative
IVIG compared to placebo, and the time to and probability of relapse maintenance therapy for patients who were responsive to IVIG treat-
was much lower for IVIG versus placebo (Hughes et al., 2008). This ment (van Schaik et al., 2018).
study resulted in the 2008 US Food and Drug Administration (FDA) In clinical practice, treatment with IVIG, SCIG, plasma exchange,
approval of IVIG therapy (Gamunex 10%) for treatment of CIDP, the or corticosteroids should be limited to patients with neuropathic defi-
first neurological disease to be approved for such a therapy. Treatment cits of sufficient magnitude to justify the risks and expense of treatment
with at least two courses of IVIG administered 3 weeks apart may be (Fig. 106.21). The increasing trend is to use IVIG as first-line treatment.
required for initial improvement, and continued maintenance therapy is The best IVIG dosage schedule in patients with CIDP has not been
necessary to achieve a maximal therapeutic response (Latov et al., 2010). established, and much needs to be learned about the optimal dosage
The high level of effectiveness combined with low incidence of adverse schedule, since each trial used different dosage and infusion regimens.
events makes IVIG a good, although costly, first treatment choice. The interval of repeat infusions is determined by the expected duration
IVIG is generally safe even in patients above the age of 60 years, of the clinical benefit and should be tailored to the individual patient.
including when administered in patients’ homes (Lozeron et al., 2016; Most patients receive an initial course of IVIG of 2 g/kg over 2–5 days.
Souayah et al., 2018). Adverse reactions to IVIG therapy are usu- The standard schedule of 0.4 g/kg daily for 5 days should be used for
ally minor and occur in less than 10% of patients (Brannagan, 2002; elderly patients and patients who have impaired renal or cardiovascular
Souayah et al., 2018; Wittstock and Zettl, 2006). Headache is the most function or who have high serum viscosity. A second dose within 3–4
common infusion-related reaction and is usually mild to moderate weeks should be given, since the positive effect may require 6–8 weeks
and could be treated with simple analgesics. Myalgias are also com- and two to three courses (Latov et al., 2010). An essential aspect of the
mon and often last 1–2 days after infusion. Severe headache, typical management of CIDP is the assessment of patients at baseline and at
migraine attacks, chills, and nausea are less common. These can be follow-up visits after treatment, using objective and validated means
TREATMENT OF CIDP
Diagnosis confirmed
Mild deficits Functionally significant deficits Severe disease,

nonambulatory
Observation IVIG 0.4 g/kg 5 days or Prednisone or PE 2–3/wk 6 wk PE 2–3/wk 6 wk

60–80 mg/day and prednisone
60–80 mg/day
NA at NA at NA at
3–6 wk 4–6 wk 6 wk
Improvement Improvement Improvement Improvement
Monthly
NA
IVIG 1 g/kg/day Taper prednisone, Taper PE schedule, Start IVIG

every 2–4 wk qod schedule add prednisone stop PE
taper prednisone
Fig. 106.21 Decision-Making Pathway in the Management of Chronic Inflammatory Demyelinating Poly-
radiculoneuropathy (CIDP). IVIG, Intravenous immunoglobulin; NA, neurological assessment; PE, plasma
exchange; qod, every other day.
of determining the severity of the neuropathic deficits. Following the inadequate dose and duration of treatment, and the negative effects of
initial two treatment courses, responders are monitored at monthly concomitant and underlying illness.
intervals. When secondary deterioration occurs, patients are re-treated
with single IVIG infusions (1–2 g/kg depending on the severity of the Prognosis
relapse), and the subsequent repeat infusions are set at every 3–8 weeks. In contrast to the good prognosis in the monophasic GBS, CIDP tends
For patients with residual deficits, small to moderate doses of pred- to be associated with prolonged neurological disability and is less likely
nisone or intermittent IV methylprednisolone may provide additional to have spontaneous remissions. About 50% of patients are severely
benefit. Patients who fail to respond to IVIG are treated either with disabled at some stage by their illness and 10% of patients remain dis-
plasma exchange or corticosteroids. Plasma exchange is combined with abled in spite of treatment. Although 95% of patients with CIDP show
prednisone for severely affected nonambulatory patients because of the initial improvement following immunosuppressive therapy, the relapse
slightly higher response rates to these treatments. rate is high and the degree of improvement modest. Despite the initial
Alternative forms of immunosuppressive treatment should be con- responsiveness, only 40% of patients remained in partial or complete
sidered for patients with CIDP who are refractory to corticosteroids, remission without receiving any medication. The presence and degree
plasma exchange, and IVIG. None of the alternative agents, however, of axonal loss have been considered responsible for incomplete recovery.
have been tested in randomized and controlled trials (Mahdi-Rogers Confirmation of this view was provided by a systematic study comparing
et al., 2017). Azathioprine, methotrexate, or mycophenolate mofetil clinical outcome and biopsy findings: Six years after onset of illness, 56%
may be used as corticosteroid-sparing adjunctive agents in long-term had good outcome, 24% deteriorated and failed to respond to all treat-
management (Bedi et al., 2010; Cocito et al., 2011). Use should be lim- ments, and 11% died of complications of the disease. Axonal loss on the
ited to patients with inadequate response to corticosteroids or those nerve biopsy correlated with poorer outcome (Bouchard et al., 1999).
who require high corticosteroid maintenance doses with unaccept-
able side effects. Other immune interventions (Kieseier et al., 2006b) Multifocal Motor Neuropathy
include cyclosporine A, monthly infusions of cyclophosphamide, MMN, with a prevalence of 1–2 per 100,000, is a treatable but incurable
and interferon α 29 (Gorson et al., 1998). Rituximab (375 mg/m2 IV immune-mediated motor neuropathy that bears a superficial clinical resem-
each week for 4 weeks) failed to reduce the IVIG dose in a pilot study blance to motor neuron disease of the lower motor neuron type. Whether
(Gorson et al., 2007); however, rituximab may be effective in the sub- MMN is a distinct nosological entity or simply variably related motor neu-
group of patients with CIDP and elevated antibodies to paranodal pro- ron disease or a multifocal motor variant of CIDP is not established.
teins such as CNTN1 and NF155 (Querol et al., 2015).
The absence of any therapeutic response from these immune-mod- Clinical Features
ulating therapies should lead to a reappraisal of the diagnosis. The MMN is more common in men and mainly affects young adults; two-
most common causes of treatment failure are incorrect diagnosis, thirds of affected individuals are age 45 years or younger. It rarely occurs
Median motor Median sensory (conduction block) may occasionally be seen in vasculitic neuropathy
during the early stage of wallerian degeneration. Needle EMG of the
19.27 µV clinically weak muscles invariably shows signs of denervation, espe-
Wrist 5.1 mV Wrist cially in advanced disease, reflecting the occurrence of as yet poorly
CV = 25 m/sec explained axonal loss. Fasciculations are common, and myokymia may
CV = 60 m/sec
be seen.
Elbow Elbow
0.9 mV The extent of reduction of the CMAP amplitude or area and the
degree of acceptable temporal dispersion necessary for diagnosis of
Fig. 106.22 Partial Motor Conduction Block of Median Nerve. Com-
conduction block continue to be controversial (Chaudhry and Swash,
pound muscle action potential (CMAP) was recorded from abductor
pollicis brevis muscle. Supramaximal stimulation at elbow produced an 2006). Despite the general acceptance of conduction block as a diag-
80% drop in amplitude of median CMAP compared with stimulation nostic criterion for MMN, some investigators report patients with sim-
at wrist. Sensory conduction along the same nerve segment was pre- ilar phenotypic presentation who lack conduction blocks but respond
served. CV, Conduction velocity. (Courtesy Dr. J.C. Stevens.) equally well to the treatment (Delmont et al., 2006). Keep in mind,
however, that conduction block in some nerves may vary significantly
within patients and over time. The extent of CB may decrease or even
in childhood (Moroni et al., 2006). MMN almost always present with disappear after several years because of a progressive reduction of distal
progressive, usually distal, asymmetric upper extremity motor weakness CMAP amplitude, which may reflect either secondary axonal degener-
in the distribution of a single peripheral nerve. This may remain con- ation or the appearance of unrecognized very distal CB. The skill of the
fined to a single nerve for several years, although MMN usually steadily electromyographer and the patient’s cooperation are essential for the
progresses to affect other nerves. Several diagnostic criteria for this neu- demonstration of difficult-to-detect conduction blocks and for avoid-
ropathy have been proposed (Joint Task Force of the EFNS and the PNS, ing misdiagnosis of other conditions.
2006; Olney et al., 2003). These criteria share the following features: The spinal fluid protein is frequently normal, although moder-
progressive, asymmetrical, predominantly distal limb weakness in the ately increased protein levels (<100 mg/dL) may be found in a third
distribution of two or more peripheral nerves, developing over months of patients. MRI of the brachial or lumbosacral plexus (Van Es et al.,
to years, with a striking predilection for the upper extremities and par- 1997) or ultrasonography (Beekman et al., 2005) may be helpful by
ticularly hands, without upper motor signs. Wrist drop, grip weakness, demonstrating focal enlargement and increased signal intensities of
or foot-drop are the most common presenting features. Despite pro- affected nerve trunks.
found weakness, muscle bulk is initially well preserved. Muscle cramps In 1993, Kaji and colleagues reported a patient with pure motor
and fasciculations, particularly after exercise, are common. Profound weakness of the arm and proximal conduction block who underwent
weakness in muscles with normal bulk, or focal weakness in the distri- biopsy of a motor nerve branch adjacent to the site of focal conduction
bution of individual nerves rather than in a spinal segmental pattern, block (Kaji et al., 1993). This revealed scattered demyelinated axons
are clues that should alert the clinician to suspect this disorder. Cranial and small onion bulbs without inflammatory changes. Another study
nerve involvement is unusual, but rare involvements of ocular, facial, using fascicular biopsies of nerves at the site of conduction block of
hypoglossal, and phrenic nerves—the latter resulting in respiratory fail- mixed upper-arm nerves found minimal evidence of inflammation but
ure—have been reported. Tendon reflexes are depressed or absent but multifocal fiber loss without demyelination, remyelination, or hyper-
may be normal. Autonomic dysfunction has not been reported. Minor trophic changes (Taylor et al., 2004). The sural nerve frequently shows
transient paresthesias are commonly reported by patients, but objective subtle pathological changes of demyelination and remyelination, quite
sensory deficits are usually absent or may involve small patchy areas in similar to those in CIDP but of lesser degree. These morphological
the distal limbs. The course is slowly or less often stepwise progressive abnormalities indicate that sensory nerves are involved in this disorder
over months to years (Nobile-Orazio et al., 2005) without progression despite the lack of clinical or electrophysiological findings. However,
to generalized immobility. routine nerve biopsies are not required but can be useful in detecting
MMN may follow immunotherapy with TNF-α inhibitor for an alternative cause.
Crohn disease, rheumatoid arthritis, and psoriasis. Most patients Controversies remain about the possible relationship between
required IVIG and the majority improved or recovered over months antiganglioside antibodies and acquired lower motor neuron syn-
to years. dromes and multifocal motor neuropathies. Among the gangliosides,
GM1 is abundantly found on the outer surface of neuronal mem-
Laboratory Studies branes where potential binding sites could serve as antigenic targets.
The diagnosis depends on careful EDX studies demonstrating per- High titers of IgM anti-GM1 antibodies can be found in 50%–60% of
sistent focal motor conduction block, defined as more than 50% patients with MMN and conduction block. High titers are occasion-
reduction in amplitude and area of proximally stimulated muscle ally seen (<15%) in amyotrophic lateral sclerosis and GBS variants
evoked response compared to distally stimulated response in one or including AMAN and the axonal form of GBS associated with C. jejuni
more motor nerves at sites not prone to compression (see Chapter 36). infection, but rarely seen (<5%) in other peripheral neuropathies and
What makes MMN unique is that the conduction block is confined to non-neurological autoimmune disorders. These observations, along
motor axons. SNAPs and sensory conduction are preserved, including with conflicting results obtained from experimental studies on the
along the same nerve segments (Fig. 106.22). The selective vulnerabil- pathogenic role of anti-GM1 antibodies, suggest that these antibod-
ity of motor fibers has not been satisfactorily explained. Other features ies are neither specific nor required for the diagnosis of MMN but
of demyelination such as motor conduction slowing, temporal disper- can be considered a marker for the disease. Whether these antibodies
sion, and prolonged F-wave and distal motor latencies may be pres- are an epiphenomenon secondary to nerve damage or have a direct
ent in nerves without conduction block. When such abnormalities are immunopathogenic role for nerve damage will require further stud-
prominent or if there are abnormal SNAPs, the possibility of CIDP or ies. Similarly, the role of C. jejuni infection in multifocal neuropathy,
Lewis-Sumner syndrome (MADSAM) should be strongly considered. despite anecdotal reports of such an association, remains unproven
Transient abnormal amplitude reduction with proximal stimulation (Terenghi et al., 2002).
TABLE 106.12 Differential Diagnosis of Multifocal Motor Neuropathy

Features Multifocal motor neuropathy CIDP Amyotrophic lateral sclerosis
Lower motor neuron weakness Distal or proximal, asymmetrical, follows Proximal and distal, usually symmetrical Distal > proximal, follows myotomal
peripheral nerve distribution (root) distribution
Upper motor neuron signs Absent Absent Often present
Sensory loss Absent Present Absent
Motor conduction block Prominent Frequent Absent
Sensory conduction Normal SNAPs Low to absent SNAPs Normal SNAPs
Cerebrospinal fluid protein Normal (70%) Elevated Normal
Anti-GM1 antibodies 50%–60% Absent <15%
CIDP, Chronic inflammatory demyelinating polyradiculoneuropathy; SNAP, sensory nerve action potential.
The differential diagnosis of progressive limb weakness and atro- Some uncontrolled studies suggest oral cyclophosphamide or
phy without sensory symptoms is mainly restricted to motor neuron interferon beta may reduce the frequency and dosage of infusions. For
disease, including amyotrophic lateral sclerosis and its lower motor non-responders to IVIG, IV cyclophosphamide is indicated depend-
neuron form, progressive muscular atrophy, bibrachial motor neuron ing on the degree of disability and the patient’s understanding of the
disease, benign monomelic amyotrophy, CIDP, Lewis-Sumner syn- seriousness of potential side effects such as bone marrow depression,
drome and MMN, and HNPP (Table 107.12). Other conditions to be gonadal damage, hemorrhagic cystitis, and a long-term increased risk
considered include postpoliomyelitis syndrome, lead- or dapsone-in- of cancer. Pestronk and coworkers (1994) suggested that monthly
duced motor neuropathies, and hexosaminidase-A deficiency. IV cyclophosphamide (1 g/m2) for 6–8 months, preceded on each
occasion by two plasma exchanges, may be an effective treatment.
Treatment However, owing to concerns over long-term side effects, cyclophos-
Identifying patients with MMN is important because many such phamide was not recommended by a group of experts. As an alterna-
patients respond to treatment. Treatment with IVIG is the preferred tive to cyclophosphamide, rituximab, a monoclonal antibody directed
treatment as shown previously by several uncontrolled studies. Other against the B-cell surface marker, CD20, has shown conflicting results
treatment options are few and, unlike with CIDP, prednisone or plasma (Gorson et al., 2007; Pestronk et al., 2003; Rojas-Garcia et al., 2003;
exchange have little or no benefit and may even worsen the disease in Ruegg et al., 2004). A recent open-label study showed that rituximab
some patients. was unable to reduce the amount of IVIG required for patients with
IVIG was shown to benefit 70% of patients in open uncontrolled MMN (Chaudhry and Cornblath, 2010). There are insufficient data
trials and four randomized double-blind controlled trials involving a to support the use of other agents such as azathioprine, mycopheno-
total of 45 patients (van Schaik et al., 2005). Improvement may be quite late mofetil, cyclosporine, or interferons. Mycophenolate as an adjunct
impressive and is often rapid (within a few days to 3 weeks of treatment) therapy did not change the course of the disease (Piepers et al., 2007).
but lasts for only weeks to months. Younger age at onset, a smaller New therapeutic strategies are required to develop more long-term-ef-
number of affected limb regions, elevated GM1 antibody titers, defi- fective, less expensive, and possibly curative treatment of MMN.
nite conduction blocks, and higher distal CMAP amplitudes (suggestive Eculizumab, a mAb that binds complement component 5 and may
of minimal axon loss) are associated with a favorable response (Van inhibit terminal complement activation, is a promising treatment for
den Berg-Vos et al., 2000). The majority of patients require repeated MMN. A single study failed to allow reduction in IVIG dosing, though
IVIG infusions, though few patients experience prolonged remissions some subjective motor improvements were reported. Further study is
of longer than 12 months. Most patients require maintenance infusions necessary to evaluate this agent efficacy.
for years, and with the passage of time, the intervals between infusions
may become progressively shorter. In a double-blinded study of 44 PERIPHERAL NEUROPATHIES ASSOCIATED WITH
patients, mean maximal grip strength declined 31% during placebo MONOCLONAL PROTEINS
and increased 3.75% during IVIG, while 35% of patients had wors-
ened during placebo and not during IVIG (Hahn et al., 2013). Based Monoclonal Gammopathy of Undetermined Significance
on this study, IVIG treatment was approved by the FDA for patients Patients undergoing evaluation for chronic peripheral neuropathy
with MMN. Based on such observations, it is appropriate to initiate should be screened for the presence of a monoclonal protein (M pro-
treatment with IVIG and continue maintenance infusions (0.4 g/kg tein) (England et al., 2009a). A monoclonal protein is produced by
once every 1–8 weeks) in patients who have a functionally meaningful a single clone of plasma cells and is usually composed of four poly-
response. Dose and frequency of repeated IVIG administration must peptides: two identical heavy chains and two light chains. The M
be individualized for each patient, giving another dose just before the protein is named according to the class of heavy chain (IgG, IgM,
anticipated time of relapse. The decline in IVIG’s effectiveness over time IgA, IgD, and IgE) and type of light chain, κ (kappa) or λ (lambda).
is attributed to the progressive and poorly understood axonal degener- In two-thirds of patients with a monoclonal protein, no detectable
ation or development of new conduction blocks (Van Asseldonk et al., underlying disease is found, and they are described as having MGUS
2006). Equivalent doses of SCIG may be as effective (Harbo et al., 2010). (monoclonal gammopathy of unknown significance) (Rajkumar
The value of higher doses of maintenance IVIG (2 g/kg monthly) is not et al., 2006). MGUS is present in 1%–3% of the population, mostly
established. Treatment may reduce the number of conduction blocks, elderly. MGUS has replaced the term benign monoclonal gammopa-
promote reinnervation, and prevent axonal degeneration (Terenghi thy because up to one-fourth of patients go on to develop malignant
et al., 2004). The presence of motor axon loss, as determined by low plasma cell dyscrasias in long-term follow-up. The risk of progres-
distal CMAP amplitudes, and longer disease duration without IVIG sion of MGUS to a malignant plasma cell proliferative disorder is
treatment denote poor longer-term prognosis (Cats et al., 2010). about 1% per year (Kyle et al., 2002). This is not affected by age or
TABLE 106.13 Relative Risk of Progression TABLE 106.14 Characteristic Findings in

in Patients with MGUS Versus General Monoclonal Gammopathy of Undetermined
Population Significance
Condition Relative Risk Common monoclonal type IgM, IgG, IgA
Multiple myeloma 25 Common light chain κ
Plasmacytoma (including osteosclerotic myeloma) 8.5 Quantity <3 g/dL
Amyloidosis 8.4 Urine light chains Rare
Waldenström macroglobulinemia 46 Marrow plasma cells <5%
Lymphoma 2.4 Skeletal lesions Absent
Chronic lymphocytic leukemia 0.9 Complete blood cell count Normal
Organomegaly, lymphadenopathy Absent
MGUS, Monoclonal gammopathy of undetermined significance.
Adapted from Kyle, R.A., Therneau, T.M., Rajkumar, S.V., et al., 2002. Ig, Immunoglobulin.
A long-term study of prognosis in monoclonal gammopathy of undeter-
mined significance. N Engl J Med 346, 564–569. begin in later life (median age of onset in the sixth decade), appear
insidiously, and progress slowly over months to years. There is a male
the duration of MGUS, although the cumulative risk of progression predominance. The most common presentation is a symmetrical sen-
during one’s lifetime is, of course, highest in younger patients (Table sorimotor polyneuropathy which may be one of three more common
107.13). A strong predictor of progression is a rise in serum mono- subtypes: CIDP phenotype, distal acquired demyelinating symmetric
clonal protein concentration (Eurelings et al., 2005; Kyle et al., 2002). (DADS) neuropathy, or an axonal sensorimotor peripheral polyneu-
The characteristic features distinguishing MGUS from other plasma ropathy. A predominantly sensory neuropathy may be seen in up to
cell dyscrasias are listed in Table 106.14. 20% of patients. Cranial nerves and autonomic functions are pre-
Routine serum protein electrophoresis frequently lacks the sensi- served. Sensory impairment can be prominent, with variable involve-
tivity required to detect small M proteins. Immunoelectrophoresis or ment of light touch, pinprick, vibration, and position sense. Muscle
immunofixation is required to detect small amounts of M proteins, stretch reflexes are universally diminished or absent. The lower limbs
confirm the monoclonal nature, and characterize the heavy- and light- are involved earlier and to a greater extent than the upper.
chain types. Urine studies detect excretion of light chains (Bence Jones Elevation of CSF protein is common, sometimes in excess of 100
protein) that often accompany multiple myeloma or primary amyloi- mg/dL. The EDX studies show evidence of acquired demyelination
dosis. All patients with neuropathy and associated M protein, as well or, more often, both demyelination and axonal degeneration. A small
as patients whose profiles suggest amyloidosis or myeloma, should number of patients, usually with IgG MGUS, have electrophysiolog-
have a 24-hour urine collection for detection of Bence Jones protein. ical features of a pure axonal polyneuropathy. SNAPs are reduced in
Following discovery of an M protein, a CBC with differential, calcium, amplitude or unobtainable. Needle EMG shows chronic and active
and renal profile are necessary, immunoglobulins should be quanti- denervation. Sural nerve biopsy findings of patients with M proteins
tated, and a radiological skeletal bone survey obtained to detect lytic of all three immunoglobulin classes show nerve fiber loss, segmental
or sclerotic bone lesions of myeloma. If the monoclonal spike exceeds demyelination, and axonal atrophy and degeneration.
1.5 g/dL, a bone marrow aspirate and biopsy should be obtained to Though the clinical and EDX studies of peripheral polyneuropa-
differentiate a malignant plasma cell dyscrasia from MGUS. Rectal, thies associated with MGUS are heterogeneous, several distinct periph-
fat, or cutaneous nerve biopsies may be required to confirm a possible eral neuropathy subgroups exist:
diagnosis of amyloidosis (Kissel and Mendell, 1995). 1. In about half of patients, a polyradiculoneuropathy occurs that
Approximately 10% of patients with idiopathic peripheral neurop- shares clinical and laboratory features with CIDP. Patients with
athy have an associated monoclonal gammopathy, which represents CIDP and MGUS tend to be older and have a more indolent course,
a sixfold increase over the general population of the same age. In with more sensory than motor findings but poorer long-term func-
contrast, about 5% of patients with MGUS have an associated poly- tional outcome than CIDP without M protein (Simmons et al.,
neuropathy. The pathophysiological relationship between the M pro- 1995). The M protein in these patients is often the IgG type.
tein and the neuropathy is often obscure, but some M proteins have 2. IgM MGUS neuropathy and DADS neuropathy represents a distinct
antibody-like properties directed against components of myelin or and often homogeneous group characterized by slowly progressive
axolemma. When the higher frequency of MGUS in older patients is sensory gait ataxia. Upper-limb postural tremor can be promi-
considered, the causal relationship between MGUS and this type of nent. EDX studies show slow motor conduction velocities in the
neuropathy becomes less clear (Notermans et al., 1996a). Finding an demyelinating range, with a predilection for distal demyelination.
M protein among patients with neuropathy may lead to the discov- SNAPs are reduced in amplitude or unobtainable. In at least 50%
ery of underlying disorders such as primary amyloidosis, multiple or of patients with IgM MGUS neuropathy, the IgM monoclonal pro-
osteosclerotic myeloma, plasma cell dyscrasia, macroglobulinemia, tein demonstrates reactivity against myelin-associated glycoprotein
cryoglobulinemia, Castleman disease, lymphoma, or malignant (MAG) (Steck et al., 2006): hence the term anti-MAG neuropathy.
lymphoproliferative disease. The frequency of monoclonal IgM is MAG is a glycoprotein that makes up only 1% of peripheral nerve
overrepresented in patients with neuropathy (60% IgM, 30% IgG, and myelin. It is concentrated in periaxonal Schwann cell membranes,
10% IgA). The light-chain class is usually κ, in contrast to patients with paranodal loops of myelin, and areas of noncompacted myelin,
osteosclerotic myeloma or amyloidosis (Ropper and Gorson, 1998). where it serves as a cytoskeletal-associated protein playing a role
as an adhesion molecule for interactions between Schwann cells
Clinical Features and axons. Knockout mice expressing no MAG activity have sig-
The clinical presentations of the neuropathies associated with differ- nificantly smaller axons than normal mice, suggesting the import-
ent heavy-chain classes are generally indistinguishable. Symptoms ant role played by MAG in the proper maintenance of structure
and function of axons. Anti-MAG antibodies cross-react with

other components of peripheral nerve, including several complex
glycosphingolipids, PMP22, and the P0 protein of myelin. Which
of these reactivities relates to the neuropathy is unclear. Antibody
activity to MAG can be detected by Western blot and enzyme-
linked immunosorbent assay or by immunocytochemical stain-
ing of nerves. Immunofluorescence studies show that IgM with
anti-MAG activity binds to the periphery and periaxonal regions
of myelinated fibers that correspond to the distribution of MAG.
Ultrastructurally, the myelin lamellae show a widened periodicity
(myelin splitting), which is considered the pathological hallmark
of anti-MAG antibodies (Fig. 106.23). In those with IgM MGUS,
predictors for progression of the neuropathy to moderate disability
(Rankin Scale score of 3 or greater) include higher age at onset and
demyelination. Anti-MAG antibodies, on the other hand, portend
a better prognosis with respect to neuropathy-related disability
(Niermeijer et al., 2010). No consistent binding of monoclonal pro-
teins to myelinated fibers is seen in nerve biopsy specimens from
patients with IgG and IgA MGUS.
The underlying mechanism of nerve fiber damage in MGUS
neuropathy remains unknown, although an immune-mediated ori-
gin is suspected. The case for pathogenic activity of IgM antibodies
directed against MAG and other glycosphingolipids is better estab-
lished than that for other antigens or for IgG and IgA antibodies.
On the other hand, the lack of correlation between the deposition Fig. 106.23 Electron Micrographs Showing Fibers with Myelin
of anti-MAG antibody and the degree of pathological nerve dam- Splitting. Upper panel, Myelinating fiber on left shows splitting of
age, as well as the poor correlation between the amount of M pro- myelin lamellae at intraperiod line, whereas nerve fiber on right has
tein in serum and the severity of neuropathy, raise questions about normal compact myelin (×15,000). Lower panel, Similar myelin splitting
the causal linkage. (×20,000). Findings are characteristic of antimyelin-associated glyco-
3. Approximately 15% of patients with IgM MGUS neuropathy have protein antibody deposits in myelin sheath. (Reprinted with permission
from Mendell, J.R., Barohn, R.J., Bosch, E.P., et al., 1994. Continu-
autoantibodies directed against gangliosides, and those with IgM
um-peripheral neuropathy. Am Acad Neurol 1, 42.)
antibodies to GD1b and GQ1b have been associated with sensory
ataxic neuropathies (Eurelings et al., 2001). Patients who have disia-
losyl-ganglioside IgM antibodies and cold agglutinins present with exchange had modest improvement over sham plasma exchange over
a chronic sensory ataxic neuropathy, areflexia, and fixed or relaps- a short-term follow-up. This short-term benefit of plasmapheresis did
ing-remitting ophthalmoplegia. This rare clinical syndrome has been not occur in the IgM subgroup. Patients with a CIDP-like picture and
described under the acronym CANOMAD: chronic ataxic neuropa- IgG gammopathy should be treated like patients with CIDP without
thy, ophthalmoplegia, IgM monoclonal protein, cold agglutinins, and gammopathy. When a prominent axonal neuropathy is associated with
disialosyl antibodies (Arbogast et al., 2007; Willison et al., 2001). IgG paraprotein, especially in the elderly, the role of these therapies
Pathologically, there is significant loss of dorsal root ganglion cells, becomes less clear.
resulting in dorsal column and root atrophy as well as infiltration of IVIG (2 g/kg given over 1–5 days) may produce only a short-
cranial and peripheral nerves with clonal IgM anti-disialyl ganglio- term and partial benefit in 50% of patients with IgM MGUS with
sides secreting B lymphocytes (McKelvie et al., 2013). or without anti-MAG neuropathy (Comi et al., 2002). Patients with
progressive disabling neuropathy caused by IgM MGUS, with or with-
Treatment out anti-MAG reactivity, may respond to aggressive immune inter-
The optimal treatment of MGUS neuropathy has not been established, ventions aimed at lowering the IgM level. This may be achieved by
and few controlled trials have been conducted. Treatment decisions intermittent courses of oral cyclophosphamide and prednisone given
depend on the severity of the neuropathy and the age of the patient. at 4-week intervals for 6 months; plasma exchanges followed by IV
Patients with minor deficits and indolent course are best followed cyclophosphamide; or fludarabine, a fluorinated purine analog, used
without treatment. This view is supported by the long-term outcome in cancer treatment (Niermeijer et al., 2006; Notermans et al., 1996b).
of patients with IgM MGUS neuropathy. In one study, not only was Another purine analog, cladribine, resulted in prolonged remission in
the neurological impairment similar in treated and untreated patients one patient with IgM neuropathy (Ghosh et al., 2002). Chlorambucil
after an average follow-up of 8 years but also the immunomodulatory with and without corticosteroids may be effective in one-third to two-
treatments resulted in serious adverse events in half of the treated thirds of patients. The long-term effects of these therapies have not
patients (Nobile-Orazio et al., 2000). However, in general, the more been established, since the neuropathy has a slow progression and
closely the neuropathy fulfills the criteria for CIDP, the more likely the follow-up of the reported patients has been generally short. The
the patient will respond to immunomodulatory therapies. About half long-term side effects of these agents, however, may be substantial.
of the patients treated with plasmapheresis, IVIG, and prednisone, The initially reported benefit of interferon alfa could not be confirmed
often in combination with other immunosuppressants, experienced in a randomized controlled trial. Rituximab, a mouse/human chime-
temporary benefit. A systematic review of treatments for IgG or IgA ric monoclonal CD20 antibody directed against B cells, is reported
paraproteinemic peripheral neuropathy identified one relevant ran- to be effective in some cases of anti-MAG neuropathy in anecdotal
domized controlled trial with 18 participants. Results showed plasma reports. However, two double-blind placebo-controlled studies
Assess clinical severity
Consider
• Multiple myeloma
Mild deficits Progressive deficits • Waldenstrom’s
• POEMS
• Amyloidosis
Follow q 6 IgM paraprotein ± anti-MAG Non-IgM paraprotein

months (DADS phenotype) (CIDP phenotype)
IVIG 2 g over 2–5 days PE, IVIG, prednisone
No improvement
*IV cyclophosphamide *PE combined with *Rituximab

and prednisone IVIG
Fig. 106.24 Decision-making pathway in the diagnosis and management of peripheral neuropathy with
monoclonal gammopathy of undetermined significance (MGUS). *There are anecdotes of improvement
with these drugs, but controlled studies are not available to support their use. CIDP, Chronic demyelinating
polyradiculoneuropathy; DADS, Distal acquired demyelinating sensory neuropathy; IgM, immunoglobulin
M; IV, intravenous; IVIG, intravenous immunoglobulin; MAG, myelin-associated glycoprotein; NP, neurop-
athy; PE, plasma exchange; POEMS, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gam-
mopathy, and skin changes.
showed conflicting results (Dalakas et al., 2009; Léger et al., 2013). neuropathy. Treatment with autologous stem cell transplantation
The reported improvement is usually associated with the reduction of may induce positive responses even in patients resistant to other
serum anti-MAG antibodies. Patients may require repeated cycles of therapies (Dimopoulos et al., 2009).
therapy to maintain improvement. An algorithm for the treatment of
MGUS neuropathy is proposed in Fig. 106.24. Patients with rapid clin- Multiple Myeloma
ical deterioration of neuropathy despite treatment should be re-evalu- Polyneuropathy occurs in approximately 5% of patients with multiple
ated for the development of underlying malignant lymphoproliferative myeloma. One-third of patients demonstrate abnormalities on careful
disorders or amyloidosis. EDX studies. The most common neurological complications of mul-
tiple myeloma are related to spinal cord and nerve root compression
Waldenström Macroglobulinemia from lytic vertebral lesions. Diffuse bone or radicular pain resulting
WM is characterized by proliferation of malignant lymphoplasma- from vertebral body involvement, anemia, renal insufficiency, and
cytic cells in bone marrow and lymph nodes that secrete an IgM hypercalcemia may provide clues to the underlying disorder. The clin-
monoclonal spike of more than 3 g/dL. WM typically affects elderly ical manifestations of myeloma neuropathy are heterogeneous, but
men and manifests with fatigue, anemia, bleeding, and hypervis- most patients present with mild distal sensorimotor polyneuropathy
cosity syndrome. Peripheral neuropathy occurs in about a third of and less frequently with a pure sensory neuropathy. Furthermore,
patients with WM and is a chronic, symmetrical, predominantly sen- AL (amyloid light chain) amyloidosis complicates multiple myeloma
sory polyneuropathy similar to that associated with nonmalignant in 30%–40% of cases. These patients have a high likelihood of death
IgM monoclonal proteins. Other presentations include pure painful within 2 years after the diagnosis and generally have a more severe
sensory or pure motor neuropathies, multiple mononeuropathies sensorimotor neuropathy. Painful dysesthesias, preferential involve-
associated with cryoglobulins, and typical amyloid neuropathy. Anti- ment of small-fiber sensory nerves, autonomic dysfunction, and CTS
MAG reactivity is found in approximately 50% of WM patients with are suggestive of amyloid neuropathy. Rectal, abdominal fat, or sural
neuropathy. Patients with positive anti-MAG antibodies have slowed nerve biopsy specimens in patients with progressive myeloma neurop-
motor NCVs and prolonged distal latencies consistent with demye- athy may lead to confirmation of an amyloidosis diagnosis.
lination. Nerve biopsy findings are indistinguishable from those seen Nerve conduction and sural nerve biopsy studies are consistent with
in IgM MGUS neuropathy. Patients with demyelinating polyneurop- an axonal polyneuropathy causing loss of myelinated fibers. Treatment
athy may respond to rituximab, chemotherapy including fludarabine of the underlying myeloma may sometimes improve the neuropathy.
or cladribine, or plasmapheresis, singly or in combination, but the Thalidomide, an effective agent in the treatment of multiple myeloma,
response appears to be less consistent than in IgM MGUS-related may in itself cause a dose- and duration-dependent neuropathy
(Mileshkin et al., 2006). Bortezomib, a cytotoxic agent used for the

treatment of refractory myeloma, also causes peripheral neuropathy
(Argyriou et al., 2008).
Osteosclerotic Myeloma and Polyneuropathy,

Organomegaly, Endocrinopathy, Monoclonal
Gammopathy, and Skin Changes Syndrome
Osteosclerotic myeloma occurs in less than 3% of all patients with
myeloma, but 85% of these patients present with an associated periph-
eral neuropathy. In this disorder, the plasma cell proliferation occurs
as single or multiple plasmacytomas that manifest as sclerotic bone
lesions. The majority of these patients have Crow-Fukase syndrome or
POEMS syndrome. POEMS is an acronym for polyneuropathy, organo-
megaly, endocrinopathy, M protein, and skin changes (Dispenzieri
et al., 2015).
The initial symptoms in the majority of patients are related to a
polyradiculoneuropathy (Li et al., 2017). The polyneuropathy usually
begins with sensory changes in the lower limbs followed by sensory
ataxia and motor weakness. The clinical course is often slowly progres-
sive but is sometimes more rapidly worsening. The polyneuropathy
of POEMS is different from that associated with multiple myeloma in A
several aspects: It occurs at an earlier age, is demyelinating, with slow
motor NCVs and elevated CSF protein levels, usually in excess of 100
mg/dL. The monoclonal protein in POEMS is usually less than 2 g/
dL and may not be detectable using immunofixation in up to 10% of
cases. It is virtually always composed of λ light chains associated with
IgG and IgA heavy chains. Vascular endothelial growth factor (VEGF)
serum level is significantly elevated in POEMS but not in other demy-
elinating neuropathies; VEGF level above 200 pg/mL has a sensitivity
of 95% and specificity of 68% in the diagnosis of POEMS (D’souza
et al., 2011).
The diagnosis of POEMS syndrome requires a high index of
suspicion. The diagnosis is confirmed by having three major cri-
teria of the disease: (1) polyneuropathy (usually demyelinating),
(2) monoclonal plasma cell disorder, and (3) elevated VEGF; along
with two minor criteria including sclerotic bone lesions, organo-
megaly (hepatomegaly, splenomegaly, or lymphadenopathy), skin
change, edema, endocrinopathy (hypogonadism, hyperestrogen-
emia, or hypoparathyroidism), polycythemia, or thrombocytosis.
These criteria have 100% sensitivity and 100% specificity (Suichi
et al., 2019).
The neuropathy of POEMS bears a striking resemblance to CIDP,
with symmetrical proximal and distal weakness with variable sensory
loss. Cranial nerves are spared except for occasional cases of papill-
edema. POEMS should be considered in patients carrying a diagno-
sis of CIDP but without good response to standard CIDP therapy,
such as IVIG, plasma exchange, or corticosteroids. The clinical and
electrophysiological similarities between this condition and CIDP
emphasize the need to screen for an occult M protein and sclerotic
bone lesions in all adult patients presenting with an acquired demy-
elinating polyneuropathy or possible POEMS by obtaining serum
and urine immunofixation, free light chain, VEGF level, and skeletal
B
survey. Fig. 106.25 A 55-year-old woman with polyneuropathy, organomegaly,
The bony lesions may be single or multiple and tend to involve endocrinopathy, monoclonal gammopathy, and skin changes, initially
the axial skeleton; the majority of lesions occur in the spine, pelvis, diagnosed with chronic inflammatory demyelinating polyradiculoneu-
and ribs. Their radiographical appearance varies from dense ivory ropathy and failed treatments with prednisone, intravenous immuno-
to mixed sclerotic and lytic lesions with a sclerotic rim (Fig. 106.25). globulin, and plasma exchange. She had IgG λ paraprotein (0.1 g/dL) and
elevated serum vascular endothelial growth factor (VEGF) at 981 pg/mL.
Radioisotope positron emission tomography (PET)-CT scans also
X- Rays showed an expansile lytic lesion of the femur with cortical scal-
identify bone lesions and assist in identifying the site for bone marrow loping (A) while positron emission tomography scan showed marked
biopsy which is usually necessary to confirm the presence of an isolated hyperintense metabolic activity corresponding to right femoral lesion
plasmacytoma (see Fig. 106.25). (B). Biopsy of the lesion showed focal lambda restricted plasmacytoma.
Most patients develop one or more of the multisystem man- EDX studies show axonal changes with denervation, particularly in
ifestations of the POEMS syndrome (Dispenzieri et al., 2015). distal leg muscles. In most cases, the sural nerve biopsy confirms nec-
Hepatosplenomegaly is often encountered. Gynecomastia and impo- rotizing vasculitis or perivascular inflammation affecting small-sized
tence in men, secondary amenorrhea in women, DM, and hypothy- epineurial vessels, together with multifocal or global myelinated fiber
roidism are the most common endocrinopathies. Hyperpigmentation, loss and acute axonal degeneration. Low serum complement levels and
hypertrichosis, diffuse skin thickening, hemangiomas, and white nail the deposition of immunoglobulin in the walls of affected vessels sug-
beds are dermatological features. Pitting edema of the lower limbs, gest cryoprecipitable immune complexes are responsible for the dis-
ascites, pleural effusions, and clubbing of the fingers are other signs. ease manifestations.
Approximately one-fourth of patients with POEMS syndrome have no Treatment of cryoglobulinemic neuropathy rests on expert opin-
associated bone lesions. Some of these patients have Castleman syn- ion and uncontrolled trials. Patients with biopsy-proven vasculitis
drome (a nonmalignant form of angiofollicular lymphadenopathy), and progressive neurological deficits initially require immunosup-
and others have a plasma cell dyscrasia restricted to the lymphoretic- pression with corticosteroids and either oral or IV cyclophosphamide.
ular system. Plasmapheresis has been recommended for the rapid removal of cryo-
The pathogenesis of this multiorgan disorder is poorly understood. globulins during acute exacerbations of neurological deficits or glomer-
The associated plasma cell dyscrasia seems to play a crucial role, as ulonephritis. Once clinical remission is achieved, immunosuppressive
clinical improvement follows the disappearance of the monoclonal therapy is tapered off, and then specific treatment directed against the
proteins. Elevated levels of proinflammatory cytokines such as TNF-α, underlying HCV infection is offered. The recommended treatment
interleukins, and VEGF have been implicated in the multisystem man- regimen consists of interferon alfa-2a in combination with ribavirin
ifestations. The alteration of endoneurial vessel permeability following for 6–12 months. Rituximab, given over a period of 3 months, also
an abnormal activation of endothelial cells by VEGF may explain the proved beneficial in both clinical and electrophysiological evaluations
polyneuropathy. Increased permeability allows serum components of neuropathy in a small open prospective study for HCV-associated
such as complement and thrombin to diffuse into the endoneurial type 2 cryoglobulinemic neuropathy (Cavallo et al., 2009).
space and induce nerve damage.
The importance of recognizing this rare syndrome lies in its poten- Primary Systemic Amyloidosis
tial for treatment. Patients with solitary lesions are treated with tumor- Systemic amyloidoses are multisystem disorders caused by extracel-
icidal irradiation, complete surgical extirpation, or both. Patients with lular deposition of insoluble fibrillar proteins arranged in a β-pleated
multiple bone lesions receive radiation combined with prednisone and sheet conformation in various organs and tissues throughout the body
melphalan. High-dose chemotherapy with autologous blood stem cell (Kwan, 2007). The β-pleated sheet configuration consisting of strands
support is another option for patients with multifocal bone lesions of polypeptides in zigzag formation seems to be responsible for the
or diffuse bone marrow plasmacytic infiltration (Karam et al., 2015; typical staining properties with Congo red stain, appearing red under
Kuwabara et al., 2008). Substantial improvement of both neurological normal light microscopy but apple-green in polarized light. Several
and systemic features is seen in some patients, but the response may unrelated proteins can form amyloid fibrils and cause specific acquired
take many months. The high serum VEGF level is usually decreased as well as inherited forms of amyloidosis. In both primary systemic
dramatically following successful treatment, implying a major role amyloidosis and amyloidosis complicating multiple myeloma or WM,
played by VEGF in the development of the syndrome and neuropathy amyloid is composed of fragments of immunoglobulin light chains
(Kuwabara et al., 2006). from the amino-terminal variable regions, or less commonly the com-
plete immunoglobulin light chain, and is designated AL amyloidosis
Cryoglobulinemia (Falk et al., 1997). In primary AL amyloidosis, clonal populations of
Cryoglobulinemia is a condition characterized by the presence of nonproliferative plasma cells synthesize light-chain polypeptides that
serum immunoglobulins that reversibly precipitate in the cold. are deposited in tissues as amyloid. Between 1200 and 3200 new cases
According to their molecular composition, cryoglobulins are clas- are diagnosed yearly in the United States. AL amyloidosis in associa-
sified into three groups: type 1 are isolated monoclonal immu- tion with multiple myeloma and WM is distinguished from primary
noglobulins associated with myeloma, macroglobulinemia, and amyloidosis by the number and morphology of plasma cells in the
other lymphoproliferative disorders; type 2 consists of a mixture of bone marrow and the amount of M protein in the serum. Amyloid
a monoclonal protein, usually IgM-κ with antirheumatoid factor fibrils from patients with familial amyloid neuropathies are composed
activity, and polyclonal IgG; and type 3 are polyclonal IgM and IgG of one of three mutant proteins: transthyretin, apolipoprotein A1, and
immunoglobulins. Types 2 and 3 are usually referred to as mixed gelsolin (see FAP, earlier). Mutations in the genes encoding fibrinogen
cryoglobulins. Mixed cryoglobulinemia may occur as a primary condi- A, apolipoprotein A2, lysozyme, and cystatin C are associated with a
tion without any apparent underlying process, termed essential mixed non-neuropathic form of familial amyloidosis. Immunohistochemical
cryoglobulinemia, or may be secondary to autoimmune diseases or techniques using specific antibodies can distinguish the different types
chronic hepatitis C virus (HCV) infections. The detection of anti- of amyloidogenic proteins in biopsy material.
HCV antibodies and HCV RNA in serum and cryoprecipitate of most
patients with essential cryoglobulinemia firmly establishes a causal Clinical Features
role for HCV in the formation of cryoglobulins (Apartis et al., 1996). Primary amyloidosis usually occurs after age 40, with a median age
Mixed cryoglobulinemia is a systemic disease characterized by recur- of onset of 65 years. Men are twice as likely to be affected. The initial
rent purpura of the legs and cutaneous vasculitis, often precipitated symptoms are frequently fatigue and weight loss followed by symp-
by cold temperatures, arthralgias, renal impairment, and peripheral toms and signs related to specific organ involvement. The organs
neuropathy. The reported prevalence of peripheral neuropathy varies most commonly affected, either individually or together, are the kid-
from 37% to 57%, using electrophysiological criteria for confirma- ney, heart, liver, and the autonomic nervous system and PNS. CNS
tion. The most common presentation is a painful sensory or senso- involvement is absent. Peripheral neuropathy occurs in 15%–35% of
rimotor polyneuropathy or, less often, mononeuropathy multiplex patients and is the presenting manifestation in 10% (Matsuda et al.,
(Tembl et al., 1999). 2011). The majority have renal or cardiac presentation, with peripheral
neuropathy as a later manifestation. The neuropathy begins with pain- increased plasma cells and clonal dominance of a light-chain isotope
ful dysesthesias in the legs and follows a chronic progressive course. by immunohistochemical staining.
Pain and temperature sensation are lost before light touch or vibra- The diagnosis is established by the histological demonstration of
tory sensation. Distal symmetrical weakness and a pansensory loss amyloid deposition in tissues. Abdominal fat aspiration, bone mar-
evolve later in the course of disease. Most patients develop features row aspirate, and rectal biopsy are convenient procedures that pro-
of autonomic dysfunction that include postural hypotension, impo- vide about an 80% yield of positive results. In patients with suspected
tence, gastrointestinal disturbances, impaired sweating, and loss of amyloid neuropathy, combined muscle and sural nerve biopsy is the
bladder control. Nearly 25% of patients develop a superimposed CTS most sensitive technique to provide confirmation in more than 90%
caused by amyloid infiltration of the flexor retinaculum at the wrist. of cases. One-tenth of patients with AL amyloidosis lack monoclonal
Infiltration of amyloid deposits in joints and cartilages also occurs. The proteins in serum or urine by immunofixation, and these patients are
constellation of painful dysesthesias, autonomic dysfunction, and a difficult to distinguish from those with familial or secondary amyloi-
history of CTS should alert the clinician to the possibility of amyloido- dosis. In most of these patients, a clonal dominance of plasma cells can
sis. Typical findings on examination are hepatomegaly, pitting edema be identified by immunocytochemical staining of a bone marrow spec-
related to hypoalbuminemia, spontaneous periorbital purpura caused imen, or positive identification of AL amyloid can be achieved in tissue
by vascular infiltration (“raccoon eyes sign”), and macroglossia, a sign samples by immunohistochemical staining using labeled antibodies
occurring in 20% of patients. Amyloid deposition between muscle specific for human light chains. If confirmation of a plasma cell clone
fibers may cause pseudohypertrophy of muscles. Renal amyloidosis cannot be obtained, familial amyloidosis should be considered even
usually manifests as proteinuria and renal failure. Rapidly progressive in the absence of a positive family history. In such patients, molecu-
congestive heart failure caused by cardiac amyloid infiltration is seen lar genetic testing to identify TTR mutations is indicated (see Familial
in a third of patients. Amyloid Neuropathy, earlier page 28-e4). Amyloidogenic mutations,
EDX studies show changes of axonal polyneuropathy, with most often in the genes encoding for fibrinogen A and TTR, were
low-amplitude or absent SNAPs and low-amplitude CMAPs but found in 10% of 350 patients who had initially been misdiagnosed
preserved motor conduction velocities (Matsuda et al., 2011). Distal with presumed AL amyloidosis (Lachmann et al., 2002). Results of
median motor latencies are prolonged in patients with CTS. Needle sural nerve biopsy show amyloid deposition around blood vessels and
EMG frequently provides evidence of active denervation. A monoclo- within the endoneurial space (Fig. 106.26), severe loss of myelinated
nal protein or light chains are detected in 90% of patients by means and unmyelinated fibers, and active axonal degeneration. The patho-
of immunofixation of serum or urine. Monoclonal λ light chains are genetic mechanism of nerve fiber damage remains uncertain.
more common than κ light chains (ratio of λ to κ, 3:1). A quantita- The prognosis in primary amyloidosis is poor, with a median sur-
tive light-chain assay is the most sensitive method for detecting low- vival of less than 18 months. Death is commonly due to progressive
level monoclonal proteins. Bone marrow examination reveals slightly congestive heart failure or renal insufficiency. Patients with amyloid
B
Fig. 106.26 Amyloid Neuropathy. A, Sural nerve biopsy shows deposition of amyloid in endoneurial vessel
wall and loss of myelinated fibers. B, Under polarized light, Congo red-positive area shows apple-green bire-
fringent deposits typical of amyloid. (Congo red, ×250.)
neuropathy without cardiac or renal involvement have a more favor- diabetes were found to correlate with increased vibratory detection
able prognosis, with a median survival of 40 months. The treatment threshold values (Resnick et al., 2001). Longer duration of diabetes
of AL amyloidosis remains unsatisfactory, but some aspects of disease and male gender may predispose to the development of neuropathy in
may respond to chemotherapy that suppresses the underlying clonal younger patients with IDDM. Those with NIDDM have an increased
plasma cell disorder. Intermittent oral melphalan and prednisone are risk for neuropathy over time; a Finnish study showed that 8.3% of
reported to slow progression of renal and cardiac amyloidosis, but such individuals have neuropathy at baseline, increasing to 41.9%
the treatment has no effect on the neuropathy. High-dose melphalan after 10 years, with an even higher percentage in those with low serum
with autologous blood stem cell transplantation has shown promising insulin concentrations (Partanen et al., 1995). In a cohort of 775 US
results, with improvement of neurological deficits in selected patients. veterans with diabetes, 50% were found to have decreased foot sensa-
Because of high treatment-related mortality, stem cell transplantation tion at baseline using monofilament sensory testing, and an additional
is currently applicable to patients without significant cardiac involve- 20% developed hypoesthesia over an average follow-up period of 2.6
ment (Sanchorawala, 2006). Bortezomib and dexamethasone have also years. Factors associated with decreased foot sensation included poor
been shown to provide a benefit in survival in patients with AL amyloi- glycemic control, height, and age. Electrophysiological studies demon-
dosis (Lamm et al., 2010). strate subclinical conduction abnormalities in most patients with
IDDM after 5–10 years of diabetes. The prevalence of neuropathy is
NEUROPATHIES ASSOCIATED WITH significantly higher among diabetics who consume excessive amounts
SYSTEMIC DISORDERS of alcohol. Tobacco use may also predispose to earlier development
and more severe symptoms of neuropathy, presumably by inducing
Diabetic Neuropathies vasoconstriction and nerve ischemia (Tesfaye et al., 2005). Diabetics
DM is estimated to affect 23.6 million people in the United States, and with lower-limb ischemia due to peripheral vascular disease also have
this number is growing by an alarming rate of 5% per year (National a more severe neuropathy than diabetics without limb ischemia.
Diabetes Information Clearinghouse, 2007). This trend is also becom- Several recent studies have shown that patients presenting with a
ing increasingly evident in other developed and developing countries, chronic “idiopathic” axonal polyneuropathy have nearly a twofold
largely attributed to the increased prevalence of overweight and obe- higher frequency of undiagnosed DM and impaired fasting blood glu-
sity. In addition to vasculopathies, the complications specific to dia- cose than age-matched controls. These studies (Hoffman-Snyder et al.,
betes include retinopathy, nephropathy, and neuropathy. Patients 2006) suggest that an axonal neuropathy may be the presenting or the
with IDDM or NIDDM of sufficient duration are vulnerable to these earliest manifestation in diabetes. It is noted, however, that only 20%–
complications. 30% of patients with impaired fasting blood glucose levels or glucose
Diabetic neuropathy is a generic term defined as the presence of intolerance will progress to frank diabetes within 3 years, and many
symptoms and signs of peripheral nerve dysfunction in individuals will revert to normal through weight loss, diet, and exercise. The prob-
with diabetes after the exclusion of other causes. The mere association ability that neuropathy in such patients may also improve following
of neuropathic symptoms with DM is insufficient for the diagnosis of these interventions seems likely, but solid evidence for this is lacking.
diabetic neuropathy, so the importance of excluding other causes that Several peripheral nerve manifestations are associated with diabetes
might be treated differently or have a different prognosis cannot be and are grouped into distinct clinical syndromes, each having a char-
overemphasized (Harati, 2007). In addition, diabetic neuropathies, acteristic presentation and course. A useful classification divides the
being common disorders, may coincide with other conditions that diabetic neuropathies into symmetrical polyneuropathies versus focal
cause similar manifestations including CIDP, vitamin B12 deficiency, or multifocal neuropathies (Box 106.14). However, there is significant
alcoholic neuropathy, and endocrine neuropathies. Additional causes overlap between these syndromes.
of polyneuropathy may be present in 10%–50% of patients with DM
(Dyck et al., 1993; Gorson and Ropper, 2006). Clinical Features
Diabetes remains the leading cause of peripheral polyneuropathy in Distal symmetrical polyneuropathy. Distal symmetrical
developed countries. There are different estimates on the prevalence of polyneuropathy is the most common form of diabetic neuropathies.
diabetic neuropathy, but taking the current prevalence of diabetes, it is
estimated that as many as 7.7 million people in the United States have
some degree of diabetic peripheral neuropathy. The varied estimates BOX 106.14 Classification of Diabetic
of the reported prevalence of diabetic neuropathy have been due in Neuropathies
part to biases of patient selection and different criteria used for the
definition of diabetic neuropathy. To some clinicians, the neuropathy Generalized Symmetrical Polyneuropathies
is present only when clinical symptoms or signs appear, but others may Distal sensory or sensorimotor polyneuropathy
diagnose diabetic neuropathy based solely on EDX, quantitative sen- Small-fiber neuropathy
sory testing, or autonomic abnormalities. Autonomic neuropathy
In general, the diagnosis of a definite diabetic neuropathy should Large-fiber sensory neuropathy
be based on clinical symptoms, objective neurological signs, and EDX
Focal and Asymmetrical Neuropathies
confirmation. Quality-of-life measurements provide an additional
Cranial neuropathy (single or multiple)
vantage point from which to judge the effect of neuropathy on every-
Truncal neuropathy (thoracic radiculopathy)
day life (Padua et al., 2001). The risk of developing symptomatic neu-
Limb mononeuropathy (single or multiple)
ropathy in patients without neuropathic symptoms or signs at the time
Lumbosacral radiculoplexopathy (amyotrophy, proximal neuropathy)
of initial diagnosis of diabetes is estimated to be 4%–10% by 5 years
and up to 50% by 25 years. In a population cohort of diabetic patients, Combinations
two-thirds of diabetics had objective evidence of some type of neurop- Polyradiculoneuropathy
athy, but only about 15% had symptomatic degrees of polyneuropa- Diabetic neuropathic cachexia
thy. Among 894 women older than age 65 in Maryland, both age and
Many physicians incorrectly assume that the term diabetic neuropathy It is now clear that peripheral neuropathy can occur before the
is synonymous with distal symmetrical polyneuropathy, because the onset of clinically definite DM; this is known as impaired glucose tol-
latter constitutes perhaps three-fourths of all diabetic neuropathies. erance (IGT) neuropathy (Hoffman-Snyder et al., 2006). Individuals
In distal symmetrical polyneuropathy, however, sensory deficits with IGT, as determined by oral glucose tolerance testing (OGTT),
predominate, and autonomic symptoms usually correlate with the have been demonstrated to have symptoms, EDX abnormalities, and
severity of the neuropathy. Most patients will develop only a minor IENFD reduction consistent with a predominantly small-fiber neu-
motor involvement affecting the distal muscles of the lower extremities. ropathy, although with changes less pronounced than in their diabetic
Sensory disturbances have a stocking-glove distribution following a counterparts (Sumner et al., 2003). The implication for clinical prac-
length-dependent pattern. Early sensory manifestations begin in the tice is that patients with undiagnosed painful peripheral neuropathy
toes, gradually spreading proximally; when these reach above knee should undergo OGTT (Singleton et al., 2001); early diagnosis followed
level, the fingers and hands become affected. In more advanced cases, by improved lifestyle may result in reversal of IGT and neuropathy.
sensation becomes impaired over the anterior chest and abdomen, An acute painful neuropathy may be precipitated following initia-
producing a truncal wedge-shaped area of sensory loss. tion of treatment of a diabetic patient with insulin (treatment-induced
The distal symmetrical polyneuropathy may be subclassified fur- neuropathy). Burning pain and paresthesias develop in the distal lower
ther into two major subgroups, depending on the nerve fiber type extremities shortly after the establishment of glucose control. Pain
most involved: large-fiber and small-fiber variants. Although diabetic persists for weeks or up to several months, with spontaneous resolu-
sensory neuropathy frequently forms a continuous spectrum ranging tion to follow. Pathological studies demonstrate active axonal regen-
between these two polar types, selective sensory nerve fiber involve- eration, which may act as generators of spontaneous nerve impulses.
ment does occur, giving rise to relatively pure large- or small-fiber- This phenomenon is said to be more common in the rare form of
type presentations. DM associated with a mitochondrial tRNA mutation at position 3243
The large-fiber neuropathy variant presents with painless paresthe- (Suzuki et al., 1997).
sias beginning at the toes and feet, impairment of vibration and joint Patients with newly diagnosed diabetes may experience transient
position sense, and diminished muscle stretch reflexes. Early large-fi- pain and paresthesias in the distal lower extremities (hyperglycemic
ber involvement is often asymptomatic, but sensory deficit may be neuropathy). The symptoms will usually resolve when the hyperglyce-
detected by careful examination. In advanced cases, significant ataxia mia is brought under control.
may develop secondary to sensory deafferentation. The term diabetic Diabetic neuropathic cachexia refers to an acute and severe pain-
pseudotabes is applied to patients having severe lancinating pains, loss ful diabetic neuropathy associated with precipitous severe weight loss,
of joint sensation, and diabetic pupillary abnormalities (pseudo-Argyll depression, insomnia, and impotence in men. Although it is rare, it
Robertson pupils). imparts major challenges in diagnosis and treatment. The syndrome
A relatively common variant of diffuse diabetic polyneuropathy is is more common in men with poor glucose control. Improved glu-
diabetic polyradiculoneuropathy. Often beginning as a distal symmetri- cose control and weight gain often result in recovery and improvement
cal polyneuropathy, this disorder comes to involve proximal segments of EDX abnormalities (Yuen et al., 2001). The reason for profound
of the PNS, including multiple lumbosacral roots, thoracic posterior weight loss, severe pain, and spontaneous recovery remains obscure.
primary rami, and (less commonly) cervical myotomes. More com- Sensory loss makes patients with diabetes susceptible to repetitive,
monly, on needle EMG, patients with ordinary distal symmetrical dia- often unnoticed injuries that set the stage for foot ulcers and distal
betic polyneuropathy sometimes have low-grade active denervation joint destruction (acrodystrophic neuropathy). Chronic foot ulcer-
changes in multiple levels of thoracic paraspinal muscles, which may ation is one of the more severe complications of DM, occurring in
herald the development of a more widespread and proximal neurop- 4%–10% of patients, and is due to a combination of unnoticed trau-
athy. The trigeminal blink reflex is often spared in advanced diabetic matic tissue damage, vascular insufficiency, and secondary infection
neuropathy and polyradiculoneuropathy, providing an important (Laing, 1998). Prevention is better than treatment. Daily inspection
method to distinguish between this and immune-related polyradiculo- and proper foot care can prevent or lessen the severity of this compli-
neuropathies such as chronic inflammatory polyradiculoneuropathies. cation (Birke et al., 2002).
Much less commonly encountered is diabetic polyradiculopathy, in Neuropathic arthropathy, or a Charcot joint formation, is a compli-
which peripheral sensory nerve conduction studies are normal. Both cation seen in patients with diabetes who often have foot ulcers and
clinically and electrodiagnostically, the focus of the disease appears autonomic impairment. Unlike the Charcot joint seen in syphilis, dia-
to be at the nerve root level. Occasional patients with either IDDM- betic arthropathy tends to involve the small joints in the feet. The role
or NIDDM-associated neuropathy meet the EDX criteria for CIDP of pronounced inflammatory reactions and cytokines following the
(Sharma et al., 2002a). Some of these patients respond to high-dose initial joint insult resulting in increased osteoclastogenesis has recently
IVIG therapy, although a controlled clinical trial has not yet been com- been emphasized (Jeffcoate et al., 2005). The abundance of osteoclasts
pleted (Sharma et al., 2002b). causes progressive bone loss, leading to further fractures and potentia-
In contrast to the large-fiber neuropathy, the small-fiber neuropathy tion of inflammation and osteoclast formation.
frequently presents with pain of a deep, burning, stinging, aching char- EDX studies are helpful in confirming the diagnosis of distal sym-
acter, often associated with spontaneous shooting pains and allodynia metrical polyneuropathy. Absent or decreased amplitudes of the sural
to light touch. Pain and temperature modalities are impaired, with rel- nerve potentials and low amplitude or absent tibial H-reflexes are
ative preservation of vibration and joint position sensation and muscle found in almost all patients. Active denervation in intrinsic foot mus-
stretch reflexes. On examination, there is often touch and pin hypoes- cles or decreased amplitudes of CMAPs, together with mild slowing
thesia, tactile hyperesthesia or allodynia, or both. These two findings of conduction velocities in the motor nerves, are found in more than
when combined have excellent sensitivity (83%) and specificity (90%) two-thirds of patients. Abnormal sensory nerve conduction studies are
for the diagnosis of neuropathic pain and diabetic small-fiber neuropa- found in more than half. Even in the small-fiber variant, nerve conduc-
thy (Spallone et al., 2012). The small-fiber variant is often accompanied tion studies and needle EMG examination are often abnormal.
by autonomic neuropathy (Santiago et al., 1999). At times, a painful Autonomic neuropathy. Autonomic neuropathy usually
small-fiber neuropathy develops soon after the onset of IDDM. correlates with the severity of somatic neuropathy. The spectrum
of autonomic involvement ranges from subclinical functional term be abandoned and replaced with diabetic proximal neuropathy,
impairment of cardiovascular reflexes and sudomotor function to emphasizing the proximal motor weakness as a distinguishing clinical
severe cardiovascular, gastrointestinal, or genitourinary autonomic feature. Diabetic amyotrophy, thoracolumbar radiculopathy, and
dysfunction (Low, 2002). proximal or diffuse lower extremity weakness should probably be
Orthostatic hypotension, resting tachycardia, or diminished heart- grouped under the single term, diabetic lumbosacral radiculoplexopathy,
rate response to respiration are the hallmarks of diabetic cardiac auto- since these disorders seem to be different presentations of the same
nomic neuropathy. Orthostatic hypotension occurs mainly because of basic involvement of multiple nerve roots or proximal nerve segments.
failure of the sympathetic nervous system to increase systemic vascular The eponymic designation Bruns-Garland syndrome avoids anatomical
resistance in the erect posture and impairment of compensatory car- inconsistencies. As the name implies, the disorder is almost always
diac acceleration. It is crucial to exclude confounding effects of medica- restricted to the lower limbs. In a significant number of patients, at
tions or coexisting hypovolemia when diagnosing neurogenic postural least one additional body region is also affected, mostly the thoracic
hypotension. Vagal denervation of the heart results in a high resting but occasionally the cervical region. Isolated cases of diabetic cervical
pulse rate and loss of sinus arrhythmia. An increased incidence of pain- radiculoplexopathy were recently reported (Massie et al., 2012).
less or silent myocardial infarction is reported in diabetic patients with Clinically, asymmetrical weakness and wasting of pelvifemoral muscles
autonomic neuropathy. It is important to investigate the cardiac auto- may occur either abruptly or in a stepwise progression in individuals
nomic neuropathy of diabetes by appropriate noninvasive autonomic with diabetes who are older than 50 years. The disorder is rare in young
function tests because the presence of such autonomic dysfunction adults or children (Fernandes Filho et al., 2005). The onset is unrelated
predicts cardiovascular morbidity and mortality (Astrup et al., 2006). to the duration of diabetes, and the condition may develop in patients
Gastrointestinal motility abnormalities involving the esopha- with long-standing NIDDM during periods of poor metabolic control
gus, stomach, gallbladder, and bowel, as well as fecal incontinence and weight loss, but it can also occur in mild and well-controlled
may occur. Delayed gastric emptying, usually of solids, leads to nau- diabetics or be the presenting feature of diabetes. Typically, unilateral
sea, early satiety, and postprandial bloating. Diabetic diarrhea due to severe pain in the lower back, hip, and anterior thigh heralds the onset of
small-intestinal involvement typically occurs at night and is explosive neuropathy. Within days to weeks weakness ensues, affecting proximal
and paroxysmal. However, constipation due to colonic hypomotility is and, to a lesser extent, distal lower-extremity muscles (iliopsoas,
more common than diarrhea. Associated weight loss or malabsorption gluteus, thigh adductor, quadriceps, hamstring, and anterior tibialis).
is rare. Bacterial overgrowth may occur and can often be successfully In some cases, the opposite leg becomes affected after a latency of days
treated with small doses of tetracycline (250–500 mg/day in a single to months. Reduction or absence of knee and ankle jerks is the rule.
dose given at the onset of a diarrheal attack) in adult patients. Numbness or paresthesias are minor complaints. Weight loss occurs in
Impaired bladder sensation is usually the first symptom of urinary more than half of patients and is more pronounced than in individuals
autonomic dysfunction. Bladder atony leads to prolonged intervals with nondiabetic lumbosacral radiculoplexopathy (Dyck et al., 2001).
between voiding, gradually increasing urinary retention, and finally The progression may be steady or stepwise and may continue for many
overflow incontinence. The symptoms of urinary autonomic dysfunc- months. The result is often a debilitating, painful, asymmetrical motor
tion develop insidiously and progress slowly. Patients with diabetes neuropathy with profound atrophy of proximal leg muscles. Pain
who have neurogenic bladder should be encouraged to void routinely usually recedes spontaneously long before motor strength begins to
every few hours to prevent urinary retention. Impotence is often the improve. Recovery takes up to 24 months because of the slow rate of
first manifestation of autonomic neuropathy in men with diabetes, axonal regeneration. In many cases, mild to moderate weakness persists
occurring in more than 60% and causing serious emotional distress. indefinitely. Overlap with distal symmetrical polyneuropathy is noted
Autonomic dysfunction involves both erectile failure and retrograde in up to 60% of patients. Those with polyneuropathy more commonly
ejaculation. Most diabetic men with impotence have some evidence of have gradual onset of symptoms, bilateral findings, significant weight
associated distal symmetrical polyneuropathy. Autonomic neuropathy loss, and diffuse paraspinal muscle denervation. Typical EMG findings
is not the only cause of impotence in diabetic males, and other factors include low-amplitude femoral nerve motor responses, prominent
such as vasculopathies, hormonal alterations, and psychological issues fibrillation potentials in thoracic and lumbar paraspinal muscles,
are equally important. and active denervation in affected muscles. Neuroimaging studies of
Sudomotor abnormalities result in distal anhidrosis, compensatory the lumbar spine, lumbosacral plexus, or both should be considered
facial and truncal sweating, and heat intolerance. A peculiar hyperhi- when lumbar root, cauda equina lesions, or structural lumbosacral
drosis called gustatory sweating is characterized by profuse sweating in plexopathy are suspected. Sural nerve biopsy specimens in these
the face and forehead immediately following food intake. This often individuals show multifocal nerve fiber loss, suggesting ischemic injury
becomes difficult to treat and socially embarrassing. Oral or topical and perivascular infiltrates in small vessels, which implies an immune
glycopyrrolate may prove partially effective in some patients. Pupillary mechanism (Dyck et al., 2000b; Fig. 106.27). A vascular pathogenesis
abnormalities include constricted pupils with sluggish light reaction, of this proximal neuropathy was documented by autopsy, showing
which occurs in 20% of unselected diabetic patients. This results infarcts of the proximal nerve trunks and lumbosacral plexus. Although
from early involvement of sympathetic nerves that dilate the iris and a beneficial effect of immunomodulating therapies has been proposed,
an imbalance between parasympathetic and sympathetic function. A controlled studies have shown no positive effect for corticosteroids in
blunted autonomic response to hypoglycemia produces an inadequate enhancing the recovery of the motor deficit.
sympathetic and adrenal response and hence an unawareness of hypo- Truncal neuropathy. Diabetic truncal neuropathy or thoracic
glycemia that may seriously complicate intensive insulin treatment radiculopathy involving the T4 through T12 spinal nerve roots
(Cryer, 2006). causes pain or dysesthesias in areas of the chest or abdomen, thereby
Lumbosacral radiculoplexopathy (amyotrophy, proximal producing diagnostic confusion. Bulging of the abdominal wall as a
neuropathy). Since Garland coined the term diabetic amyotrophy result of weakness of abdominal muscles may also occur, mimicking a
to describe this special type of diabetic neuropathy, its clinical hernia (Fig. 106.28).
definition and limits have been the subject of debate, largely because This unique truncal pain is seen in older patients with NIDDM and
the term itself is ambiguous. Some experts have suggested that this may occur either in isolation or together with the typical lumbosacral
Fig. 106.28 Bulging of right lower thoracic abdominal wall at level of

umbilicus, associated with diabetic truncal monoradiculopathy.
nerve infarctions. These two conditions can usually be distinguished

by clinical and electrophysiological features. EDX studies demonstrate
axonal loss in nerve infarction in contrast to focal conduction block or
focal slowing often mixed with axonal loss in entrapment.
DM is a risk factor for single or multiple entrapment neuropa-
thies. Diabetes is found in 8%–12% of patients presenting with CTS.
B Electrophysiological abnormalities consistent with CTS without symp-
toms are found in one-fourth of diabetic patients, whereas popula-
Fig. 106.27 A, Sural nerve biopsy from patient with diabetic lumbar tion-based studies have shown symptomatic CTS in 8% of diabetics.
radiculoplexopathy. Perivascular lymphocytic inflammation involves
The risk for CTS is more than twofold for patients with diabetes than
two epineurial arterioles. (Hematoxylin and eosin, ×25.) B, In the same
in the general population. The reason diabetes predisposes to nerve
patient, semi-thin transverse section illustrates selective involvement
of one fascicle, with marked loss of myelinated fibers, a pattern highly entrapment is unknown, but aggravation of ischemia in nerves already
suggestive of nerve ischemia. (Paraphenylenediamine-stained semi- stressed by chronic endoneurial hypoxia may be one factor. The possi-
thin epoxy section, 80.) (Courtesy Dr. P.J. Dyck, Mayo Clinic, Roches- bility of occult diabetes should always be kept in mind in every case of
ter, MN.) entrapment neuropathy.
Multiple mononeuropathies. Multiple mononeuropathies refers
to the involvement of two or more nerves. As in mononeuropathy,
radiculoplexopathy. The regions of sensory loss or dysesthesia involve the onset is abrupt in one nerve, and then other nerves are involved
the trunk in a highly variable pattern, affecting either the entire derma- sequentially at irregular intervals. Multiple mononeuropathies
tomal distribution of adjacent spinal nerves or, more often, restricted involving the proximal nerves are considered the cause of diabetic
areas limited to the distribution of the dorsal or ventral rami of spi- amyotrophy. Nerve infarction results from occlusion of the vasa
nal nerves. Patients describe burning, stabbing, boring, beltlike pain. nervorum. Because multiple mononeuropathies occur most frequently
Contact with clothing can be very unpleasant. The onset may be either in systemic vasculitis, this possibility should always be considered in
abrupt or gradual and in some patients preceded or accompanied by a the differential diagnosis of diabetic multiple mononeuropathies.
profound weight loss. The clinical picture may mimic intraabdominal, Cranial mononeuropathies. A detailed description of cranial
intrathoracic, or intraspinal disease, or even herpes zoster, requiring mononeuropathies is given in Chapter 103. A third-nerve palsy is
careful differential diagnostic consideration. Neurological findings are the most commonly encountered diabetic cranial mononeuropathy.
limited to hypoesthesia or hyperpathia over the thorax or abdomen. Pupillary sparing, the hallmark of diabetic third-nerve palsy, results
The symptoms may persist for several months before gradual and from ischemic infarction of the centrifascicular oculomotor axons due
spontaneous resolution within 4–6 months. to diabetic vasculopathy of the vasa nervorum. The peripherally located
EDX studies help by demonstrating active denervation in paraspi- pupillary motor fibers are spared as a result of collateral circulation
nal and abdominal muscles, although these features are not specific for from the circumferential arteries. With decreasing frequency, the
truncal mononeuropathy. Focal anhidrosis on the trunk correlating fourth, sixth, and seventh nerves are also affected. Patients with Bell
with the area of pain is detected with the help of the thermoregulatory palsy have a significantly higher frequency of diabetes than an age-
sweat test (TST). matched population. Most make a full recovery in 3–5 months.
Limb mononeuropathy. Single mononeuropathies, often seen in Two serious infectious syndromes occur occasionally in patients
diabetic patients, are thought to be caused by two basic mechanisms: nerve with DM and characteristically affect one or more cranial nerves by
infarction or entrapment. Limb mononeuropathies secondary to nerve local inflammation. Rhinocerebral mucormycosis and “malignant”
infarction is rare and much less common than cranial mononeuropathies. external otitis were often fatal before the advent of early diagnosis and
They have a stereotyped presentation, with abrupt onset of pain followed effective treatment strategies (Smith, 1998).
by variable weakness and atrophy. Because the primary pathological
lesion results in acute axonal degeneration, recovery tends to be slow. Laboratory Findings and Diagnostic Studies
The median, ulnar, and fibular nerves are most commonly affected. The revised 2003 American Diabetes Association criteria for diagnosis
Mononeuropathies due to nerve entrapment are more common than of diabetes (Genuth et al., 2003) define a normal fasting plasma glucose
as being equal or less than 100 mg/dL (5.55 mmol/L). Impaired fasting of diabetes/prediabetes, hypertension, dyslipidemia, and central obe-
glucose (IFG) occurs when the glucose level is above 100 mg/dL but sity (Zhou et al., 2011). Corneal confocal microscopy assesses corneal
below 126 mg/dL (6.99 mmol/L). An IGT is defined as a 2-hour plasma nerve fiber and nerve branch density and significantly correlates with
glucose level between 140 mg/dL (7.77 mmol/L) and 199 mg/dL (11.04 IENFD in patients with small-fiber neuropathy (Jiang et al., 2016).
mmol/L) following ingestion of 75 g of oral glucose. Diabetes is defined In diabetics, reduced corneal sensation and corneal nerve fiber and
as fasting blood glucose above 126 mg/dL or the 2 hours level of greater nerve branch density correlates with disease duration and with IENFD
than 200 mg/dL (11.1 mmol/L) in the OGTT. (Cruzat et al., 2017; Jiang et al., 2016). Cutaneous nerve biopsy is rarely
The diagnosis of IGT (prediabetes) remains challenging and often indicated and is kept when the diagnoses of amyloidosis or vasculitis
under dispute by both physicians and patients. Glycosylated hemo- are being considered.
globin (HbA1c) is a useful indicator of the long-term control of
hyperglycemia but is not generally used to diagnose IGT, or IFG. The Pathology
diagnostic sensitivity of HbA1c for prediabetes is unclear, although The underlying pathological processes differ in the various types of
the specificity is very high. In at-risk patients with prediabetes and diabetic neuropathy. Cranial and limb mononeuropathy and multiple
normal HbA1c, an OGTT is recommended. The American Diabetes mononeuropathies are thought to be caused by small-vessel occlusive
Association recommends that two tests (fasting glucose, HbA1c mea- disease. The precise location of the primary pathological process in dia-
surement, 2-hour plasma glucose level after OGTT) obtained at two betic asymmetrical proximal neuropathy remains unsettled. Postmortem
separate visits should be abnormal for confirmation of the diagnosis examination of the obturator nerve in a single case of proximal neurop-
of diabetes (American Diabetes Association, 2018). More recently, ele- athy showed multiple infarcts due to occlusion of the vasa nervorum.
vated levels of fasting glucose and HbA1c from a single baseline blood However, lumbar nerve roots were not examined. Studies of peripheral
sample was shown to have moderate sensitivity (55%) but high spec- sensory nerves in patients with diabetic lumbosacral radiculoplexopathy
ificity to identify patients who will develop frank diabetes in the next reveal microangiopathy and evidence of ischemia (Dyck et al., 2001).
5 years of follow-up (98%), with specificity increasing to 99.6% at 15 Whether ischemic or inflammatory lesions in multiple lumbar roots,
years (Selvin et al., 2018). plexus, or proximal nerve segments are responsible for this particular
The EDX features of diabetic sensorimotor peripheral polyneu- diabetic complication still remains to be decided.
ropathy are characteristic of a primarily axon loss polyneuropa- The pathological lesions of symmetrical distal polyneuropathy have
thy. Abnormalities occur more commonly in sensory than in motor been extensively investigated (Engelstad et al., 1997). The sural nerve
fibers, in the legs more than in the arms, and in distal more than shows loss of myelinated fibers, acute axonal degeneration, some degree
proximal nerve segments. Sensory nerve and CMAP amplitudes are of demyelination, and, almost invariably, evidence of a small endo-
often reduced in patients with diabetic polyneuropathy. Conduction neurial blood vessel vasculopathy. This last condition is characterized
velocities are typically slower in this group than in healthy subjects, by narrowing or closure of the endoneurial capillary lumen by hyper-
although strict criteria for demyelinating neuropathy are not often plastic endothelial cells, thickening of the capillary wall, and marked
met (Herrmann and Griffin, 2002; Sharma et al., 2002a). In severe dia- redundancy of basement membranes. Dying-back centripetal axonal
betic polyneuropathy, there is often complete absence of all routine degeneration is evident. Painless distal polyneuropathy affects predom-
sensory and motor conduction studies in the legs and absent sensory inantly the large-nerve fiber populations, whereas painful distal diabetic
responses in the hands with very low amplitude median and ulnar polyneuropathy often shows marked depletion of small myelinated and
motor responses in the upper limbs. Needle EMG shows long-dura- unmyelinated fibers. In the latter condition, active axonal regeneration
tion, high-amplitude, and rapidly recruited MUAPs with fibrillation gives rise to abnormal nerve impulses and neuropathic pain.
potentials in distal muscles. This is usually symmetrical and worse in The demyelinating process in diabetes has been interpreted as
the leg muscles distally with a distal to proximal gradient. either the result of primary progressive axonal atrophy or direct dam-
Autonomic testing is indicated in patients with diabetic auto- age to Schwann cells secondary to ischemia or metabolic disturbances.
nomic neuropathy and provides a useful assessment in patients with Nerve fiber loss in diabetic neuropathy is distributed multifocally
distal symmetric polyneuropathy. Cardiac response to deep breathing within individual and different fascicles (differential fascicular involve-
evaluates cardiovagal functions by assessing heart rate variability to ment), a pattern similar to that seen experimentally from injection of
deep breathing, a very sensitive method for detecting early cardio- microspheres into the peripheral nerve vasculature to cause occlusion
vagal denervation. Cardiac response to Valsalva maneuvers also tests of multiple endoneurial blood vessels. Fiber depletion increases from
parasympathetic innervation to the heart. A tilt-table test evaluates proximal to distal in the nerves. This finding correlates with electro-
adrenergic vasomotor function and cardiac sympathetic function physiological studies demonstrating a diffuse abnormality of NCVs
and is essential when orthostatic hypotension is suspected. QSART to with proximodistal gradients.
evaluate the postganglionic segment of the thermoregulatory pathway
and TST provides a widespread “geographic” screen of the sudomo- Pathogenesis of Diabetic Neuropathy
tor loss. These studies are recommended (Level B) by the American Although the causes of diabetic neuropathies remain unknown, cur-
Academy of Neurology (England et al., 2009b). Gastrointestinal auto- rently accepted hypotheses focus on the possibilities of metabolic
nomic dysfunction and atony is best assessed by demonstrating the and ischemic factors and their interactions in causing nerve injury.
abnormally slow passage of barium through the gut. Neurogenic uri- Hyperglycemia has been implicated in many different pathogenic
nary bladder and sphincter dysfunction is assessed by quantitating mechanisms in diabetic neuropathy (Simmons and Feldman, 2002),
the postvoiding residual urine, cystoscopy, and urodynamic studies. but there is also a role for insulin deficiency and its effect on neuro-
Male sexual dysfunction, including erectile impotence, could be eval- trophic factors in the pathogenesis of neuropathy. Hyperglycemia gen-
uated during rapid eye movement (REM) sleep by penial tumescence erates rheological changes that increase endoneurial vascular resistance
studies. and reduce nerve blood flow. Hyperglycemia also causes depletion of
Skin biopsy with quantification of the IENFD is particularly useful nerve myoinositol through a competitive uptake mechanism and acti-
in confirming small-fiber neuropathy (Lauria et al., 2010). Small-fiber vates protein kinase C (Das Evcimen and King, 2007). In addition, per-
neuropathy is closely linked to the metabolic syndrome, which consists sistently elevated blood glucose levels activate the polyol pathway in
nerve tissue through the enzyme aldose reductase, which leads to the of DCCT, underscoring the importance of continuous good diabetes
accumulation of sorbitol and fructose in nerve and enhancement of control. Successful pancreatic transplantation is beneficial in preventing
nonenzymatic glycosylation of structural nerve proteins (Thornalley, the progression of diabetic neuropathy, and the effect may be sustained
2002). Another adverse effect of hyperglycemia is auto-oxidation of in long-term follow-up (Navarro et al., 1997). Unfortunately, once the
glucose, which results in the generation of toxic reactive oxygen inter- diabetic neuropathy is established, the existing damage is largely irre-
mediates (Sheetz and King, 2002). Overly exuberant activation of pro- versible (Coppini et al., 2006). Attempts to treat diabetic neuropathy
tein kinase C has been linked to vascular damage in diabetic neuropathy by manipulating nerve metabolism have been disappointing. Clinical
(Eichberg, 2002). These metabolic changes are likely to cause abnormal trials of myoinositol supplementation have shown conflicting results,
neuronal/axonal and Schwann cell metabolism and impaired axonal and those of aldose reductase inhibitors have so far failed to produce
transport. Direct measurements of sugar alcohols in sural nerves from convincing clinical improvement or proved toxic, though there were
patients with diabetes confirm the correlation between increased levels modest changes in nerve conduction and nerve pathology.
of glucose, sorbitol, and fructose and the severity of the neuropathy. Despite promising preliminary evidence, neurotrophin treatments
Endoneurial hypoxia is produced by decreased blood flow to the for diabetic neuropathy, such as NGF, have been disappointing (Apfel,
nerve and increased endoneurial vascular resistance from endothelial 2002). Based on experimental data suggesting that oxidative stress medi-
cell hyperplasia. Once hypoxia is established, a vicious cycle of further ated by free-radical species may be involved in diabetic neuropathy,
capillary damage escalates hypoxia. Endoneurial hypoxia is thought to two large multicenter randomized controlled clinical trials of α-lipoic
impair axonal transport and reduces nerve sodium-potassium-ATPase acid, either oral or IV, showed benefit in reducing neuropathic symp-
activity. The impairment of these functions causes axonal atrophy, toms and deficits (Ametov et al., 2003; Ziegler et al., 2006). Despite two
leading to reduced NCVs. Although the precise mechanisms leading to multicenter controlled clinical trials of α-linoleic acid in diabetic neu-
capillary abnormalities that initiate hypoxia are unknown, the hypoxic ropathy which showed lessening of neuropathic deficits and improve-
hypothesis provides a framework for further research into the patho- ment in measures of nerve conduction (Horrobin, 1997), because of
genesis of diabetic neuropathy. Autoimmune mechanisms and amino licensing problems, no further trials with this substance are planned.
acid, electrolyte, and lipid biochemical abnormalities also play a role in VEGF gene transfer into small mammals has been shown to improve
the neuropathies of DM. NCVs, increase blood vessel density, and enhance nerve blood flow
(Schratzberger et al., 2001), giving impetus to pursuing this approach to
Treatment treat human diabetic neuropathy. Because human C-peptide prevents
The cornerstone in the treatment of diabetes and its complications neuropathy in diabetic rats in a dose-dependent fashion (Zhang et al.,
remains optimal glucose control. Considerable evidence supports the 2001), clinical interest has developed for this compound as well.
idea that good diabetic control is associated with less frequent and Symptomatic treatment for pain, autonomic manifestations, and
less severe peripheral nerve complications. Although the data are less the complications of sensory loss can be offered to mitigate the impact
compelling for NIDDM, poor glycemic control has been associated of neuropathic symptoms. It should be remembered that about 20% of
with neuropathic deficits (Adler et al., 1997). A larger, more recent patients with chronic painful diabetic neuropathy of over 6 months’ dura-
prospective study with a 6-year follow-up, however, compared intention demonstrate a complete remission of symptoms over time (Daousi
sive glucose control versus standard glucose control in a population et al., 2006). Intravenous methylprednisolone therapy for patients with
with long-standing poorly controlled NIDDM (average HbA1c of diabetic lumbosacral radiculoplexopathy showed no beneficial effect in
9.4%) and showed no benefit with respect to new cases of neuropathy, the weakness and atrophy but some lessening of pain and positive neuro-
despite achieving the goal of a reduction of HbA1c by 1.5% (Duckworth pathic symptoms. IVIG reversed the weakness rapidly in a teenager with
et al., 2009). The Action to Control Cardiovascular Risk in Diabetes diabetic lumbosacral radiculoplexopathy (Fernandes Filho et al., 2005).
(ACCORD) trial, an even larger study of over 10,000 patients with Use of high-dose IVIG or methylprednisolone has been reported to bene-
poorly controlled NIDDM (HbA1c of 8.1%), specifically assessed the fit patients with progressive deficits and biopsy evidence of inflammation
effect of intensive treatment of hyperglycemia on microvascular com- in uncontrolled studies (Dyck and Windebank, 2002). The long-term use
plications including neuropathy. The study, which aimed for a HbA1c of corticosteroids in diabetic patients is, however, problematic.
of less than 6% in the intensive treatment group, was limited by the Several therapeutic interventions may reduce the symptoms of auto-
fact that a 22% relative risk of death from all causes was discovered at nomic dysfunction. Patients with symptomatic orthostatic hypoten-
an average of 3.7 years into the 5-year planned follow-up in the group sion are advised to sleep with the head of the bed elevated 6–10 inches.
being treated with intensive therapy. Those patients in the intensive The head-up tilt prevents salt and water losses during the night and
treatment group were then transitioned to standard treatment. At the will combat supine hypertension. Practical suggestions include drink-
end of the study, new cases of neuropathy were significantly reduced in ing two cups of strong coffee or tea with meals, eating more frequent
the intensive treatment group, but no significant difference was found small meals rather than a few large ones, and increasing the daily fluid
at the time of transition to standard therapy (Ismail-Baig et al., 2010). intake (>20 oz/day) and salt ingestion (10–20 g/day). Elastic body stock-
A third trial of over 11,000 patients with NIDDM (average HbA1c of ings may be beneficial by reducing the venous capacitance in bed but
7.5%), the ADVANCE trial, also assessed vascular outcomes in patients are poorly tolerated by many patients. Plasma volume expansion can be
with intensive versus standard glycemic control. New or worsening achieved by fludrocortisone (0.1–0.6 mg/day). NSAlDs inhibit prosta-
neuropathy, a secondary outcome, was not found to be significantly glandin synthesis; ibuprofen, 400 mg four times a day, is better tolerated
affected by intensive glucose control after a median follow-up of 5 years than indomethacin. Midodrine, an α1-adrenergic agonist that causes
(The ADVANCE Collaborative Group, 2008). The Diabetes Control vasoconstriction, and droxidopa, a synthetic amino acid analog that
and Complication Trial (DCCT; 1995) showed that intensive glucose is directly metabolized to norepinephrine by dopa decarboxylase, are
management by insulin pump or by multiple daily insulin injections in effective in neurogenic orthostatic hypotension (Kaufmann et al., 2014;
patients with IDDM reduces the development of neuropathy by 64% at Wright et al., 1998). Both may cause supine hypertension and should not
5 years compared to conventional therapy. Recent follow-up studies of be taken late in the evening. Subcutaneous recombinant human erythro-
the DCCT study cohort indicate that the beneficial effect of intensive poietin has proved effective in some patients with orthostatic hypoten-
glucose management persisted for at least 8 years after the completion sion and anemia.
Delayed gastric emptying is often relieved with metoclopramide, a Entrapment

dopamine antagonist, which may induce extrapyramidal symptoms at Individuals who lose substantial weight or are bedridden are subject to
higher doses. Diabetic diarrhea may be treated with short courses of fibular and ulnar compression neuropathies (Rubin et al., 1998).
tetracycline or erythromycin if appropriate. In some cases, clonidine
has been reported to reduce the troublesome diarrhea. Genitourinary Iatrogenic Neuropathies
complications of diabetic autonomic neuropathy require close collab- Chemotherapeutic agents that cause primarily peripheral neurotox-
oration with a urologist. Patients with a neurogenic bladder should icity, including vinca alkaloids, platinum compounds, and taxanes,
be encouraged to adhere to a frequent voiding schedule during the are discussed in the section on Toxic Neuropathies. The neurological
day, which helps diminish the amount of residual urine. For more complications of radiation plexopathy are discussed in Chapters 86,
severe involvement, manual abdominal compression or intermit- 97, and 105. Surgical resection of bulky cancers may result in trauma
tent self-catheterization may be needed. Treatment of erectile impo- to peripheral nerves, though this may be unavoidable because of inex-
tence should be directed by a urologist, who can counsel the patient tricable adherence or transit of nerve fibers through the tumor mass.
regarding the options of either oral treatment with sildenafil or sim-
ilar drugs, direct injections into the corpora cavernosa, or penile Paraneoplastic Neuropathies
implants. Proper skin care in diabetics with cutaneous sensory loss, Definition. Paraneoplastic neurological disorders are remote effects
impaired sweating, and vascular disease is extremely important to of cancer that involve either the CNS or PNS alone or both. They are
prevent foot ulcers. not caused by invasion of the tumor or its metastases or by infection,
ischemia, metabolic and nutritional derangements, surgery, or other
Peripheral Neuropathy in Malignancies forms of tumor treatment (deBeukelaar and Sillevis Smith, 2006)
Advances in the diagnosis and management of malignancies have (see Chapter 80). Classical syndromes including limbic encephalitis,
accelerated in recent years, leading to novel chemotherapeutic strate- subacute cerebellar degeneration, opsoclonus-myoclonus, subacute
gies and prolonged survival rates for many cancer patients. With these sensory neuronopathy, Lambert-Eaton myasthenic syndrome,
welcome improvements comes an increasing awareness of peripheral or dermatomyositis. Patients are considered to have a definite
nerve complications in patients with various forms of neoplasm and paraneoplastic neurological syndrome if they have (Graus et al., 2004):
chemotherapy. The frequency with which neuropathy occurs in cancer • A classical PNS syndrome and cancer that develops within 5 years
depends on the type of neoplasm and the method of detection. If clin- of the diagnosis of the neurological disorder, regardless of the pres-
ical criteria alone are used, 2%–16% of cancer patients are estimated ence of paraneoplastic antibodies.
to have peripheral neuropathy. When quantitative sensory testing or • A non-classical PNS syndrome that objectively improves or resolves
electrophysiological studies are carried out, approximately 30%–40% after cancer treatment (provided that the syndrome is not suscepti-
of patients have abnormalities suggestive of peripheral nerve involve- ble to spontaneous remission).
ment (Amato and Collins, 1998). • A non-classical syndrome with paraneoplastic antibodies and can-
Peripheral nerve complications may result from one or more mech- cer that develops within 5 years of the diagnosis of the neurological
anisms related to cancer or its treatment. These include (1) compres- disorder.
sion or invasion of nerve roots or nerve plexus by direct extension of • A neurological syndrome (classical or not) with well-characterized
primary or metastatic tumor; (2) meningeal metastases with involve- paraneoplastic antibodies.
ment of multiple nerve roots; (3) remote effects of cancer affecting Small-cell carcinoma of the lung (SCLC) is the most common
neuronal cell bodies, nerve axons, Schwann cells or myelin, terminal malignancy associated with paraneoplastic neurological syndromes,
axons, neuromuscular junction, and muscle; (4) entrapment neuropa- but carcinoma of breast, ovaries, kidney, prostate, thymoma, and
thies in individuals with profound cachexia; and (5) neurotoxic effects Hodgkin and non-Hodgkin lymphoma may also trigger these syn-
of chemotherapy or radiation. dromes. The neurological symptoms may precede the detection of the
underlying cancer by 4–12 months. The clinical course is often rapidly
Compression/Invasion of Nerves progressive, leaving patients severely disabled in only a few weeks or
Apart from head and neck tumors invading cranial and cervical months.
peripheral nerves, focal neuropathies from primary neoplasms are Paraneoplastic neurological syndromes are considered autoim-
uncommon. Salivary gland cancers are known to affect the facial and mune disorders because of the presence of autoantibodies in serum
other cranial nerves, often growing insidiously by perineurial spread, and CSF that are reactive with protein antigens in the neoplastic tis-
thereby eluding early detection even by sophisticated imaging pro- sue and neurons (onconeural antibodies). Paraneoplastic neuropathies
cedures. Nasopharyngeal carcinomas, meningiomas, and skull base have been associated with an ever-increasing number of autoantibod-
tumors may interrupt cranial nerve fibers directly. Primary or recur- ies (Chan et al., 2001; Table 106.15). A positive antibody test mandates
rent neoplasms of the breast or lung apex in particular may invade the a thorough search for an underlying malignancy. The majority of these
brachial plexus. Similarly, primary or recurrent pelvic or retroperito- antibodies are directed against intracellular antigens in the nucleus or
neal cancers may involve the lumbosacral plexus. cytoplasm of neurons while others are directed at surface channels.
Antibodies against surface antigens are sensitive and specific for neu-
Metastases rological syndrome, are not highly predictive of malignancy (autoim-
Discrete single metastatic lesions may rarely cause cranial or somatic mune variants), cause reversible loss of synaptic function rather than
mononeuropathy. The numb chin syndrome results from invasion of neuronal damage, and have better potential for recovery. In contrast,
the inferior alveolar nerve by metastases to the mandible. Patients antibodies against intracellular antigens are quite specific for presence
complain of numbness of the chin and lower lip. Leukemias, lympho- of cancer, are surrogate markers of specific immune responses and
mas, and breast cancer are the most common neoplasms responsible triggers cytotoxic cell-mediated immunity with inflammatory infiltrate
for numb chin syndrome. More commonly, widespread metastases which results in neuronal destruction of irreversible nature.
arise in the leptomeninges from carcinoma or lymphoma, leading to Antibodies directed against neuronal nuclear antigens include the
leptomeningeal carcinomatosis or lymphomatosis, respectively. type 1 antineuronal nuclear antibody (ANNA-I or anti-Hu, named
TABLE 106.15 Autoantibodies in Neurological Paraneoplastic Syndromes

Antibody Neurological Manifestations Types of Tumors
ANNA-I (anti-Hu) Sensory ataxia (MISP), GI dysmotility, autonomic N, PEM SCLC
ANNA-II (anti-Ri) Opsoclonus/myoclonus, jaw dystonia, ataxia, SMN SCLC, breast
ANNA-III Sensory N, SMN, ataxia, PEM SCLC, adenocarcinoma of lung, esophagus
CRMP-5 (anti-CV-2) Dementia, SMN, vision loss, chorea SCLC, thymoma
PCA-1 (anti-Yo) Cerebellar ataxia, SMN Ovary, breast
PCA-2 PEM, ataxia, autonomic and motor N SCLC
Amphiphysin Stiff person syndrome, sensory N SCLC, breast
P/Q-type calcium channel LEMS SCLC
N-type calcium channel LEMS, SMN SCLC, breast, ovary
Ganglionic AChR Autonomic N, GI dysmotility, PN hyperexcitability SCLC, thymus
Voltage-gated potassium channel PN hyperexcitability, Isaacs syndrome, Morvan syndrome Thymus, lung
AChR, Acetylcholine receptor; ANNA, antineuronal nuclear antibody; CRMP-5, collapsin response-mediator protein-5; LEMS, Lambert-Eaton myas-
thenic syndrome; MISP, malignant inflammatory sensory polyganglionopathy; N, neuropathy; PCA-1, type 1 Purkinje cell cytoplasmic antibody; PCA-
2, type 2 Purkinje cell cytoplasmic antibody; PEM, paraneoplastic encephalomyelitis; PN hyperexcitability, peripheral nerve hyperexcitability; SCLC,
small-cell lung carcinoma; SMN, sensorimotor neuropathy.
after the first two letters of the name of the patient in whom Hu anti- autoantibody testing may result in a large proportion of false positives,
body was first discovered). This is associated with subacute sensory particularly in patients with clinical presentations that are not consid-
neuronopathy, autonomic neuropathy, and limbic encephalomyeli- ered paraneoplastic in origin (Ebright et al., 2018). Panels that are tar-
tis. SCLC is found in more than 80% of ANNA-I seropositive patients geted to specific clinical presentations are likely more useful.
(Lucchinetti et al., 1998). These polyclonal IgG autoantibodies are In paraneoplastic neuromuscular disorders, sensory or autonomic
directed against 35- to 40-kDa proteins that belong to the Hu-family of ganglia, peripheral nerves, nerve terminals, neuromuscular junc-
RNA-binding proteins expressed in nuclei of neurons and malignant tions, and muscle may be affected, causing diverse clinical syndromes.
cells. The type 2 antineuronal nuclear antibody (ANNA-II, or anti-Ri) Peripheral neuropathies associated with carcinoma may be classified
was originally described in women with opsoclonus/myoclonus asso- according to the distribution of involvement into the following clinical
ciated with breast cancer, but it may also be seen in men with periph- types: (1) paraneoplastic sensory neuronopathy, (2) autonomic neu-
eral neuropathy in association with lung cancer. ANNA-III is highly ropathy, (3) sensorimotor polyneuropathy (either axonal or demy-
associated with SCLC or adenocarcinoma of the lung in patients with elinating types), and (4) mononeuritis multiplex. Any neuropathy,
sensorimotor neuropathies, cerebellar ataxia, and encephalomyelitis. especially a sensory or autonomic neuropathy of subacute onset occur-
Three IgG autoantibodies related to lung cancer are directed against ring in at-risk individuals such as smokers, should raise suspicion of a
neuronal cytoplasmic antigens. These are amphiphysin antibody, type paraneoplastic disorder.
2 Purkinje cell cytoplasmic antibody (PAC-2), and the collapsin Paraneoplastic sensory neuronopathy (malignant inflammatory
response-mediator protein-5 (CRMP-5) antibody. CRMP-5 IgG (or sensory polyganglionopathy). The terms subacute sensory
anti-CV-2) antibodies are associated with SCLC and (rarely) thymoma neuronopathy, carcinomatous sensory neuropathy, paraneoplastic
and occur in patients with multifocal neurological signs that include sensory neuropathy, paraneoplastic sensory ganglionopathy,
sensory or sensorimotor neuropathies, chorea, optic neuropathy, and and malignant inflammatory sensory polyganglioneuropathy
disturbance of smell and taste (Yu et al., 2001). Amphiphysin antibody are synonyms to describe the distinct progressive, severe sensory
is associated with breast carcinoma and stiff person syndrome. neuropathy associated with cancer. Although the sensory ganglion
Autoantibodies directed against neuronal surface ion-channel anti- cell is the primary site of injury, other neurons including autonomic
bodies include P/Q and N-type calcium channel antibodies, ganglionic ganglia and CNS nerve cells are often involved as well (Hlubocky
acetylcholine receptor, and voltage-gated potassium channel antibodies. and Smith, 2014). The presence of an autoantibody directed against
P/Q-type calcium channel antibodies are present in more than 90% of a nuclear protein that is shared by neuronal nuclei and tumors, and
patients with Lambert-Eaton syndrome (LES). N-type calcium channel the intense inflammatory response found in the affected dorsal root
antibodies are markers for lung, breast, or ovarian cancers and are found ganglia, support an immune-mediated mechanism.
in patients with various neurological manifestations, including LES and Clinical features. Patients are middle-aged or older, and many
peripheral neuropathy. Ganglionic acetylcholine receptor antibodies are heavy smokers. Women are affected twice as often as men in the
are found in patients with both idiopathic and paraneoplastic types of United States, in contrast to a European study and to the overall
autonomic neuropathy (Vernino et al., 2000). Voltage-gated potassium male predominance of SCLC (Graus et al., 2001). The most common
channel antibodies are detected in patients with autoimmune disorders underlying neoplasm is SCLC (≈90%), followed in decreasing order
of peripheral nerve hyperexcitability. These include Isaacs syndrome, of frequency by breast carcinoma, ovarian cancer, and lymphoma.
Morvan syndrome, and cramp-fasciculation syndrome (Sawlani and In 9 of 10 cases, neurological symptoms are the presenting features
Katirji, 2017). These rare disorders can be seen in association with thy- and precede the discovery of the tumor by several months. The
moma, lung cancer, and Hodgkin lymphoma (Hart et al., 2002). median interval from onset of neuropathic symptoms to diagnosis
When a paraneoplastic neuropathy is suspected in relation to of the underlying neoplasm is 5 months. Symptoms may develop
cancers, including lung cancer, screening for an entire panel of auto- within days in a fulminant fashion or progress more gradually over
antibodies that includes ANNA-I, CRMP-5, amphiphysin, PCA-2, months. Numbness, painful paresthesia, and lancinating pain often
ANNA-type 2, and ANNA-type 3, and calcium channel antibodies begin in one limb and progress to involve all four limbs. Upper
provides an even greater diagnostic yield. However, paraneoplastic limbs are usually involved first or almost invariably involved with the
progression of the disease. Occasionally the trunk, face, and scalp are diagnosis of ataxic sensory neuronopathies because of its high
affected in somatotopic regions highly suggestive of neuronopathies. specificity (99%) and sensitivity (82%) for the detection of cancer
There is global loss of all sensory modalities, with a striking loss of (Molinuevo et al., 1998).
proprioception and inability to localize the limb in space, resulting in In addition, the discovery of prominent dysautonomia or presence
sensory ataxia and pseudoathetosis of the upper extremities. Tendon of neurological signs suggesting disease outside the dorsal root gan-
reflexes are globally reduced or absent. Although muscle strength is glion (particularly CNS deficits) should prompt a careful search for
preserved or only mildly decreased, patients are often severely disabled malignancy, especially SCLC.
and unable to walk because of their sensory deficits. Treatment and prognosis. The outlook for patients with
About half of affected patients have symptoms and signs reflecting paraneoplastic sensory neuronopathy is poor (Vedeler et al., 2006).
more widespread involvement of the central and PNS including para- Early diagnosis and prompt treatment of the underlying neoplasm
neoplastic encephalomyelitis, cerebellar degeneration, and autonomic provide the best chance to stabilize the condition. More often the
neuronopathy, as evidenced by involvement of the myenteric plexus neuronopathy pursues a relentless independent course despite
neurons, autonomic ganglia, spinal cord, brainstem, cerebellum, and treatment of the underlying tumor. In the absence of a detectable tumor,
limbic cortex. These patients display varying degrees of gastrointesti- antitumor treatment may be considered in patients with anti-Hu
nal dysmotility, autonomic dysfunction, myelopathy, cerebellar signs, antibodies, age greater than 50 years, and with a history of smoking.
brainstem findings, and subacute dementia. Treatment with plasmapheresis, IVIG, and immunosuppressive agents
Laboratory and diagnostic studies. The hallmark of has had disappointing results. Nevertheless, minor modifications
paraneoplastic sensory neuronopathy is the absence of, or marked of the clinical course have been observed in a few patients receiving
reduction in, SNAPs. Motor conduction studies are normal with immunomodulatory therapy (Graus et al., 2001). Symptomatic
relatively preserved amplitudes of CMAPs, though the motor conduction treatment is directed at neuropathic pain and accompanying
velocities may be mildly reduced. Needle EMG may demonstrate dysautonomic symptoms such as orthostatic hypotension.
minor neurogenic changes. The CSF is frequently abnormal with a Paraneoplastic autonomic neuropathy. Subacute panautonomic
mild pleocytosis, elevated protein, and occasionally oligoclonal bands. failure may be associated with malignancies, most commonly SCLC.
The sural nerve frequently shows a combined loss of myelinated Most patients have focal or generalized gastrointestinal dysmotility
and unmyelinated fibers, axonal degeneration, and minimal axonal presenting with abdominal pain, nausea, vomiting, and severe
regeneration, sometimes with mononuclear inflammatory cells around constipation, with subtle or no sensory deficits. High titers of ganglionic
epineurial vessels. The principal neuropathological features include acetylcholine receptor or ANNA-I (Hu) antibodies may be found in
degeneration of dorsal root ganglion cells with intense mononuclear cell some patients with cancer. Although high serum titers of ganglionic
inflammation, subsequent loss of sensory axons, and degeneration of the acetylcholine receptor antibody may be seen in 14%–30% of patients
posterior roots, peripheral sensory nerves, and the posterior columns of with cancer, this antibody is found in patients with autoimmune and
the spinal cord. Many patients have pathological evidence of a more paraneoplastic autonomic neuropathy and is generally not a marker of
generalized encephalomyelitis characterized by inflammatory infiltrates malignancy (Li et al., 2015; McKeon et al., 2009; Vernino et al., 2000).
and neuronal loss in hippocampus, brainstem, and spinal cord. Sensorimotor polyneuropathy. It is far more common for cancer
About 90% of patients with sensory neuronopathy associated with patients to have distal symmetrical sensorimotor polyneuropathy
SCLC have significantly elevated titers of ANNA-I (Hu) antibodies by than sensory neuronopathy. Clinically, these length-dependent
immunohistochemistry or Western blot analysis. Although low titers neuropathies are often of slow onset, progress gradually, and are
have been found in 20%–40% of patients with SCLC without neuro- indistinguishable from distal axonal neuropathies in individuals
logical disease, only about 0.1% of patients with SCLC have anti-Hu without malignancy. The neoplasms reported in association with
paraneoplastic syndrome. Other associated tumors include breast this nondescript polyneuropathy, in decreasing order of frequency,
cancer, ovarian cancer, sarcoma, and Hodgkin lymphoma. Anti-Hu originate in lung, stomach, breast, colon, pancreas, and testis. Whether
antibody discovery has a specificity of 99% and sensitivity of 82% these neuropathies are truly paraneoplastic remains to be proven.
for the detection of cancer (Molinuevo et al., 1998). Hence, a positive Anti-CRMP5/CV2 (collapsin response mediator protein) antibod-
antibody implies the presence of cancer while negative anti-Hu anti- ies also occur with paraneoplastic peripheral neuropathies (Antoine
body does not exclude an underlying cancer. Seropositive patients et al., 2001). These patients usually have more motor involvement, less
should have chest CT because the tumor may go undetected by chest frequent upper limb involvement, and frequent cerebellar ataxia. Anti-
x-rays. If negative, abdominal and pelvic CT or MRI are indicated. CRMP5/CV2 antibodies are usually associated with SCLC, neuroendo-
When cancer is not found by conventional radiological procedures, crine tumors, and thymoma.
PET has been shown to reveal findings suggestive of cancer in 28% Acute and chronic inflammatory demyelinating polyradiculoneu-
of patients and leads to a diagnosis of cancer in 12% (McKeon et al., ropathies have occasionally been linked to underlying malignancies.
2010). GBS has been rarely reported in patients with Hodgkin lymphoma.
Differential diagnosis. The diagnostic possibilities of acquired CIDP may occur in association with hematological malignancies,
sensory neuronopathies include malignant inflammatory sensory particularly non-Hodgkin lymphoma and melanoma (Rajabally and
polyganglioneuropathy, the ataxic sensory neuronopathy associated Attarian, 2018). Molecular mimicry of common antigens shared by
with Sjögren syndrome or HIV infection, and idiopathic sensory both melanoma and Schwann cells may explain the increased asso-
neuronopathies. These conditions share similar pathological ciation of CIDP with melanoma. CIDP is often diagnosed before the
characteristics of an inflammatory ganglionopathy. The toxic sensory malignancy. Atypical clinical features such as ataxia, cranial/respira-
neuronopathies caused by high-dose pyridoxine (generally >500 mg/ tory/autonomic involvement, abdominal pain, diarrhea, constipation,
day) or following chemotherapy with cisplatinum should be excluded poor appetite, or weight loss should raise the suspicion of an under-
by history. Although it may be difficult to distinguish patients with lying malignancy. It is important to recognize these acquired acute or
malignant inflammatory sensory polyganglioneuropathy from those chronic immune-mediated polyradiculoneuropathies in the clinical
with other causes of sensory neuronopathy, serological testing for setting of malignancies since both respond to immunomodulatory
ANNA-I (Hu) antibodies is extremely valuable in the differential therapies.
Mononeuritis multiplex. Paraneoplastic vasculitis is recognized restricted to lower motor neuron syndromes and named subacute
to occur as a remote effect of cancer and frequently presents as motor neuronopathy, occurring as a remote effect of lymphoma. Only a
cutaneous vasculitis in hairy cell leukemia and lymphoma. Peripheral few patients with pure lower motor neuron syndromes have improved
nerve vasculitis is a rare complication of Hodgkin and non-Hodgkin following treatment of the concurrent lymphoproliferative disorder.
lymphoma; SCLC; adenocarcinoma of the lung, prostate, endometrium; Neurological complications of chronic lymphocytic leukemia
and renal cell cancer. Patients present with multiple mononeuropathy develop in the advanced stages of the disease. These include herpes zos-
or painful asymmetrical sensorimotor neuropathy that precedes the ter infection, followed by opportunistic infections and treatment-related
discovery of tumor in most. The association of vasculitis with SCLC complications. Peripheral nerve involvement is rare (<1%) and consists
and seropositive ANNA-I autoantibodies supports a paraneoplastic of leukemic nerve infiltrations and immune-mediated neuropathies.
origin. Two-thirds of patients have responded to either chemotherapy Neurological complications of acute leukemias stem from hemor-
of the underlying malignancy or cyclophosphamide with or without rhage into the brain or nerve trunks; leukemic infiltration of the brain,
corticosteroids (Oh, 1997). leptomeninges, cranial nerves, spinal roots, and peripheral nerves;
CNS infections; or chemotherapy-related neurotoxicity.
Lymphoma, Neurolymphomatosis, Leukemia, Mild distal sensory neuropathy is a rare complication of polycythe-
and Polycythemia Vera mia vera. Positive sensory complaints such as pruritus, paresthesias,
Neurological complications of lymphoma result from (1) direct and burning feet are common. Polycythemia vera-associated pruri-
involvement of the leptomeninges, spinal cord, or brain; (2) compres- tus, typically precipitated by contact with water, may be an agonizing
sion of the spinal cord or nerve roots by epidural masses; (3) bacte- aspect of the disease. Selective serotonin reuptake inhibitors such as
rial, fungal, and viral infections; (4) complications of treatment (e.g., paroxetine or fluoxetine have been beneficial in alleviating pruritus.
chemotherapy, radiation, bone marrow transplantation); and (5)
remote effects. Spinal cord compression is the most frequent compli- Neuropathies Related to Bone Marrow Transplantation
cation, followed by VZV infection and toxic neuropathies related to Peripheral neuropathy is an uncommon complication of bone marrow
chemotherapy (Kelly and Karcher, 2005). Peripheral neuropathy unre- transplantation. In a prospective study of 115 patients with leukemia
lated to chemotherapy is found in approximately 5% of patients with undergoing allogeneic bone marrow transplantation, 4% developed
lymphoma. neuropathy in the first 3 months after transplantation. A number of
Neurolymphomatosis is a rare condition with diffuse infiltration potential neuropathic complications may occur in the post-transplant
of peripheral and cranial nerves, plexus, or nerve roots by neuro- period, including neurotoxicity of drugs used in the conditioning reg-
tropic neoplastic cells in a patient with a hematological malignancy. imen and critical illness neuropathy. Immune-mediated polyradic-
Approximately 90% of patients have non-Hodgkin lymphoma, while uloneuropathies have all been described in association with chronic
the remainder of patients carry a diagnosis of acute leukemia. Patients graft-versus-host disease (Openshaw, 1997). The observed predomi-
present in several ways, depending on the site of PNS involvement, nantly motor polyradiculoneuropathy meets clinical and laboratory
as ascending paralysis mimicking GBS, progressive polyradiculoneu- criteria for CIDP. Patients improve after immunomodulatory therapy
ropathy, cauda equina syndrome, distal sensorimotor polyneurop- consisting of IVIG, plasma exchange, or immunosuppressant therapy.
athy, or multiple mononeuropathy. Peripheral nerves are affected Acute inflammatory demyelinating polyradiculoneuropathy or GBS
most commonly (60%), followed by spinal nerve roots in 48%, cranial has also been reported in patients after allogeneic and autologous bone
nerves in 46%, and plexus in 40%. Over half of patients have involve- marrow transplantation (Wen et al., 1997). IVIG and plasmapheresis
ment of more than one of these regions of the PNS (Grisariu et al., are considered effective treatments. Skin sclerosis and nodular thick-
2010). The diagnosis is confirmed by positive CSF cytology or lym- ening associated with chronic graft-versus-host disease may also lead
phomatous infiltration of nerves as seen by nerve biopsy or autopsy. to single or multiple sensory mononeuropathies such as the saphenous
Neurolymphomatosis responds poorly to systemic chemotherapy, or antebrachial nerves (Al-Shekhlee and Katirji, 2001).
because the nerve–blood barrier limits the access of cytotoxic drugs
(Odabasi et al., 2001). Median survival is 10 months (Grisariu et al., Peripheral Nerve Vasculitis
2010). The vasculitides represent a clinicopathological spectrum of disorders
Intravascular lymphomatosis, or angiotropic large-cell lymphoma, characterized by inflammation and destruction of the walls of blood
is characterized by the proliferation of malignant lymphocytic cells vessels of different calibers, leading to luminal occlusion and isch-
within small blood vessels of the brain, spinal cord, peripheral nerves, emia or hemorrhage in the affected organ systems (Burns et al., 2007).
and skin. Neurological manifestations include multifocal strokes, Vasculitis can be observed in two clinical settings: primary vasculitis
myelopathy with or without cauda equina lesions, and polyradiculo- without known underlying cause, or secondary vasculitis occurring in
neuropathies. Intravascular lymphoma may be confirmed by biopsy the setting of infectious, malignant, or metabolic diseases or resulting
of involved tissues such as skin, muscle, or peripheral nerves. A sig- from drug exposure (Collins, 2012). PNS involvement is a common
nificantly raised serum lactate dehydrogenase (LDH) and sedimenta- complication of systemic vasculitis (50%–80%), especially in poly-
tion rate is seen in over two-thirds of patients (Wong et al., 2006). If arteritis nodosa and small-vessel vasculitides because the small- and
untreated, the disease is rapidly fatal. Survival has been reported after medium-sized vessels affected in these types of vasculitides correspond
chemotherapy (Oei et al., 2002). to the size of the vasa nervorum (Langford, 2003). The types of vas-
Acute and chronic inflammatory demyelinating polyradicu- culitides that may affect the PNS are listed in Box 106.15. Systemic
lopathies have been described in association with Hodgkin and necrotizing vasculitis occurs in a diverse group of diseases affecting
non-Hodgkin lymphoma. About 8% of patients with monoclonal multiple organ systems, including the PNS and CNS. On the other
gammopathy have a low-grade lymphoma or lymphocytic leukemia hand, peripheral neuropathy may be the only manifestation of a more
and may develop a distal demyelinating neuropathy in association with indolent condition—nonsystemic vasculitic neuropathy.
IgM paraproteinemia. Polyarteritis nodosa, by far the most common vasculitis in this
Lymphoproliferative disorders are claimed to be overrepresented group, is characterized by necrotizing inflammation of medium-sized
in patients with motor neuron disease. This association was initially or small arteries affecting the kidneys, skeletal muscle, gastrointestinal
Nonsystemic Vasculitic Neuropathy

BOX 106.15 Classification of Vasculitides
A restricted necrotizing vasculitis affecting only peripheral nerves and
Affecting the Peripheral Nervous System skeletal muscle is the most common cause of vasculitic neuropathy in
Primary systemic vasculitis: patients presenting to a neurologist. One-third of patients with biopsy-
Predominantly large-vessel vasculitis proven vasculitic neuropathy lack evidence of systemic disease or a
Giant cell arteritis definable connective tissue disease. Multiple mononeuropathies are
Predominantly medium-vessel vasculitis the most common clinical presentation with stepwise sensory-mo-
Polyarteritis nodosa tor deficits following peripheral nerve territories. This is followed by
Predominantly small-vessel vasculitis progressive asymmetrical neuropathy or symmetrical distal polyneu-
Microscopic polyangiitis ropathy (Collins and Hadden, 2017; Davies et al., 1996). Generally the
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) patients have no constitutional symptoms or serological abnormalities
Granulomatosis with polyangiitis (formerly Wegener granulomatosis) because joints, visceral organs, and skin are unaffected. The severity of
Essential mixed cryoglobulinaemia (non-hepatitis C virus [HCV]) symptoms and deficits varies considerably. The disease course may be
Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) indolent and protracted over years without ever becoming life threat-
Vasculitis associated with systemic disease: ening. The diagnosis depends exclusively on results of nerve and mus-
Connective tissue diseases cle biopsy, though the sedimentation rate and C-reactive protein levels
Rheumatoid vasculitis may be increased. The pathological features are identical to those seen
Systemic lupus erythematosus in classic polyarteritis nodosa, affecting small and medium-sized arter-
Sjögren syndrome ies in muscle and nerve.
Systemic sclerosis
Mixed connective tissue disease Pathogenesis
Infections (hepatitis B, hepatitis C, HIV, cytomegalovirus, human T cell- The precise immunological events leading to vessel injury in vasculitis
lymphotropic virus I) are not well understood. Immune complex deposition within vessel
Malignancy walls and T-cell-dependent, cell-mediated cytotoxic reactions are the
Nonsystemic vasculitis neuropathy two basic immunopathogenic mechanisms causing destruction of ves-
sel walls. Vascular endothelial cells may serve as antigen-presenting
cells and have important functions initiating the cell-mediated
tract, skin, PNS, and occasionally CNS. Peripheral nerve involvement immune process. Although drugs and certain infectious agents, includ-
occurs in 50%–75% of patients. Hepatitis B surface antigen is found ing HIV-1 and hepatitis B and C viruses, have been implicated as trig-
in one-third of cases. Churg-Strauss syndrome typically presents with gers of the immune responses, in most instances a causal agent cannot
asthma, sinusitis, eosinophilia, and systemic vasculitis of small and be identified. Small-vessel vasculitis and pathological features of isch-
medium-sized vessels. The frequency of peripheral nerve involvement emic nerve injury have been described in peripheral sensory nerves of
is similar to that seen in polyarteritis nodosa (Hattori et al., 1999). patients with diabetic and nondiabetic lumbosacral radiculoplexopa-
Granulomatosis with polyangiitis (formerly Wegener granulomatosis) thies (Dyck et al., 2001).
affects the upper and lower respiratory tract and is accompanied by The final common pathway of vasculitic neuropathy is extensive occlu-
glomerulonephritis and necrotizing vasculitis. The PNS is involved in sion of vasa nervorum at the level of epineurial arterioles of 50–300 μm
10%–20% of cases. Cranial nerve involvement and external ophthal- in diameter, leading to nerve ischemia. Nerve ischemia results in axonal
moplegia occur in 11% of patients as a result of granulomatous infil- degeneration. Because of the random focal nature of vasculitis, axonal
tration of the orbit or cavernous sinus. degeneration typically shows a pattern of asymmetrical patchy involve-
When vasculitis develops in association with a well-defined con- ment both between and within nerve fascicles (differential fascicular
nective tissue disorder, the clinical and pathological features resemble involvement). The ischemia is most pronounced in proximal nerves such
polyarteritis nodosa. Among the connective tissue disorders, rheuma- as the fibular division of the sciatic nerve at the midthigh or the ulnar
toid vasculitis is by far the most common cause of vasculitic neuropa- nerve at the mid–upper arm in watershed areas between the distribu-
thy. Approximately 15%–30% of patients cannot be categorized and tions of major nutrient arteries. The extensive branching and intermix-
are classified as having microscopic polyangiitis. In the hypersensitivity ing of nerve fibers may result in a more homogeneous nerve fiber loss in
vasculitides, cutaneous manifestations dominate the clinical picture, distal sensory nerves. Large myelinated fibers appear to be more suscep-
although peripheral nerves may be involved. Peripheral nerve lesions tible to ischemia than unmyelinated fibers.
complicate giant-cell arteritis in 14% of cases. More than 10% of
patients with vasculitic neuropathy present in the setting of malignan- Clinical Features
cies, most commonly myeloproliferative or lymphoproliferative disor- In systemic vasculitis, multisystem signs are evident together with
ders, and infections including HIV and hepatitis B and C virus. fever, malaise, weight loss, and hypertension. The majority of patients
Hepatitis B and hepatitis C are the most common viruses asso- with PNS involvement present with peripheral neuropathy as the
ciated with systemic vasculitis, usually in the context of polyarteritis initial manifestation of disease. Initially, acute onset of deep-seated
nodosa and mixed cryoglobulinemia, respectively. Polyarteritis nodosa proximal pain in the affected limb is common. Burning pain, sensory
predominantly affects medium-size vessels and mixed cryoglobulin- loss, and weakness in the distribution of affected nerves develop over
emia is more selective toward small vessels. Multiorgan involvement several days. However, a more chronic and indolent course with pro-
is common in both disorders, with gastrointestinal, renal, and cutane- gressive deficits is common. Irrespective of the underlying vasculitic
ous involvement being almost always present in hepatitis B- associated syndrome, the clinical features of vasculitic peripheral neuropathy are
vasculitis/polyarteritis nodosa while cutaneous manifestations, renal similar and depend on the extent, distribution, and temporal progres-
failure, and hypertension are most prominent in hepatitis-C associ- sion of ischemia. Three types of peripheral nerve involvement can be
ated vasculitis/mixed cryoglobulinemia syndrome (Collins, 2012; Ferri distinguished, although considerable overlap occurs between types
et al., 2004; Stübgen, 2011). (Fig. 106.29):
Fig. 106.29 Clinical Patterns of Neuropathic Involvement in Vasculitic Neuropathy. Left figure illustrates
multiple mononeuropathies or mononeuritis multiplex. Middle figure illustrates asymmetrical sensorimotor
polyneuropathy due to overlapping multiple mononeuropathies obscuring individual nerve involvement. Right
figure illustrates symmetrical sensorimotor polyneuropathy resulting from extensive proximal ischemic nerve
lesions. (Adapted from Mendell, J.R., Barohn, R.J., Bosch, E.P., et al., 1994. Continuum-peripheral neuropa-
thy. Am Acad Neurol 1, 31.)
1. Multiple mononeuropathies with motor and sensory deficits microscopic polyangiitis. Two types of ANCA may be detected with
restricted to the distribution of individual nerves (10%–15%). The indirect immunofluorescence by using alcohol-fixed neutrophils
most common mononeuropathies affected are the fibular nerve as substrate, producing two major staining patterns, cytoplasmic
in the lower extremity and the ulnar nerve in the upper extremity (c)-ANCA and perinuclear (p)-ANCA; c-ANCA directed against the
(Collins and Periquet-Collins, 2009). neutrophil proteinase 3 (PR3 ANCA) is strongly (75%–90%) associ-
2. Overlapping or confluent multiple mononeuropathies (60%– ated with Wegener granulomatosis; p-ANCA directed against the neu-
70%), in which anatomically contiguous nerves will eventually be trophil enzyme myeloperoxidase (MPO-ANCA) is found with variable
affected, obscuring individual nerve involvement. This often results frequency (5%–50%) in microscopic polyangiitis, Churg-Strauss syn-
in asymmetrical flaccid weakness and pansensory loss in one or drome, and Wegener granulomatosis.
more extremities. EDX studies are helpful in establishing the pattern of involvement
3. Subacute symmetrical, distal sensorimotor neuropathy caused by and documenting axonal nerve damage. Careful study may reveal that
extensive widespread vasculitis (≈30%). This presentation of vascu- what clinically appeared to be a symmetrical polyneuropathy may
litic neuropathy can be difficult to distinguish from other types of in fact be an asymmetrical neuropathy resulting from overlapping
distal axonopathies and requires a high index of clinical suspicion. mononeuropathies. Nerve conduction studies reveal low-amplitude
A detailed history may indicate that the neuropathy began focally, SNAPs and CMAPs in a multifocal distribution with normal or mini-
then followed a course of stepwise progression of deficits before mally reduced conduction velocities. Partial motor conduction block
becoming generalized. may be seen transiently with acute nerve infarcts before the comple-
tion of wallerian degeneration (Jamieson et al., 1991; Mohamed et al.,
Laboratory Features 1998). EMG demonstrates more widespread denervation than antici-
The laboratory evaluation of patients with suspected vasculitis should be pated clinically.
directed toward identifying an underlying disorder or documenting sero- A definite diagnosis of vasculitis depends on confirmation of vas-
logical abnormalities that may point to a specific vasculitic syndrome, as cular lesions in nerve or muscle biopsies. Combined muscle and nerve
well as investigating involvement of other organs. These studies should biopsies may also increase the diagnostic yield (Vital et al., 2006). Of the
include sedimentation rate, C-reactive proteins, CBC with total eosin- cutaneous nerves suitable for biopsy, the sural nerve or superficial fibu-
ophil count, renal function, urinalysis, hepatic enzymes, serum protein lar nerve are preferred. A simultaneous peroneus brevis muscle biopsy
electrophoresis, angiotensin-converting enzyme, rheumatoid factor, can be obtained through the same incision when sampling superfi-
antinuclear antibody, extractable nuclear antigens, serum complements, cial fibular nerve or, alternatively, the gastrocnemius muscle could be
C-reactive proteins, antineutrophilic cytoplasmic antibodies, cryoglobu- sampled through a second incision. However, it is not useful to obtain
lins, hepatitis B antigen and antibody, and hepatitis C antibody. a vastus lateralis muscle biopsy in patients undergoing sural nerve
Antineutrophilic cytoplasmic antibody (ANCA) is helpful in the biopsy at the ankle for the purpose of identifying vasculitis (Bennett
diagnosis of Wegener granulomatosis, Churg-Strauss syndrome, and et al., 2008). This proximal muscle biopsy may be too distant from the
(Jones et al., 2010; Stone et al., 2010). The role of plasmapheresis in the
management of severe vasculitis remains controversial but may pro-
vide additional benefit in patients with life-threatening disease (Allen
and Bressler, 1997). In patients with nonlife-threatening mild systemic
vasculitis, prednisone given together with methotrexate (20–25 mg/
week) is effective. High-dose prednisone is often adequate in patients
with nonsystemic vasculitic neuropathy. The role of drugs such as
mycophenolate mofetil or leflunomide in the treatment of vasculitis
remains less known. Similarly, the beneficial effects of IVIG have not
been proven by randomized control trials.
Cyclophosphamide is associated with substantial toxicity including
bone marrow suppression, life-threatening infections, hemorrhagic
cystitis, infertility, myeloproliferative disease, and bladder cancer. This
Fig. 106.30 Sural Nerve Biopsy from Patient with Systemic Vasculitis. is more common when using the oral form. From the onset of treat-
A medium-sized epineurial blood vessel with fibrinoid necrosis of its ment, CBCs should be monitored frequently. Liberal fluid intake and
wall and perivascular and transmural mononuclear cell infiltration is frequent voiding may lessen the risk of hemorrhagic cystitis. Urine
shown. (Hematoxylin and eosin, ×75; bar = 25 μm.) should be monitored for the presence of microscopic hematuria.
Once clinical remission is achieved, prednisone can be tapered over
usually distal pathological process in vasculitic neuropathy. In a cohort a period of 4–6 weeks to a dosage of 1 mg/kg every other day. Patients
of patients with clinically suspected vasculitis, the estimated sensitivity are kept on both drugs until significant improvement occurs, at which
of a definitely positive combined superficial fibular nerve/peroneus bre- time prednisone is gradually tapered further. Cyclophosphamide, aza-
vis muscle biopsy was 60% and increased to 86% if pathological features thioprine, or methotrexate are useful in maintaining remission and
suggestive of vasculitis were included (Collins et al., 2000). should be maintained for 1 year after the disappearance of all traces
A definite pathological diagnosis of vasculitis requires the pres- of disease activity. Physical and occupational therapy is indicated to
ence of vascular wall inflammation accompanied by vascular wall optimize activities of daily living.
damage necrosis (Fig. 107.30). Cellular infiltrates are composed pre- Meaningful recovery has been reported in 60% of patients at 6
dominantly of T cells and macrophages. Additional common and months and 86% at 1 year. Long-term treatment results may be com-
supportive findings in vasculitic neuropathies include: (1) vascular plicated by chronic sequelae from organ damage, disease relapses, and
deposits of immunoglobulins and complement, including membrane medication side effects.
attack complex demonstrated by immunostaining in more than 80% Other neuropathies associated with system disorders, includ-
of cases; (2) inflammation of microvessels without vascular damage ing neuropathy in connective tissue diseases, rheumatoid arthritis,
(termed microvasculitis); and (3) differential fascicular involvement SLE, systemic sclerosis, Sjögren syndrome, trigeminal sensory neu-
with asymmetric nerve fiber loss or multifocal subfascicular or central ropathy in connective tissue disorders, and neuropathy in sarcoid-
fascicular loss of fibers with acute axonal degeneration on cutaneous osis are discussed in the online version of this chapter, available at
nerve biopsy. These findings are much less specific when seen in isola- http://www.experconsult.com.
tion (without vascular wall inflammation and damage) since they may
occur in other immune nonvasculitic neuropathies. Alcoholic Neuropathy and Nutritional Deficiencies
Alcoholic Neuropathy
Treatment Alcoholic neuropathy (also see Chapter 84) is one of the most com-
In systemic necrotizing vasculitis, disease activity must be suppressed mon peripheral neuropathies seen in general practice. Depending on
rapidly to limit ongoing organ and nerve damage. Induction ther- the diagnostic criteria used, its frequency varies from 12.5% to 48.6%
apy is often initiated rapidly with a combination of prednisone and in chronic alcoholism. Covert alcoholism may only be uncovered by
a cytostatic agent (usually cyclophosphamide). Combination therapy a focused history provided by family members. A close association
was significantly more effective than corticosteroid monotherapy in between alcoholic neuropathy and nutritional deficiency is well estab-
inducing sustained improvement at 6 months and reducing disabil- lished. The neuropathic picture of chronic alcoholism is essentially
ity. Combination immunosuppressive therapy results in an 80%–90% indistinguishable from thiamine deficiency.
remission rate in Wegener granulomatosis and systemic necrotizing Clinical features. The symptoms of alcoholic neuropathy begin
vasculitis. Treatment is started with daily prednisone (1 mg/kg/day) insidiously and progress slowly. Muscle weakness begins distally and
together with monthly IV cyclophosphamide at 0.75 g/m2 body surface spreads to more proximal muscles. Gait difficulty, weakness, and
area per month for 6 months, adjusted monthly upward to 1 g/m2 or muscle cramps are common. Sensory loss and burning paresthesias
downward to 0.5 g/m2 on the basis of the patient’s leukocyte count are frequent. Hyperpathia and dysesthesias are troublesome in many
2 weeks after the infusion. The dose of cyclophosphamide should be patients. The legs are always more affected than the arms. Distal muscle
adjusted to lower the total lymphocyte count to about 750/μL, while wasting, loss of tendon reflexes, and sensory loss of all modalities in a
maintaining the total leukocyte count above 3000/μL and the total stocking-glove distribution are common. In advanced cases, sensory
neutrophil count above 1500/μL. Oral cyclophosphamide at 2 mg/kg ataxia caused by loss of joint position sense may coexist with alcoholic
of body weight per day may be a substitute of the intravenous form, cerebellar ataxia. Autonomic dysfunction due to vagal nerve or
but carries more side effects. In fulminant cases, corticosteroids may sympathetic nerve involvement may be present and is associated with
also be initiated by giving IV methylprednisolone (500–1000 mg) daily higher mortality rates.
for 3–5 days followed by oral prednisone. Rituximab, at a dose of 375 EDX studies show an axonal sensorimotor polyneuropathy. Low-
mg/m2 body surface area/week for 4 weeks, may be used instead of amplitude or absent CMAPs or SNAPs are common, particularly in the
cyclophosphamide for induction therapy and is shown to be as effec- legs. Needle EMG shows active denervation with chronic reinnervation
tive for induction of remission in the ANCA-associated vasculitides in distal muscles. Sural nerve biopsy specimens demonstrate loss of
Neuropathy in Connective Tissue Diseases subacute or chronic axonal polyneuropathy with predominant sen-
Peripheral nerves, including cranial nerves, are affected frequently in sory symptoms and reduced epidermal nerve density is most common.
connective tissue disorders (Olney, 1998). Peripheral nerve manifesta- Mononeuropathies of limb or cranial nerves, brachial plexopathy, and
tions may develop in patients with a well-established diagnosis or may GBS or CIDP have occasionally been described in association with
be the initial manifestation of an undiagnosed connective tissue dis- SLE. The basis for such associations is unknown, but autoantibodies
ease. Neuropathy may occur as part of the multisystem disease process against peripheral nerve antigens or an immune-mediated vasculitis
itself, or it may be secondary to complications of other organ involve- are proposed pathogenetic mechanisms.
ment (e.g., uremic neuropathy, nerve entrapment as a result of joint In sural nerve biopsy specimens, perivascular inflammatory cell
deformities) or due to iatrogenic drug toxicity. Neuropathy may also infiltration is seen around epineurial vessels, but only occasionally is
be coincidental and unrelated to underlying disease. The pathogenesis there definite vasculitis. Immune-complex deposition leading to vas-
of peripheral neuropathy in connective tissue disorders is complex and culitis is the presumed basis of nerve damage.
variable depending on the specific disorder. Circulating immune com- If the polyneuropathy associated with SLE results in significant
plexes detected in a variety of connective tissue disorders may play a sig- disability, immunosuppressive treatment should be considered. In
nificant role. Varying degrees of vascular nerve lesions are found in all patients with proven vasculitis, treatment with plasmapheresis, pred-
types of connective tissue disorders. In some, the small vasa nervorum nisone, and cyclophosphamide has led to improvement.
is occluded, whereas in others epineurial arterioles and small arteries are
involved by necrotizing vasculitis, producing ischemic nerve damage. Systemic Sclerosis
Systemic sclerosis (scleroderma) is a connective tissue disease charac-
Rheumatoid Arthritis terized by excessive deposition of collagen. It affects the skin, gastroin-
Peripheral neuropathy has been noted to occur in 1%–10% of patients testinal tract, lungs, heart, and kidneys. Neurological complications are
with rheumatoid arthritis, although EDX evidence of neuropathy may be uncommon, consisting mainly of myositis. Peripheral nerve involve-
found in 57% (Agarwal et al., 2008). In addition to neuropathies caused by ment unexplained by gastrointestinal or renal complications is rare.
treatments, at least four distinct types of peripheral neuropathies are seen Peripheral sensorimotor neuropathy, isolated trigeminal neuropathy,
in association with rheumatoid arthritis: (1) compression neuropathies, auditory neuropathy, and mononeuropathy related to carpal and
often found with early disease and caused by periarticular inflammation cubital tunnel syndromes have been reported. Multiple mononeurop-
and fibrosis; (2) a chronic distal symmetrical sensory polyneuropathy, athies are seen with greater frequency in CREST (calcinosis, Raynaud
possibly related to occlusive vasculopathy; (3) mononeuropathy or mul- phenomenon, esophageal dysmotility, sclerodactyly, and telangiecta-
tiple mononeuropathies; and (4) a severe fulminating sensorimotor poly- sia) syndrome than in control subjects. Frank vasculitis, perivascular
neuropathy; both (3) and (4) are caused by rheumatoid vasculitis. inflammation, and multifocal fiber loss are found in sural nerve biopsy
Compression neuropathies in rheumatoid arthritis occur as a specimens of CREST patients with multiple mononeuropathies (Dyck
result of joint deformity or, on rare occasions, rheumatoid nodules. et al., 1997).
Treatment includes splint applications, local corticosteroid injection,
or surgical decompression. Sjögren Syndrome
A chronic symmetrical, predominantly sensory polyneuropathy Sjögren syndrome is an autoimmune inflammatory disorder of exo-
causes dysesthesias, paresthesias, and loss of sensation in a patchy crine glands characterized by diminished lacrimal and salivary gland
stocking-glove distribution. It is not associated with severe active secretion, resulting in dry eyes and dry mouth (sicca complex). The
rheumatoid arthritis. The pathogenesis is poorly understood. Ischemia sicca complex is related to lymphocytic and plasma cell infiltration and
caused by occlusive vasculopathy or low-grade vasculitis has been destruction of lacrimal and salivary glands. Sjögren syndrome occurs
suggested as a possible mechanism. Because the prognosis is generally either as a primary disorder or as a secondary condition in association
good, no specific treatment is recommended. with other connective tissue disorders. Diagnostic criteria for Sjögren
Systemic vasculitis develops in the setting of severe chronic rheu- syndrome have been proposed (Fox et al., 1999). Peripheral nerve
matoid arthritis, characterized by severe joint deformities, rheumatoid involvement (Mori et al., 2005) occurs in 10%–30% of patients with
nodules, and cutaneous vasculitic lesions such as digital ulcerations, pur- primary Sjögren syndrome and has a strong predilection for women
pura, and livedo reticularis. Rheumatoid vasculitis is the second most (9:1). Neuropathic symptoms may precede and overshadow the sicca
frequently identified cause of vasculitic neuropathy because rheumatoid symptoms and may be the major presenting complaint (Grant et al.,
arthritis is a common disorder affecting 2%–5% of the general popula- 1997). A distal symmetrical sensory neuropathy with mixed large- and
tion. Acute mononeuropathy, multiple mononeuropathies, and a distal small-fiber deficits is the most common presentation. Less common
symmetrical sensorimotor polyneuropathy may develop. In contrast to patterns of nerve involvement include sensorimotor neuropathy,
other connective tissue disorders, cranial nerve involvement is rare. small-fiber neuropathy (Chai et al., 2005; Goransson et al., 2006;
The sedimentation rate and rheumatoid factor titer are always ele- Lopate et al., 2006), polyradiculoneuropathy, multiple mononeurop-
vated. The C4 complement level is frequently low. Cutaneous nerve athies, painful dorsal root ganglionopathy, and trigeminal sensory
or muscle biopsy demonstrates a necrotizing vasculitis. The develop- neuropathy. A distinct subgroup of patients with sensory ataxic neu-
ment of systemic vasculitis confers a poor prognosis in rheumatoid ronopathy presents with loss of kinesthesia and proprioception caused
arthritis, with a reported 5-year survival rate of 60% (Puéchal et al., by an inflammatory sensory polyganglionopathy (eFig. 106.31). When
1995). Treatment should be started with high-dose prednisone and severe, this neuropathy may be confused with SCA. Autonomic neu-
cyclophosphamide. Early aggressive intervention may arrest the pro- ropathy may also occur. This may be associated with cardiac parasym-
gression of neuropathy. pathetic dysfunction, variably reduced sweat production, constipation,
and unilateral or bilateral tonic (Adie) pupil. Pupillary abnormalities
Systemic Lupus Erythematosus may also be seen in patients with sicca syndrome in whom a definitive
Peripheral neuropathy develops in 6%–21% of patients with SLE; diagnosis of Sjögren syndrome has not yet been made. Autoantibodies
the higher frequency is found by using quantitative sensory testing against M3-muscarinic acetylcholine receptors have been demon-
combined with extensive nerve conduction studies. A symmetrical strated in patients with Sjögren syndrome (Naito et al., 2005).
Trigeminal Sensory Neuropathy in Connective Tissue

Disorders
Slowly progressive trigeminal sensory neuropathy is characterized by
advancing unilateral or bilateral facial numbness. An association has
been reported with several connective tissue diseases including sys-
temic sclerosis, mixed or undifferentiated connective tissue disease,
Sjögren syndrome, SLE, rheumatoid arthritis, and dermatomyositis.
Sensory loss begins in perioral and cheek areas and progresses slowly.
Painful paresthesias may accompany the sensory loss but typical
neuralgia does not occur. The frequent bilateral involvement (70%),
sparing of muscles of mastication, slow progression, and negative
neuroimaging study results help distinguish this condition from other
causes of facial numbness such as cerebellopontine angle meningioma
or brainstem stroke. Disfiguring neuropathic ulceration of the nares
may occur. The trigeminal blink reflex study shows a delayed or absent
ipsilateral R1 and bilateral R2 responses in 50% of patients, confirming
an afferent trigeminal nerve defect. The precise cause of this presumed
immune-mediated cranial sensory ganglionopathy remains unclear.
Immunosuppressive therapy is not recommended in isolated trigemi-
nal sensory neuropathy.
Other causes of trigeminal neuropathy are acute toxic reactions to
trichloroethylene and the numb chin syndrome associated with a car-
cinoma or leukemia.
Neuropathy in Sarcoidosis
Because of its unknown cause and protean clinical manifestations, sar-
coidosis is a difficult disease to define. It is a multisystemic granuloma-
tous disorder that commonly affects young and middle-aged adults,
eFig. 106.31 Thoracic dorsal root ganglion and sural nerve biopsies usually involving lung, lymph nodes, skin, and eyes. Neurological
from patient with Sjögren syndrome and nonmalignant inflammatory involvement (neurosarcoidosis) occurs in approximately 5% of
sensory polyganglionopathy. Upper panel, Prominent mononuclear cell patients, and 6%–18% of neurological manifestations are various
infiltrate is seen adjacent to neuronal cell bodies. (Hematoxylin and forms of peripheral neuropathy. Cranial neuropathies, particularly
eosin, ×25.) Lower panel, Sural nerve in same patient showing marked facial nerve palsy, are the most common neurological manifestations
decrease in fiber density and abnormality in size distribution of myelin- (73%). PNS involvement includes multiple mononeuropathies, bilat-
ated fibers. (Paraphenylenediamine-stained semi-thin epoxy section, eral phrenic nerve palsies, truncal sensory mononeuropathies, acute
×25.) (Reprinted with permission from Smith, B.E., 1992. Inflammatory polyradiculoneuropathy resembling GBS, cauda equina syndrome,
sensory polyganglionopathies. Neurol Clin 10, 735–759.)
and chronic symmetrical sensorimotor polyneuropathy (Burns et al.,
2006). This last condition may produce severe wrist extensor and foot
Laboratory abnormalities include elevated sedimentation rate, pos- dorsiflexor weakness and distal sensory loss in the legs. At times, a pain-
itive rheumatoid factor, and hypergammaglobulinemia. Antibodies ful small-fiber neuropathy may predominate. Neurological manifesta-
to extractable nuclear antigens (especially SS-A), considered to be the tions may be the presenting feature in more than 50% of cases or may
most specific serological test for Sjögren syndrome, are less common develop at a time when there is little evidence of systemic sarcoidosis.
in patients with neuropathy. The diagnosis depends on specific inquiry EDX studies show evidence of axonal degeneration. Sarcoid
about sicca symptoms and ophthalmological tests for keratoconjunc- granulomas may be seen in muscle and sural nerve biopsy spec-
tivitis sicca (e.g., rose Bengal staining of the cornea, Schirmer test: imens. The nerve damage has been attributed to granulomas and
<5 mm wetting of a paper strip at 5 minutes). When the test result angiitis of vasa nervorum that produces axonal degeneration (Said
is abnormal, a minor salivary gland biopsy of the lower lip showing et al., 2002). Inflammatory changes in the CSF (e.g., pleocytosis,
chronic lymphocytic infiltrates is helpful for confirmation. Reduced increased protein level, elevated IgG index, and occasionally hypo-
or absent SNAPs and normal or only mildly abnormal motor conduc- glycorrhachia) imply granulomatous leptomeningeal involvement.
tion studies are typical electrophysiological findings. High-intensity A positive gallium scan of the lungs may be useful in the search
lesions of the posterior columns may be detected on T2-weighted MRI for systemic involvement. An elevated serum angiotensin-convert-
of the cervical cord in patients with sensory ganglionopathy (Mori ing enzyme level may suggest active systemic sarcoidosis. Biopsies
et al., 2001). Sural nerve biopsy frequently shows nonspecific perivas- of lymph nodes, muscle, or conjunctiva, or bronchoalveolar lavage
cular lymphocytic (T-cell) infiltrates together with diffuse decrease in may be needed to obtain tissue for histological confirmation, since
myelinated fibers. Vasculitis is rarely found in patients with multiple all the other tests are nonspecific.
mononeuropathies. The response to corticosteroid therapy in sarcoid neuropathy is
Treatment recommendations are based on small retrospective uncon- generally favorable. In patients refractory to corticosteroids, cyclospo-
trolled series or individual case reports. Nerve and/or muscle biopsies rine, cyclophosphamide, or azathioprine may be used as adjunctive
showing necrotizing vasculitis predict a better response to immunosup- therapy (Agbogu et al., 1995). However, the benefit of these agents
pressive therapy (Terrier et al., 2007). Most report some improvement remains inconclusive. Recent interest has focused on TNF-α blockers
with the use of corticosteroids, either alone or in combination with such as infliximab, which provide a modest beneficial response when
immunosuppressants, neutralizing antibodies to TNF-α, or IVIG. used for refractory disease (Doty et al., 2005).
nerve fibers of all sizes. Acute axonal degeneration is particularly com- Folate Deficiency
mon in patients after binge drinking, whereas axonal regeneration is Folate functions as a coenzyme or co-substrate and is involved in the
frequently seen in chronic alcoholism. metabolism of nucleic and amino acids. Its deficiency rarely exists in
Etiology. Deficiency of thiamine and other B vitamins, caused by the pure state and is usually associated with other deficiencies. Folate
inadequate dietary intake, impaired absorption, and greater demand deficiency is seen in alcoholism (especially with hard liquor), small-
for thiamine to catalyze the metabolism of the alcohol, is considered bowel diseases, “blind-loop” syndrome, partial gastrectomy, atrophic
the major cause of polyneuropathy in alcoholic patients. It is likely that gastritis, antacid therapy, and gastric acid neutralization. Increased
in at least a subgroup of patients, the direct toxic effect of alcohol is folate requirements are also seen in pregnant and lactating women and
responsible for the neuropathy (Koike and Sobue, 2006). in hemolytic anemia. Drugs such as methotrexate that inhibit dihydro-
Treatment. Abstinence from alcohol, addiction counseling, and folate reductase act as folate antagonists. Folate deficiency may cause
a nutritionally balanced diet constitute the principal therapy. In one an axonal sensory polyneuropathy characterized clinically by loss of
study, a good prognosis for mild to moderate polyneuropathy after joint position and vibratory sense and absent tendon reflexes. In addi-
3–5 years of abstinence is reported. Supplementation with thiamine tion, there may be evidence of spinal cord involvement, with spasticity
and other B vitamins is important. In patients with significant of the legs and extensor plantar responses. The neuropathy of folate
gastrointestinal symptoms, parenteral vitamin treatment is initially deficiency is, in general, similar to that of cobalamin deficiency but
required. Improvement in the polyneuropathy may be very slow of a milder degree. In severe cases, encephalopathic symptoms may
because it requires axonal regeneration. For the management of painful predominate. Macrocytic anemia is an important clue to either folate
alcoholic neuropathy, see Management of Neuropathic Pain, later. or vitamin B12 deficiency. Patients with clinically significant folate defi-
ciency may also have elevated plasma homocysteine levels. Coexisting
Niacin Deficiency (Pellagra Neuropathy) vitamin B12 deficiency must be excluded because, in such cases, folate
Niacin (nicotinic acid, vitamin B3), an end-product of tryptophan therapy without cobalamin replacement may exacerbate neurological
metabolism, is incorporated into the coenzymes nicotinamide adenine manifestations. Patients have been reported with neurological disease,
dinucleotide (NAD) and NADPH, and their reduced forms. These indistinguishable from subacute combined degeneration, who rapidly
coenzymes play important roles in carbohydrate metabolism. responded to folate replacement.
Dietary deficiency of niacin is rare in developed countries but is
seen in populations dependent on corn (maize) as the main source Vitamin B12 Deficiency: Subacute Combined Degeneration
of carbohydrate because corn contains little niacin or tryptophan. Cobalamin (vitamin B12) and folate are essential vitamins necessary
Nonendemic pellagra rarely occurs in patients with alcoholism or malfor effective DNA synthesis. Impaired DNA synthesis could interfere
absorption. Excessive conversion of tryptophan to serotonin in carci- with oligodendrocyte growth and myelin formation. Animal products
noid syndrome also results in niacin deficiency and pellagra. Deficiency (meat, poultry, fish, and dairy products) are the primary dietary source
of vitamin B6 and diets rich in neutral amino acids that interfere with of cobalamin. The average Western diet provides an excess of the vita-
tryptophan metabolism may also cause niacin deficiency. In Hartnup min (daily requirement 3–9 μg), which is stored in the liver. Excessive
disease, in which tryptophan transport is impaired and requirement for intake of vitamin B12 has not been associated with any adverse effect.
dietary niacin is increased, a pellagra-like illness can also develop. Oral Within the acid environment of the stomach, cobalamin is released
nicotinic acid (50–250 mg/day) is sufficient to treat most symptomatic from dietary proteins. Free cobalamin initially binds to glycopro-
patients. However, the response to treatment may be incomplete. teins known as R-binders, which are secreted by salivary glands and
Deficiency of niacin leads to pellagra, which affects the gastrointes- gastric mucosa. In the duodenum, the cobalamin-R-binder complex
tinal tract, skin, and nervous system, resulting in the triad of dermatitis, is degraded by pancreatic enzymes, and the released cobalamin then
diarrhea, and dementia (the 3Ds). A distal sensorimotor polyneuropa- binds avidly to intrinsic factor, a 60-kD glycoprotein produced by gas-
thy develops in 40%–56% of patients with pellagra; if diarrhea and skin tric parietal cells. The vitamin B12–intrinsic factor complex is absorbed
changes are absent, it is clinically indistinguishable from thiamine-de- by means of binding to intrinsic factor receptors in the terminal ileum.
ficiency neuropathy. A small portion of ingested cobalamin is also absorbed by passive
diffusion.
Pyridoxine (Vitamin B6) Deficiency Cobalamin deficiency is common, including in the elderly, and
Vitamin B6 is required for cellular functions and growth. Niacin, folate, mainly produces pernicious anemia (Stabler, 2013). This results from
and carnitine require vitamin B6 for their metabolism. Humans and other lack of intrinsic factor caused by progressive autoimmune destruction
mammals cannot synthesize vitamin B6, thus requiring it from exoge- of parietal cells in the gastric mucosa. Acquired malabsorption of vita-
nous sources. The regular diet of most adults is adequate for the daily min B12 may occur also following gastric and terminal ileal resection
requirement of 1.5–2 mg of vitamin B6. Isolated pyridoxine deficiency, and in the setting of a wide range of gastrointestinal disorders. Large
however, may occur during treatment with isoniazid (INH), hydralazine, stores of cobalamin in the body may delay development of deficiency
or (rarely) penicillamine. These drugs structurally resemble vitamin B6 symptoms for several years after bariatric surgeries. Unusual causes
and interfere with pyridoxine coenzyme activity. Pregnant and lactating include dietary insufficiency in strict vegetarians (vegans) and intesti-
women and elderly individuals are at a greater risk of developing vitamin nal infection with fish tapeworms. The prevalence of cobalamin defi-
B6 deficiency. It may also occur in chronic alcoholism, celiac disease (CD), ciency is increased in AIDS patients with neurological involvement. A
and renal insufficiency with dialysis. The deficiency of vitamin B6 can be low level of cobalamin may be seen in pregnancy, oral contraceptive
detected by direct assay. Vitamin B6-deficient peripheral polyneuropathy and anticonvulsant use, and in multiple myeloma. Intraoperative use
is characterized by distal sensory and motor deficits of insidious onset. Up or recreational abuse of nitrous oxide, which inactivates cobalamin-de-
to 50% of slow inactivators of INH may develop neuropathy that causes pendent enzymes, may cause acute or subacute vitamin B12-dependent
axonal degeneration of both myelinated and unmyelinated fibers. When neurological disease, particularly in patients with marginal cobalamin
using INH, supplementary pyridoxine (100 mg/day) is recommended. stores. Prophylactic B12 injections given weeks before anesthesia will
Paradoxically, high-dose (≥500 mg/day) pyridoxine may cause a predom- prevent the neurological deterioration. In a number of elderly patients
inantly sensory polyneuropathy (see Toxic Neuropathies, later). with cobalamin deficiency, no specific cause is found. Intracellularly,
cobalamin is converted into two coenzymes required for the forma- Maintenance schedules of monthly injections of 100 μg or 1 mg every
tion of methionine and succinyl-CoA synthesis. Reduced methionine 3 months have been found satisfactory in preventing relapses (Savage
synthesis may be responsible for the neurological manifestations of and Lindenbaum, 1995). This treatment corrects the anemia and may
cobalamin deficiency. Serum cobalamin level may be falsely elevated reverse the neurological complications completely if given soon after
in renal failure, hepatic insufficiency, and myeloproliferative disorders. their onset. Major neurological improvement can be expected to occur
Population surveys estimate that 2% of persons age 60 years and during the first 3–6 months of therapy. If maintenance therapy is inter-
older have undiagnosed pernicious anemia. The disease is especially rupted, neurological symptoms may not occur immediately because of
common in those of Northern European heritage and Blacks. The the large stores of vitamin B12 in the liver but may reappear as early as
full-blown clinical picture of vitamin B12 deficiency consists of mac- 6 months later (Stabler, 2013). Megaloblastic anemia may take several
rocytic anemia, atrophic glossitis, and peripheral and central neuro- years before it appears. For maintenance therapy, oral administration
logical complications (Toh et al., 1997). These last conditions include of large quantities of vitamin B12 (1 mg) in compliant patients is also
peripheral polyneuropathy and optic atrophy, as well as lesions in the feasible, because 1% of vitamin B12 is absorbed without intrinsic factor
posterior and lateral columns of the spinal cord (subacute combined mediation (Kuzminski et al., 1998). The efficacy of nasal or sublin-
degeneration of the spinal cord) and in the brain. The neurological gual cobalamin delivery as well as oral preparations of intrinsic factor
dysfunction may be the earliest and often the only manifestation of remains unproven. The initial severity of neurological deficits, dura-
vitamin B12 deficiency. The peripheral polyneuropathy manifests with tion of symptoms, and hemoglobin level before treatment correlate
paresthesias and large-fiber modality sensory loss (vibration and pro- with neurological outcome. The inverse correlation between degree
prioception), which may begin or be prominent in the hands. The of anemia and neurological damage is not understood. If symptoms
spinal cord manifestations consist of posterior column damage, par- progress despite adequate therapy and normalization of vitamin B12
ticularly of thoracic and cervical cord, which may include a truncal levels, other conditions such as copper deficiency neuromyelopathy
sensory level, and upper motor neuron signs of limb weakness, spas- (see Copper Deficiency Myelopathy and Myeloneuropathy, later)
ticity, and extensor plantar responses. Cerebral involvement ranges should be investigated.
from subtle behavioral changes and forgetfulness to dementia or stu-
por. Vitamin B12 deficiency may also cause autonomic dysfunction Vitamin E Deficiency
and orthostatic hypotension (Beitzke et al., 2002; Skrabal, 2004). An Significant vitamin E (α-tocopherol) deficiency develops in children
unsteady gait, positive Romberg sign reflecting a sensory ataxia, dif- and young adults with chronic severe intestinal fat malabsorption, as
fuse hyperreflexia, and absent ankle jerks should raise the suspicion of occurs in cholestatic liver disease, cystic fibrosis, CD, following exten-
cobalamin deficiency. sive intestinal resections, and in the inherited disorder of abetalipo-
Nerve conduction studies show low-amplitude or absent SNAPs. proteinemia (see Hereditary Neuropathies, earlier). Rarely, vitamin E
Conduction velocities are normal. The dorsal columns of the spi- deficiency develops in the absence of fat malabsorption (Jackson et al.,
nal cord may show a decreased signal on T1- and increased signal 1996). Isolated familial vitamin E deficiency is an AR disorder in which
on T2-weighted MRI images, and temporary contrast enhancement mutations in the α-tocopherol transfer protein gene cause failure to
involving the dorsal and lateral column may be present (Locatelli incorporate α-tocopherol into very-low-density lipoprotein in the
et al., 1999). CNS involvement is also suggested by abnormal visual liver. About 25%–50% of affected individuals are compound hetero-
and somatosensory evoked potentials. Evidence of axonal degenera- zygotes, which may help explain the clinical variability.
tion is found in sural nerve biopsy specimens. The diagnosis is con- Prolonged vitamin E deficiency of any cause may lead after years
firmed by low serum vitamin B12 levels (<170 pg/mL) and normal to a spinocerebellar syndrome with a large-fiber sensory neuropathy,
serum folate concentration. Some 30%–40% of patients with neuro- ataxia, proprioceptive loss, areflexia, ophthalmoplegia, and pigmen-
logical symptoms due to vitamin B12 deficiency have borderline-low tary retinopathy that may be indistinguishable from Friedreich ataxia.
levels (150–200 pg/mL). A megaloblastic anemia with elevated red cell Myopathy and peripheral nerve disease may predominate in some
mean corpuscular volume (>94 fL) may be absent in about 30% of cases. In adults with chronic cholestasis, it may take 2 years to deplete
patients. Elevated serum methylmalonic acid and homocysteine levels, vitamin E stores and an additional 5–10 years to develop neurological
which are the substrates for cobalamin-dependent enzymes, are help- complications.
ful when there is diagnostic uncertainty or when the vitamin B12 level Vitamin E is an antioxidant and free-radical scavenger, and its
is below 350 pg/mL. However, in folate and pyridoxine deficiency, deficiency results in a central and peripheral distal axonopathy of
hypothyroidism, psoriasis, alcohol abuse, INH use, and leukemia, as large-caliber sensory axons affecting peripheral nerves and the pos-
well as increased age, the homocysteine level may be elevated. Serum terior columns of the spinal cord. Lipofuscin-like accumulations
methylmalonic acid level may be raised in hypovolemia, renal insuf- are found in the Schmidt-Lanterman clefts of large-diameter myelin
ficiency, or methylmalonyl-coenzyme A mutase deficiency. The two- sheaths in sural nerve biopsy specimens. Impaired antioxidant protec-
part Schilling test confirms that vitamin B12 deficiency is the result of tion may account for neurological and retinal lesions in long-standing
intestinal malabsorption and is caused by intrinsic factor deficiency, deficiency. EDX study results show normal motor conduction studies
but the test is now rarely performed owing to concerns of radiation and low-amplitude or absent SNAPs. Evoked potential studies may be
exposure and cost. Antibodies to intrinsic factor are found in 70% of abnormal. Vitamin E deficiency is established by low fasting plasma
patients with pernicious anemia; antiparietal cell antibodies are more levels of vitamin E (<5 μg/mL). However, in the presence of hyper-
sensitive (90%) but lack specificity. A combined antiparietal cell anti- lipidemia, the vitamin E level may be normal even in the presence of
body test and serum gastrin level, a marker for hypochlorhydria, may clinical symptoms. Laboratory studies used to confirm fat malabsorp-
increase the accuracy of diagnosis. tion include 72-hour fecal fat determination, vitamin A and D levels,
Initial treatment consists of daily intramuscular injections of 1 amylase levels, liver function tests, peripheral blood smear to search
mg of cyanocobalamin or hydroxycobalamin for the first week, fol- for acanthocytes (present in Bassen-Kornzweig syndrome), and apo-
lowed by weekly injections of 1 mg until 12 doses have been given. lipoprotein B level.
The serum levels of methylmalonic acid and homocysteine will return Vitamin E is abundant in many foods including vegetable
to normal no later than 2–3 weeks after completion of the course. oils, nuts, fruits, leafy vegetables, and cereals. Its bioavailability is
dependent on the fat content of the food. Vitamin E supplementation Neuropathy Associated with Bariatric Surgery
is indicated regardless of cause in all patients with low serum vitamin Bariatric surgery for morbid obesity is becoming increasingly common.
E levels. An initial oral supplementation with vitamin E in large doses Multiple surgical techniques have been employed. Of these, the Roux-
(1500 IU–6000 IU/day) may result in cessation of further deteriora- en-Y gastric bypass, biliopancreatic diversion, and biliopancreatic
tion, neurological improvement, and attainment of a normal ratio of diversion with duodenal switch are particularly known to cause defi-
α-tocopherol to total lipids in the serum. In isolated vitamin E deficiencies of vitamins and other micronutrients (Bloomberg et al., 2005).
ciency, 400–1200 IU/day is sufficient. If no absorption can be docu- Vomiting, which is a common complication of obesity surgery, places
mented after large oral doses of standard vitamin E, a water-soluble these patients at a greater risk for such deficiencies. If unrecognized,
form of α-tocopherol is recommended. these deficiencies lead to a number of metabolic and neurological com-
plications that include neuropathy, myelopathy, optic neuropathy, and
Neuropathy Associated with Malabsorption Syndromes encephalopathy (Juhasz-Pocsine et al., 2007; Koffman et al., 2006). The
Malabsorption may occur as a result of a primary gastrointestinal neuropathy, which takes several forms (sensory-predominant polyneu-
disease or after extensive resection of gastrointestinal tract. Intestinal ropathy, mononeuropathy multiplex, and radiculoplexoneuropathy),
malabsorption may lead to myopathy or peripheral polyneuropathy. is seen in about 16% of patients. Rate and absolute amount of weight
A careful search for occult malabsorption or CD should be part of loss, prolonged gastrointestinal symptoms, low serum albumin and
the routine investigation of all patients with neuromuscular disease transferrin, postoperative surgical complications, and, most impor-
of obscure cause, particularly in patients with ataxia and peripheral tantly, poor nutritional compliance are considered the main risk fac-
neuropathy. Gluten-sensitive enteropathy or CD is the prototype of tors for the development of neuropathy (Thaisetthawatkul et al., 2004).
gluten-sensitive disorders and is characterized by malabsorption due Except for vitamin B12 and copper deficiencies in patients with myelop-
to relapsing inflammatory injury to the mucosa of the small intestine athy, no specific nutritional deficiency correlates with the neurologi-
after ingestion of wheat gluten in genetically predisposed individuals. cal complications (Juhasz-Pocsine et al., 2007). If discovered early, the
The typical symptoms include diarrhea, weight loss, and dermatitis neuropathic symptoms may be reversed by adequate supplementation
herpetiformis. More than 90% of patients with CD express the human or reversal of the surgical bypass (Thaisetthawatkul et al., 2010).
lymphocyte antigen HLA-DQw2 or DQ8. It is a T-cell-mediated disor-
der and may be associated with other autoimmune conditions such as Copper Deficiency Myelopathy and Myeloneuropathy
DM, dermatitis herpetiformis, Sjögren syndrome, rheumatoid arthri- Many foods are rich in copper, and therefore dietary copper deficiency
tis, primary biliary cirrhosis, and thyroid diseases. Patients develop is rare. After absorption in the stomach and proximal small intestine
antibodies against gliadin, tissue transaminases, and other intestinal and passage through liver, about 95% of copper becomes bound to
antigens. It is claimed that patients with or without gastrointestinal ceruloplasmin. The absorption and bioavailability of copper may be
symptoms may rarely (5%–8%) develop varied neurological compli- impaired by a number of factors, including excessive zinc ingestion,
cations including a predominantly sensory and mostly mild axonal iron deficiency, and ascorbic acid and antacid intake. Zinc and cop-
neuropathy, multiple mononeuropathies, autonomic neuropathy, per compete in using a common transporter in the intestinal wall, and
cerebellar ataxia, myopathy, epilepsy, and encephalopathy (Grossman, excessive zinc intake results in the displacement of copper. The most
2008; Hadjivassiliou et al., 2006). The issue, however, remains conten- frequent causes of copper deficiency are malabsorption syndromes
tious, since antigliadin antibodies are also raised in more than 10% of (e.g., protein-losing gastroenteropathy, CD, and Menkes syndrome),
normal adults or patients with other disorders (e.g., hereditary atax- gastrointestinal surgeries (especially bariatric surgery), prolonged
ias), and a gluten-free diet may not result in a satisfactory neurological parenteral nutrition, and use of copper chelating agents. Ingestion of
improvement or a fall in antigliadin antibodies (Gibbons and Freeman, excess zinc in the form of zinc supplements, denture cream, and coins
2005; Rosenberg and Vermeulen, 2005; Serratrice et al., 2004; Wills has also been associated with copper deficiency (Gabreyes et al., 2013;
and Unsworth, 2002). Nations et al., 2008; Rowin and Lewis, 2005). In some patients, no
The cause of PNS involvement is poorly understood. Earlier studies obvious cause can be identified.
have implicated vitamin deficiencies (B12, E, D, folic acid, or pyridoxine). Deficiency of copper impairs the function of several important
However, vitamin replacement rarely improves neurological deficits. oxidases. Acquired copper deficiency with hypocupremic myelopathy
Immunological factors have been proposed in patients without vitamin with or without a peripheral polyneuropathy (myeloneuropathy) may
deficiencies and are supported by the common association of CD with mimic combined system degeneration caused by cobalamin deficiency
other autoimmune disorders. The diagnosis is facilitated by the determi- and follows a progressive course (Kumar, 2007). A number of hemato-
nation of more specific serological markers such as antiendomysial and logical abnormalities may be present: macro-, micro-, and normocytic
tissue transglutaminase IgA antibodies. Unlike antigliadin antibodies, anemia; sideroblastic anemia; neutropenia; iron-containing plasma
these antibodies are highly predictive of CD (>90%). Rapid assays for cells; vacuolated erythroid cells; megaloblastic changes; myelodys
tissue transglutaminase antibodies have been developed (Nemec et al., plastic syndrome; and, rarely, thrombocytopenia. These hematological
2006), and other tests involving antibodies to synthetic gliadin peptide features are present in more than 80% of patients. The neurological
are being developed. The diagnosis is established by small-bowel biopsy manifestations of copper deficiency may precede the hematological
or HLA typing. A strict gluten-free diet, which is difficult to maintain, abnormalities and are present in 75% of patients (Gabreyes et al.,
may stabilize the neurological disease but improvement is rare. 2013). The neurological, EDX, and imaging characteristics of hypocu-
Severe sensorimotor or predominantly sensory polyneuropathies premic myeloneuropathy are similar to those of cobalamin deficiency
with ataxia or burning feet may occur in starvation. Multiple micro- (combined system degeneration) with spastic paraparesis, with or
nutrient deficiencies including thiamine, folate, cobalamin, and sul- without sensory polyneuropathy as the most common findings. The
fur amino acids, in the absence of an apparent malnutrition but with optic nerves or CNS may occasionally be involved (Prodan et al.,
high sugar intake, were thought to be responsible for the outbreak of 2002). The peripheral polyneuropathy is axonal and is often overshad-
polyneuropathy, optic neuropathy, hearing loss, and combined system owed by a severe myelopathy.
degeneration that occurred in Cuba in 1992 and 1993 as a result of the Patients suspected of having hypocupremic myeloneuropathy
US embargo. often have cytopenia. They should have their serum copper, zinc,
and ceruloplasmin measured. Serum zinc may be elevated even in the systemic diseases such as DM, vasculitis, or amyloidosis that may affect
absence of excessive zinc ingestion (Gabreyes et al., 2013). In copper both kidneys and peripheral nerves must first be excluded. CSF pro-
deficiency, both serum copper and ceruloplasmin levels fall. In con- tein is often elevated, but rarely beyond 100 mg/dL. Low-amplitude
ditions where the level of ceruloplasmin is raised, the copper level will CMAPs and SNAPs with mild generalized slowing of motor and sen-
also increase, therefore masking a true copper deficiency. Elevation of sory velocities are common, and distal latencies are prolonged. Late
serum ceruloplasmin, an acute-phase reactant, occurs in a large num- responses (H-reflex and F-wave latencies) become abnormally pro-
ber of conditions including infections, inflammatory diseases, oral longed early in the course of chronic renal failure at a time when motor
contraceptive use, pregnancy, renal and hepatic diseases, malignancies, conduction velocities are still normal. Needle EMG examination shows
diabetes, and in cigarette smokers. It has been suggested that the red evidence of active denervation in distal foot muscles. Regular hemo-
blood cell level of zinc-copper superoxide dismutase is independent of dialysis rarely improves impaired conduction velocities in patients,
the serum copper level and may serve as the measure of body copper despite clinical improvement. Sural nerve biopsy shows axonal loss of
stores. large myelinated fibers and segmental demyelination. Morphometric
Treatment consists of elimination of the cause of deficiency and investigations led to the conclusion that the segmental demyelination
copper supplementation. Identifying sources of excess zinc and its dis- is secondary to primary axonal atrophy.
continuation is often sufficient to improve the condition. Oral sup- Occasionally, exacerbation of the polyneuropathy occurs in patients
plementation with copper gluconate, 2 mg/day, is usually sufficient to with chronic renal failure at the onset of hemodialysis. Acute fluxes of
correct the deficiency, but an equivalent IV dose may be used for 1 water and solutes may be the cause, and reduction in the intensity of
week before initiating the continued oral supplementation. Although dialysis is usually recommended.
hematological improvement is usually rapid and complete in more The precise cause of uremic polyneuropathy remains unknown,
than 90% of patients, only one-fourth of patients showed improve- although a number of potential neurotoxins accumulate in end-stage
ment in their neurological function, while more than two-thirds renal disease (Gallassi et al., 1998). Ethylene oxide used to sterilize dial-
remained unchanged (Gabreyes et al., 2013). ysis tubing has been proposed as a contributing neurotoxin in patients
on hemodialysis.
Uremic Neuropathy Severe uremic polyneuropathy has become less common as a result
Peripheral neuropathy develops in 60% of patients with end-stage renal of earlier treatment with dialysis and renal transplantation. This is
failure who require chronic dialysis. Uremic polyneuropathy is inexpli- also related to the earlier initiation of dialysis in uremic patients and
cably more common in men than in women. The clinical features are improved techniques using more biocompatible dialyzer membranes
those of a slowly progressive, predominantly sensory polyneuropa- and high-flux dialyzers. Attention should be given to avoiding drugs
thy. Severe pain is unusual, but cramps, unpleasant dysesthesias, and such as colchicine or nitrofurantoin, which are potentially neurotoxic
restless legs are common symptoms. Neurological signs include distal and may accumulate in renal insufficiency. Numerous investigations
sensory loss, especially of vibratory sensation, absent reflexes, and sym- have been conducted to assess the long-term effects of hemodialysis
metrical toe-extensor weakness. On occasion, a rapidly progressive, on peripheral nerve function. A consensus has emerged that chronic
predominantly motor polyneuropathy mimicking GBS may develop hemodialysis will stabilize an existing uremic polyneuropathy in most
during the initial weeks of dialysis. Some patients have improved by patients. Manipulating the frequency or duration of dialysis may not
switching from conventional to high-flux hemodialysis, possibly as a alter its course. Chronic peritoneal dialysis provides no advantage
result of the enhanced removal of advanced glycosylation products over hemodialysis. Successful renal transplantation results in signifi-
(Bolton et al., 1997). cant clinical, EDX, and morphological recovery over a period of 3–12
Chronic renal failure and the commonly associated malnutri- months. However, renal transplantation may have little effect on the
tion render peripheral nerves (e.g., ulnar nerve at the elbow, fibular course of the polyneuropathy in diabetic patients with end-stage renal
nerve at the knee) susceptible to compression neuropathies. CTS may disease.
develop in more than 20% of patients on hemodialysis. Nerve com-
pression from local edema secondary to the forearm arteriovenous Peripheral Neuropathy in Liver Disease
shunts or ischemia from a fistula-induced vascular steal syndrome are Various peripheral neuropathies may develop as a direct consequence
likely mechanisms in the early course of dialysis. Patients on long-term of acute and chronic liver disease. Although many reported series of
hemodialysis may develop CTS because of the deposition of β2-micro- patients with neuropathy and hepatic cirrhosis have included alco-
globulin amyloid deposited in the carpal ligament. Ischemic monomelic holics, a neuropathy also occurs among nonalcoholic individuals with
neuropathy is an acute complication of the placement of a more prox- hepatic disease. The neuropathic syndromes associated with liver dis-
imal shunt between the cephalic vein and brachial artery; it usually eases include (1) cryoglobulinemic neuropathy linked to HCV infec-
occurs in diabetic or hypertensive patients with concomitant periph- tion, (2) vitamin E deficiency in chronic cholestatic liver disease, and
eral vascular disease (Tsao et al., 2014). This neuropathy is character- (3) neuropathies associated with end-stage liver disease and primary
ized by abrupt, painful sensory loss of the affected hand and weakness biliary cirrhosis. Viral hepatitis types A, B, and C have been reported
of the distal median, ulnar, and radial innervated distal muscles. The as antecedent infections in the GBS. Isolated cases of CIDP have been
weakness and sensory loss follow a distal-to-proximal gradient starting described in chronic hepatitis B and as a complication after orthotopic
at the level of the fistula in the affected upper limb only. The EDX stud- liver transplantation. Hepatitis B antigenemia is found in a third of
ies reveal an axonal disorder with absent or low-amplitude SNAPs and patients with polyarteritis nodosa and vasculitis.
CMAPs in the affected hand only. Needle EMG shows active dener- Although a clinically overt polyneuropathy is uncommon in patients
vation and loss of MUAPs in the affected limb in a distal-to-proxi- with chronic liver disease, EDX studies are frequently abnormal. The
mal fashion. Prompt surgical closure of the fistula is recommended to highest frequency of neuropathy by clinical criteria (75%) and confirmed
avoid permanent neurological deficits. by electrophysiological studies in an even greater percentage (87%) was
The diagnosis of uremic polyneuropathy should only be made in reported in a cohort of patients who were candidates for liver transplan-
the context of chronic end-stage renal failure (creatinine clearance <10 tation for end-stage liver disease (Iani et al., 1999). The polyneuropathy
mL/min) of at least several months’ duration. Drug toxicity or other is not disabling and often remains clinically unapparent. Paresthesias
in the feet, distal loss of vibratory sensation, and loss of ankle reflexes multiple axonal mononeuropathies that develop distally in the isch-
are the most common findings. EDX abnormalities consist of reduced emic limb (ischemic monomelic neuropathy). Abrupt lightning or
SNAPs and mild slowing of motor conduction velocities. Histological burning pains affect the involved extremity. Sensory examination
studies of the sural nerve show evidence of demyelination and remye- shows a graded impairment of all modalities, particularly those medi-
lination. A high incidence of autonomic dysfunction has been reported ated by large-diameter fibers (Tsao et al., 2014). Muscle strength is
in patients with end-stage liver disease by means of formal autonomic usually maintained, although distal weakness may often develop in
testing. The presence of autonomic neuropathy in such patients has been severe cases. Tendon reflexes may be preserved.
associated with a fivefold increase in mortality over that seen in individ- EDX studies provide evidence of multiple axonal mononeuropa-
uals with normal autonomic function. Early liver transplantation should thies in the involved ischemic limb, with a distal-to-proximal pattern.
be considered for patients with autonomic neuropathy. SNAPs and CMAPs are either absent or markedly reduced in ampli-
Patients with primary biliary cirrhosis may develop a sensory polyneu- tude, and motor conduction velocities are slowed. Acute denervation
ropathy or sensory ganglionopathy. In a few patients with strikingly elevated is limited to very distal extremity muscles. Both large and small fibers
serum lipid levels and cutaneous xanthomas, xanthomatous infiltration of appear to be affected equally. Surgical endarterectomy or bypass sur-
nerves is found on nerve biopsy. The prevalence of associated autoimmune gery may result in recovery of neurological deficits in a period of sev-
diseases, most notably Sjögren syndrome, is high in primary biliary cirrho- eral months, even in long-standing ischemic neuropathy. Ischemic
sis, which in turn is linked to predominantly sensory neuropathies. Large- monomelic mononeuropathy following shunt placement demands
fiber sensory polyneuropathies develop in children and young adults with immediate surgical closure of the arteriovenous fistula.
chronic cholestatic liver disease and secondary vitamin E deficiency. Severe aortoiliac occlusive disease or prolonged use of an intra-aor-
tic balloon pump may occasionally lead to lesions of the proximal sci-
Endocrine Disorders Associated with Peripheral atic and femoral nerve or the lumbosacral plexus.
Neuropathy
Hypothyroid Neuropathy Peripheral Neuropathy in Chronic Obstructive Lung
CTS is the most common peripheral nerve complication of hypothy- Disease
roidism. One-third of patients with hypothyroidism may have clini- Approximately 20% of patients with chronic obstructive lung disease
cal evidence of a general polyneuropathy, which is predominantly may develop a mild distal sensorimotor polyneuropathy that appears
sensory with pain and paresthesias, muscle pain, distal sensory loss, to be correlated with severe hypoxemia.
and incoordination. This may coexist with hypothyroid myopathy and
elevated serum CK level. Nerve conduction studies show absent or Critical Illness Polyneuropathy
decreased SNAPs and slow motor conduction velocities. Sural nerve Acquired weakness in ICU patients is common, tends to be underap-
biopsy demonstrates demyelination, remyelination, and increased gly- preciated, and may be due to a myopathy or polyneuropathy; however,
cogen and lysosomes in axons and Schwann cell cytoplasm. Thyroid both critical illness neuropathy and myopathy may occur concurrently
hormone replacement usually improves the polyneuropathy, but the (Latronico and Bolton, 2011). Critical illness polyneuropathy is char-
improvement may be partial. Thyroid function studies should be con- acterized by acute limb and respiratory weakness after prolonged res-
sidered in patients presenting with a sensory polyneuropathy. idence in the ICU (Visser, 2006). Excluding cardiac and pulmonary
etiologies, it is a major cause of difficulty in weaning patients from
Acromegaly the respirator. It occurs in all ages but is rare in children. Males are
CTS is a well-recognized complication of acromegaly, but a generalized affected more than females. Clinical evaluation of muscular weakness
polyneuropathy also may develop independent of concomitant DM. acquired in the ICU is difficult because patients are often encephalopa-
About half of affected patients have distal paresthesias, sensory loss in thic or sedated, and the examination may be hindered by multiple lines
a stocking-glove distribution, diminished muscle stretch reflexes, and required for intensive support. Most patients have generalized flac-
distal muscle weakness. SNAPs are reduced in amplitude, and motor cid weakness with distal prominence and depressed tendon reflexes.
NCVs are slightly reduced. Nerve biopsy shows a reduced number of Muscle wasting is absent in a third of patients. It is rare to see facial
myelinated and unmyelinated fibers and enlargement of nerve fascicles weakness or other cranial nerve involvement. Pain or paresthesias are
caused by an increase in endoneurial and subperineurial tissue. not features of critical illness neuropathy. When prospectively inves-
tigated, at least 50% of critically ill patients with sepsis and multiple
Hypoglycemic Neuropathy organ failure who were resident in ICUs for at least 2 weeks have EDX
Primary hypoglycemia due to an insulinoma may cause slowly progres- features indicative of an axonal polyneuropathy.
sive motor-sensory polyneuropathy with predominant motor features EDX studies are necessary to establish the diagnosis. Nerve conduc-
of distal muscle atrophy and weakness, especially of the upper limbs. tion studies reveal a distal axonal polyneuropathy with reduced CMAP
Painful paresthesias are common, but there are usually no objective and, to a lesser extent, SNAP amplitudes in conjunction with fibrilla-
signs of sensory loss. The muscle atrophy and weakness (amyotrophy) tion potentials and decreased MUAPs on needle EMG. CSF is almost
may precede the onset of clinically apparent hypoglycemic episodes always normal. Primary axonal degeneration, more severe distally than
by a few years. EDX studies show evidence of acute denervation and proximally, is seen at autopsy.
reinnervation. Hypoglycemic neuropathy may assume a greater role The polyneuropathy is thought to be a complication of the systemic
among diabetic patients receiving intensive insulin therapy. In fact, an inflammatory response syndrome that is triggered by sepsis, severe
average patient with IDDM has a low plasma glucose level about 10% trauma, or burns. The pathophysiology of this syndrome is currently
of the time. Experimental studies suggest that hypoglycemia prefer- under intense investigation. Severe infections or trauma of any type
entially causes large-nerve fiber damage (Jamali and Mohseni, 2006). appear to initiate a series of events that ultimately lead to impaired micro-
circulation and multiple organ dysfunction. In burn neuropathy, which
Ischemic Monomelic Neuropathy affects 11% of severe burn patients, it is postulated that occlusion of vasa
Ischemia due to acute thromboembolic occlusion of major limb arter- nervorum or dissemination of neurotoxins (or both) are responsible for
ies or proximal arteriovenous shunt placement infrequently causes the more severe form of critical illness neuropathy (Koualske et al., 2001).
Critical illness myopathy is another cause of acquired weakness Central axonal involvement has been linked to incomplete clinical
in residents of ICUs and is difficult to distinguish clinically from its recovery. Agents such as n-hexane and organophosphates cause simul-
neuropathic counterpart. This complication usually occurs in patients taneous degeneration of peripheral nerve, dorsal column axons, and
with acute respiratory distress syndrome or severe asthma who have corticospinal pathways, often resulting in spasticity that may become
been treated with IV corticosteroids, nondepolarizing neuromuscu- apparent following recovery from the peripheral axonopathy.
lar blocking agents, or most commonly, both. Plasma CK levels are The second type of toxin-induced injury targets nerve cell bodies
transiently and marginally elevated. Muscle biopsy may show a necro- (toxic neuronopathy) such as the dorsal root ganglion cell. Cisplatin,
tizing myopathy with many fibers with loss of thick myosin filaments methyl-mercury compounds, high-dose pyridoxine, and doxorubicin
(Lacomis et al., 1996). The presence of normal sensory conduction are examples of toxins that produce neuronal degeneration. When the
studies in the setting of small, short-duration, polyphasic MUAPs on neuronal insult leads to apoptosis and cell death, the resulting sensory
needle EMG helps support a diagnosis of critical illness myopathy. In neuropathy is often severe and irreversible with limited functional
critical illness myopathy, the muscles become unresponsive to direct recovery.
electrical stimulation, whereas in critical illness polyneuropathy, this Primary toxic demyelinating neuropathy is a less common neuropa-
response is largely preserved. The difficulty in differentiating a critical thy but occurs with diphtheria, buckthorn toxin, and exposure to per-
illness myopathy from polyneuropathy was demonstrated in one study hexiline, amiodarone, or suramin. Slowed NCVs can also be seen in
in which severe weakness was found in 25% of consecutively admitted certain forms of hexacarbon neuropathy, as in habitual glue sniffers, as
ICU patients requiring mechanical ventilation, all of whom demon- a result of axonal swelling from neurofilament accumulation causing
strated an axonal neuropathy on EDX testing, as well as myopathic secondary demyelination. In buckthorn intoxication, the neuropathy
changes unrelated to denervation on muscle biopsy (De Jonghe et al., may closely resemble GBS. Ingestion of the fruit of the buckthorn shrub
2002). Repetitive nerve stimulation studies should be performed to (Karwinskia humboldtiana), which grows in Mexico, Central America,
exclude a defect of neuromuscular transmission caused by defective the southern United States, and Caribbean countries, results in a pro-
clearance of neuromuscular blocking agents. It is of utmost impor- gressive and ascending flaccid paralysis of the limbs in 3–4 weeks. Both
tance to exclude a preexisting known or unrecognized neuromuscular electrophysiological and pathological studies of the peripheral nerves
condition leading to ICU admission before contemplating the diagno- show extensive demyelination. However, the CSF studies are usually
ses of critical illness neuropathy and myopathy. normal. Recovery will occur if the amount of ingestion is limited but
It has been suggested that intensive insulin therapy to maintain a is usually slow and may take 6–12 months. The responsible toxins are
blood glucose level of 80–110 mg/dL in ICU patients reduces the pos- anthracenone compound (T-514) or peroxisomicine A1, T-544, T-496,
sibility of critical illness neuropathy or myopathy (from 52% to 29%). and T-516, but the exact pathophysiological mechanism responsible
The role of insulin in reducing inflammation and in decreasing the for Schwann cell injury remains obscure (Salazar-Leal et al., 2006).
level of nitric oxide, which leads to the protection of endothelium, has Other toxins causing demyelinating neuropathies are discussed later.
been proposed as the mechanism of insulin effect (Langouche et al., To establish a causal link between a putative neurotoxin and neu-
2005). Adequate aggressive and early treatment of sepsis and septic ropathy, two clinical criteria should be met:
shock may also reduce the incidence of critical illness neuropathy and 1. Exposure can be verified and temporally related to the onset of clin-
myopathy. ical symptoms. Neuropathic symptoms usually occur concurrently
The prognosis of critical illness myopathy and neuropathy is directly with the exposure or following a variable latency of up to several
dependent on the prognosis of the underlying illness. However, those months. There must be neurological signs and abnormal EDX
who survive the underlying conditions improve slowly, with the myop- studies. Because many toxic neuropathies are subclinical, subjective
athy having a relatively better and more favorable prognosis. Patients symptoms may or may not occur.
recover spontaneously in 3–6 months following discharge from the 2. Removal from the exposure results in cessation of progression of
ICU, but many patients will require intensive rehabilitation, and some symptoms and deficits. This is variably followed by improvement,
degree of persistent functional disability is common. although in certain axonopathies, cessation of exposure may be
attended by a worsening of symptoms for up to 2 months (so-called
coasting) before worsening ceases.
TOXIC AND DRUG-INDUCED NEUROPATHIES In addition, the clinician must recognize that certain factors may
Peripheral neuropathy is one of the most common reactions of the increase susceptibility to toxic neuropathy. These include preexisting
nervous system to toxic chemicals. Industrial, environmental, and neuropathy (e.g., CMT), simultaneous use of multiple neurotoxic
biological agents as well as heavy metals and pharmaceutical agents drugs or compounds, and systemic disorders that cause impaired drug
are known to cause toxic neuropathies (see Chapter 86). Medications, metabolism (Chaudhry et al., 2003). Any of these may increase the risk
most notably anticancer drugs, are the leading offenders in clinical and severity of toxic neuropathy.
practice today. Neurotoxic agents may produce distal axonal degen- A focused history probing for a background of occupational, envi-
eration (axonopathy), nerve cell body degeneration (neuronopathy), ronmental, or drug exposure is important. Most toxic neuropathies
or primary demyelination (myelinopathy) (see Pathological Processes present clinically with length-dependent sensorimotor or purely sen-
Involving Peripheral Nerves, earlier). For most toxic neuropathies, the sory deficits. Autonomic dysfunction is rarely a prominent feature,
biochemical mechanisms underlying the pathogenesis of nerve dam- though exceptions include acrylamide, cisplatin, and vinca alkaloids.
age remain poorly understood. Predominantly motor toxic neuropathy is rare, being limited to
Most toxins produce symmetrical axonal degeneration in a dying- dapsone, lead, and organophosphate-induced delayed polyneurop-
back (length-dependent) pattern beginning in the distal segments athy. Rarely do typical pathological features such as neurofilamen-
of long, large-caliber nerve fibers, eventually spreading proximally tous axonal swellings in hexacarbon neuropathy, axonal vacuolation
with continued exposure. A number of toxic axonopathies also affect in thallium, or lamellar Schwann cell inclusions in amiodarone and
the CNS, showing evidence of concurrent degeneration of dor- perhexiline intoxication allow specific identification of the cause by
sal column projections of sensory neurons and optic nerve axons. nerve biopsy. Attention should be paid to the systemic symptoms and
Electrophysiological investigations typically disclose an axonal pattern. a thorough general examination because many toxins cause systemic
toxicity as well. The most important steps in treatment involve recog- TABLE 106.16 Neuropathies Caused by
nition of the offending agent and elimination of exposure. Industrial
Pharmaceutical Drugs
and environmental agents that cause toxic neuropathies are discussed
in Chapter 86 (see also London and Albers, 2007). Clinical and
Many medications can cause a peripheral neuropathy that is Pathological
generally reversible when the offending drug is discontinued. If Drugs Features Comments
a clear causal relationship between a potentially neurotoxic drug Antineoplastic
and neuropathy is established, additional investigations to search Cisplatin S, DA, N Binds to DNA; disrupts axonal
for alternative causes may be unnecessary. Premedication with such transport?
compounds as neurotrophins may in the future allow clinicians to Suramin SM, DA, SD DA: inhibits binding of growth
blunt or prevent the dose-limiting neurotoxic effects of anticancer factors; SD: immunomodulat-
drugs. ing effects?
A careful drug history including over-the-counter nutritional Taxanes (paclitaxel, S, DA Promote microtubule assembly;
supplements and vitamin preparations should be obtained for every docetaxel) disrupt axonal transport
patient with polyneuropathy. Some of the drugs reported to produce Vincristine S>M, M, DA Interferes with microtubule
peripheral neuropathy are listed in Table 106.16. Many anecdotal assembly; disrupts axonal
reports of neuropathy possibly induced by other drugs may represent transport
coincidental occurrences and remain to be substantiated.
Antimicrobial
Amiodarone Chloroquine SM, DA Myopathy
Amiodarone is a class III antiarrhythmic drug used in the management Dapsone M, DA Optic atrophy
of refractory ventricular arrhythmias. Nearly all patients on chronic Isoniazid SM, DA Pyridoxine antagonist
therapy develop one or more adverse effects, including thyroid abnor- Metronidazole S, DA
malities, photosensitivity dermatitis, corneal microdeposits, hepatic Nitrofurantoin SM, DA
dysfunction, pulmonary fibrosis, myopathy, action tremor, basal
Antiviral (NRTIS)
ganglia dysfunction, encephalopathy, pseudotumor cerebri, optic Didanosine (ddl) SM, DA Reversible neuropathy
neuropathy, and a dose-dependent polyneuropathy. A more recent Fialuridine (FIAU) S, DA Irreversible neuropathy; also
retrospective study, however, found that neurological complications myopathy
are far less frequently encountered in the modern era than in the 1980s Lamivudine (3TC) S, DA Least common NRTI neuropathy
when amiodarone was introduced, owing to differences in mainte- Stavudine (d4T) SM, DA More associated with lipodys-
nance dosages. In this study, neurological adverse events of any kind trophy syndrome
were seen in only 2.8% of patients, and peripheral neuropathy was Zalcitabine (ddC) SM, DA Single most neurotoxic NRTI
noted in less than 1% (Orr and Ahlskog, 2008). Sensorimotor polyneu- Zidovudine (AZT) — Myopathy only
ropathy, either subacute or chronic, may develop in patients receiv-
ing long-term amiodarone (400 mg/day) therapy. Length of therapy Cardiovascular
is a greater risk factor for neuropathy than dose. Moderate sensory Amiodarone SM, SD Lysosomal lamellar inclusions;
impairment and distal and sometimes proximal muscle weaknesses myopathy
occur. Electrophysiological studies show mild slowing of NCVs, as well Hydralazine SM, DA Pyridoxine antagonist
as distal denervation. The clinical and electrophysiological features Perhexiline SM, SD Lipid inclusions
may resemble CIDP, and when motor symptoms predominate and the
course is rapid, GBS. Nerve biopsy demonstrates variable findings of Other
loss of myelinated and unmyelinated fibers, axonal degeneration, and Colchicine SM, DA Neuromyopathy, raised creatine
segmental demyelination. A distinctive feature is the presence of lyso- kinase levels
somal lamellar inclusions in Schwann cells, fibroblasts, and endothelial Disulfiram SM, DA
cells resulting from inactivation of the lysosomal enzyme sphingomye- Gold SM, DA Myokymia
linase. There is up to 80 times greater concentration of amiodarone and Lipid-lowering agents SM, DA May also cause rhabdomyolysis
desethylamiodarone in the peripheral nerve than in the serum. Because (statins)
of the prolonged half-life (up to 100 days) of amiodarone, recovery Nitrous oxide S, DA Inhibits vitamin B12-depen-
following the cessation of drug can be very slow. The long half-life also dent methionine synthase;
heightens the importance of correctly attributing the neuropathy to myelopathy
amiodarone and not to other causes. Few equivalent antiarrhythmics Phenytoin SM, DA Asymptomatic in most
exist for many patients, and a lengthy observation period is required to Pyridoxine S, N, DA Doses > 250 mg/day
assess whether or not the progression has halted. Thalidomide S, N
L-Tryptophan (tainted) SM, DA Eosinophilia-myalgia syndrome
Bortezomib DA, Distal axonopathy; M, motor; N, neuronopathy; NRTI, nucleoside analog
Bortezomib (Velcade), used in the treatment of multiple myeloma, reverse transcriptase inhibitor; S, sensory; SD, segmental demyelination;
is a proteasome inhibitor that frequently causes a predominantly SM, sensorimotor neuropathy.
sensory reversible axonal neuropathy in a dose-dependent manner,
which may rarely also affect the autonomic nervous system. The neuropathy may be significantly less common. The well-docu-
neuropathy of bortezomib is more pronounced in patients with a mented reversibility of neuropathic symptoms after stopping or
preexisting neuropathy or other risk factors for neuropathy such reducing the dose, however, strongly suggests a primary causative
as diabetes. As the scope of bortezomib has widened to include role for bortezomib. Rates of neuropathy are also high in retreat-
treatment of solid tumors, early observations have suggested that ment (Argyriou et al., 2008).
Chloramphenicol suppression of gout. Markedly elevated serum CK levels and EDX find-
Chloramphenicol can produce an often reversible peripheral and optic ings of a neuromyopathic process occur. This often is misdiagnosed as
neuropathy following prolonged high-dose therapy. The mechanism uremic myopathy and neuropathy. Grip and percussion myotonia is
of neurotoxicity is unclear. sometimes evident while myotonic discharges on EMG are frequently
observed. Although the sural nerve biopsy shows only nonspecific
Chloroquine and hydrochloroquine changes, muscle biopsy reveals autophagic vacuoles and lysosomal
Chloroquine and hydrochloroquine are antimalarial drugs that are accumulation. The weakness and CK elevations typically remit after
also used in the treatment of connective tissue disorders. Typically, the drug is discontinued. Colchicine probably causes neuropathy
a painful vacuolar myopathy with increased serum muscle enzymes by interfering with axoplasmic transport and impairment of axonal
develops after prolonged therapy. Both also produce only mild microtubular assembly.
neuropathy. Often there is evidence of both myopathy and neurop-
athy. Cardiac myotoxicity may also be present. Concomitant renal Dapsone
dysfunction is a predisposing factor for neuromyotoxicity. Muscle Dapsone is used in the management of leprosy and other skin disorders.
and sural nerve biopsies show lamellar inclusions in muscle fibers High doses may cause a predominantly motor neuropathy characterized
and Schwann cells. Other antimalarial agents in the same chemical by weakness and atrophy of distal muscles, particularly intrinsic hand
class may cause a similar neuropathy. The mechanism of toxicity is muscles. Severe optic neuropathy may also occur. Reduction of motor
thought to be lysosomal enzyme inhibition similar to amiodarone. NCV is slight, even in the presence of severe denervation, suggesting an
axonal neuropathy. Recovery after the discontinuation of drug is slow.
Cisplatin
Several platinum compounds are used in cancer chemotherapy. The Dideoxynucleosides
prototype of these is cisplatin, which is used widely in the treatment of Zalcitabine (dideoxycytidine [ddC]), didanosine (dideoxyinosine
ovarian, bladder, and testicular malignancies, as well as squamous cell [ddI]), and stavudine (didehydrodeoxythymidine [d4T]) are nucle-
carcinomas. Cisplatin exerts its chemotherapeutic effects by cross-link- oside analogs that inhibit reverse transcriptase and are used to treat
ing DNA, thereby disrupting cell division. The effect of cisplatin on HIV-1 infection. These agents cause a dose-limiting dysesthetic sensory
tumor vasculature has also been implicated in its antineoplastic effect. neuropathy (Dalakas, 2001). Combined use of these drugs increases
Sensory polyganglionopathy is the dose-limiting side effect. Cisplatin the risk of neuropathy substantially. High doses of ddC produce an
causes a dose-dependent, predominantly sensory neuronopathy affect- acute painful sensory neuropathy that may progress for 3 weeks, or
ing large cells of long-fiber nerves, causing loss of large long myelin- even months, after treatment is stopped (coasting). Lower doses cause
ated fibers (Krarup-Hansen et al., 2007). Ototoxicity is common, a less painful sensory neuropathy in 10%–30% of patients. Preexisting
manifested by tinnitus and high-frequency hearing loss. Paresthesias, neuropathy, DM, heavy alcohol consumption, and low serum cobal-
Lhermitte sign, loss of tendon reflexes, prominent proprioceptive loss, amin levels are risk factors that predispose to nucleoside neuropathy.
and sensory ataxia usually occur when cumulative doses exceed 400 Partial reversal of symptoms following withdrawal of drug allows the
mg/m2. At the onset of symptoms, it may be difficult to distinguish this ddC neuropathy to be distinguished from the clinically similar HIV-1-
neuropathy from a paraneoplastic neuronopathy. associated distal sensory polyneuropathy. Substantial evidence is now
Autonomic symptoms, especially gastroparesis and vomiting, are being accumulated on the role of mitochondrial dysfunction in the
common and may reflect enteric ganglion cell loss. The neuropa- pathogenesis of nucleoside analog neuropathy. Mitochondrial alter-
thy may develop as late as 4 months after the drug has been stopped ations with mitochondrial DNA depletion in the axons and Schwann
(coasting). Nerve conduction studies show reduced or absent SNAPs. cells of sensory nerves of patients treated with ddC have been reported.
Nerve biopsy reveals loss of large myelinated fibers and acute axonal
degeneration. Most patients receiving cumulative doses below 500 mg/ Disopyramide
m2 improve following cessation of therapy, but the neuropathy may A few cases of reversible sensorimotor peripheral neuropathy have
persist long after the cessation of medication (Strumberg et al., 2002). been associated with the cardiac antidysrhythmic agent disopyramide
Neurotrophins to prevent or ameliorate the neurotoxicity of cisplatin (Briani et al., 2002).
and experimental gene transfer therapy with VEGF are currently being
investigated. Vitamin E supplementation (α-tocopherol 400 mg/day) Disulfiram
has been shown to reduce the severity of neuropathy when adminis- Disulfiram is used in the treatment of alcoholism. The incidence of
tered along with and after cessation of cisplatin (Pace et al., 2010). neuropathy is dose related; most patients receiving daily doses of 500
The second-generation platinum compound carboplatin is less mg or more develop nerve damage after 6 months. The clinical man-
neurotoxic. There are other available and emerging platinum com- ifestations are initially distal sensory impairment and later progres-
pounds including oxaliplatin, nedaplatin, and lobaplatin. Up to 90% sive weakness. Nerve conduction studies and EMG indicate an axonal
of patients receiving a cumulative dose of 540 mg/m2 or greater of neuropathy. Encephalopathy or basal ganglia dysfunction may also be
oxaliplatin develop a predominantly sensory neuropathy (Cersosimo, observed in patients receiving high doses of the drug. Acute axonal
2005; Krishnan et al., 2005). Some patients also develop Lhermitte degeneration and loss of myelinated fibers, as well as accumulation
sign. During or shortly after the infusion of oxaliplatin, many patients of neurofilaments in the swollen axons, are seen in sural nerve biopsy
experience transient sensory symptoms in the limbs, perioral region, specimens. After the drug is stopped, improvement takes place over a
and in the throat, possibly due to a temporary dysfunction of nodal period of months. The mechanism of neurotoxicity is unknown, but
voltage-gated sodium channels of peripheral nerve. toxicity caused by carbon disulfide, a metabolite of disulfiram, and
mitochondrial injury have been proposed.
Colchicine
Colchicine is used primarily for the treatment of gout. Subacute prox- Ethambutol
imal weakness and an associated mild distal axonal neuropathy may Ethambutol is an antituberculous drug that causes peripheral sensory
occur in patients with mild renal insufficiency receiving conventional and optic neuropathy after prolonged administration at doses above
doses of colchicine, or in patients receiving long-term colchicine for 20 mg/kg/day.
Etoposide neuropathy (Kolb et al., 2018; Supakornnumporn and Katirji, 2017).

Etoposide is a semisynthetic derivative of podophyllotoxin with estab- The onset was time locked to the use of checkpoint inhibitors, occur-
lished antineoplastic activity in SCLC and lymphoma. Distal sensory ring 2–22 weeks from the first treatment. Slightly more than half of the
axonal neuropathy develops in approximately 10% of patients after patients had, in addition to elevated CSF protein, CSF pleocytosis with
high-dose therapy with this agent. lymphocytic predominance. Most are treated with corticosteroids (1–2
mg/kg/day of prednisone) in addition to plasma exchange or IVIG.
Gold The prognosis of GBS as an irAE is variable with several reported lethal
Organic gold salts are sometimes used in the treatment of rheumatoid cases (Kolb et al., 2018). In contrast to GBS, CIDP is less commonly
arthritis. Toxic allergic reactions involving skin, kidneys, and blood are well reported and most presently acutely fulfilling the diagnosis of acute
known, whereas neurotoxic complications are uncommon. A dose-related onset CIDP (Kolb et al., 2018; Supakornnumporn and Katirji, 2018).
distal axonal polyneuropathy may develop in patients receiving gold ther-
apy. Many patients have the distinctive features of profound myokymia, Isoniazid
muscle aches, insomnia, and autonomic dysfunction such as sweating INH is an effective antituberculous drug that interferes with vitamin
and labile hypertension. After the drug is discontinued, improvement is B6-dependent coenzymes and thus leads to pyridoxine deficiency. INH
the rule. Isolated case reports suggest that gold therapy may precipitate a is acetylated in the liver by the enzyme acetyltransferase. Individuals
Guillain-Barré-like syndrome with rapidly ascending limb weakness, sen- unable to acetylate at a normal rate (slow acetylators) maintain high
sory paresthesia, and elevated CSF protein. In these cases, nerve conduc- blood levels of free INH longer than rapid acetylators and are there-
tion studies show evidence of demyelinating neuropathy. fore more susceptible to toxic neuropathy. The slow acetylation is
inherited as an AR trait. INH polyneuropathy occurs in approximately
Heroin 2% of patients receiving conventional doses (3–5 mg/kg/day), its inci-
Both nontraumatic brachial and lumbosacral plexopathies have been dence increasing with higher doses. Typically, 6 months of treatment
reported in heroin addicts. On resumption of heroin use after a period is needed before neuropathic symptoms of paresthesias, impaired
of abstinence, the symptoms recur in one-third of patients. Intense distal lower extremity sensation, and weakness begin. The primary
pain is a common clinical presentation, whereas weakness and sen- pathological process is axonal degeneration affecting both myelin-
sory impairment are less prominent. Spontaneous recovery occurs ated and unmyelinated fibers, often with prominent axonal regener-
slowly over weeks or months. The mechanism of these plexopathies ation. Unless recognition of this complication is delayed, recovery is
is unclear. A variety of mononeuropathies, usually compression-in- rapid. Co-administration of vitamin B6 (50–100 mg/day) prevents the
duced, also occurs among heroin addicts. neuropathy.
Hydralazine Leflunomide
Hydralazine is an antihypertensive drug that can produce a lupus-like Leflunomide is an antiinflammatory disease-modifying drug used in
syndrome and rarely produces a predominantly sensory polyneurop- rheumatoid arthritis. A sensory, and sometimes motor, axonal neu-
athy. Distal “tingling asleep numbness” in the extremities, without ropathy may develop a few months after initiation of therapy (Bonnel
overt clinical signs, may develop in 15% of patients on hydralazine. and Graham, 2004; Martin et al., 2005). Patients who stop the drug
The neuropathy may be caused by pyridoxine deficiency by a mech- within 30 days of symptom onset are more likely to have improvement
anism similar to that associated with INH. Symptoms improve after of symptoms or complete recovery than patients who continue to use
withdrawal of the drug or with low-dose vitamin B6 supplementation the drug for a longer time.
(50–100 mg/day).
Linezolid
Immune Checkpoint Inhibitors Linezolid is an oxazolidinone used against methicillin- and vancomy-
The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), pro- cin-resistant gram-positive microorganisms. Its long-term use (>28
grammed death 1 (PD-1), and programmed cell death ligand 1 days) may result in a predominantly sensory and poorly reversible
(PD-L1) immune checkpoints play important roles as negative reg- neuropathy with both large- and small-nerve fiber involvement. The
ulators of T-cell activation, prevent autoimmunity, and help tumor mechanism of nerve toxicity is unknown but may be related to inhibi-
cells escape from recognition by the host immune system. Immune tion of nerve protein synthesis or mitochondrial dysfunction (Bressler
checkpoint inhibitors inhibit the immune checkpoint pathways and et al., 2004; Zivkovic and Lacomis, 2005). With prolonged use, an optic
enhance T-cell immunity. Ipilimumab inhibits CTLA-4, nivolumab neuropathy may also develop.
and pembrolizumab inhibit PD-1, while atezolizumab, avelumab, and
durvalumab inhibit PD-L1. They are increasingly used for patients Lipid-Lowering Agents
with various cancers including melanoma, non–small-cell lung cancer, The 3-hydroxymethylglutaryl-(HMG)-CoA-reductase inhibitors, or
and urothelial carcinoma and have shown increased overall survival statins, have been claimed in various case reports and a small number
(Darvin et al., 2018). of case-controlled and cohort studies to cause an axonal and reversible
Immune-related adverse events (irAEs) due to immune check- sensorimotor polyneuropathy (Gaist et al., 2002). However, substan-
point inhibitors are increasingly recognized affecting most commonly tial controversy and doubt accompanies the true existence of such an
skin and gastrointestinal tract. Most of these irAEs are reversible, association, its severity and extent, pathophysiology, and the benefits
but some result in permanent damage and, rarely, deaths (Postow versus the risks of statins (Bays, 2006; Guyton, 2006; Leis et al., 2005).
et al., 2018). Neurological irAEs of treatment with immune check- Even if statins do cause peripheral polyneuropathy, the attributable
point inhibitors included autoimmune encephalitis, transverse risk is small and should be considered in the light of the benefit of
myelitis, myositis, myasthenia gravis, and immune polyneuropathies these drugs in preventing and reducing cardiovascular and cerebro-
(Supakornnumporn and Katirji, 2018). Most immune polyneurop- vascular events (McKenney et al., 2006). The incidence of neuropa-
athies were demyelinating and consistent with the clinical diagnoses thy is estimated at 12 per 100,000 person-years or a prevalence of
of GBS including AIDP, MFS, and acute motor and sensory axonal 60 per 100,000 persons. The direct role of the underlying metabolic
syndrome, hyperlipidemia, or an unrecognized IGT (Hoffman-Snyder Phenytoin

et al., 2006) on the development of neuropathy in patients receiving Phenytoin, a widely used antiepileptic drug, may cause mild and
statins cannot be entirely excluded. largely reversible or asymptomatic polyneuropathy after many years
of exposure. Typical manifestations are confined to lower-extrem-
Metronidazole and Misonidazole ity areflexia, distal sensory loss, and mildly reduced motor conduc-
Metronidazole is commonly used for the treatment of protozoal and tion velocities. The degree of abnormality is generally proportional
anaerobic bacterial infections, as well as inflammatory bowel disease, to the duration of phenytoin treatment. Folate deficiency, which
peptic ulcers caused by Helicobacter pylori, and genitourinary tract may develop during phenytoin therapy, is unrelated to the onset of
infections. It may produce a painful, predominantly sensory polyneuropathy.
neuropathy or sensory neuronopathy following the chronic use of
cumulative doses of drug exceeding 30 g. Patients taking large doses Pyridoxine
in a short period for acute infections may also develop such neurop- High-dose pyridoxine (vitamin B6, 250–3000 mg/day) may cause
athies. Axonal degeneration of both myelinated and unmyelinated a severe and remarkably uniform sensory polyganglionopathy.
fibers can occur, with slow improvement after the agent is stopped. Painful paresthesias, sensory ataxia, perioral numbness, and
Misonidazole, a related compound used as an experimental radia- Lhermitte sign are common features. Nerve conduction studies
tion-sensitizing agent, causes a similar sensory neuropathy. The mech- show low-amplitude or absent SNAPs. Severe depletion of myelin-
anism may involve DNA binding. ated fibers and acute axonal degeneration are found in sural nerve
biopsy specimens. Pyridoxine use should be queried in all patients
Nitrofurantoin with sensory neuropathy. Although its use as a prescribed agent is
Nitrofurantoin is a broad-spectrum antibiotic used to treat urinary tract now limited, it is still self-administered by patients without proof
infections. A sensorimotor polyneuropathy of the distal axonal type of efficacy in CTS, premenstrual syndrome, hyperemesis grav-
may develop weeks to months after beginning therapy. Distal numb- idarum, and in body building. In experimental studies, high-dose
ness, paresthesias, and weakness are common. At times, the neuropa- pyridoxine (300 mg/kg) produced widespread dorsal root ganglion
thy progresses rapidly. Renal insufficiency, particularly in the elderly degeneration. The vulnerability of dorsal root ganglia to circulating
and females, predisposes patients to the development of neuropathy pyridoxine is thought to be due to weak blood–brain barrier in this
because of excessive tissue concentrations of nitrofurantoin, which is region. It appears that the toxic effect is exerted by pyridoxine itself
normally excreted by the kidneys. Patients with preexisting diabetes and not through its metabolites. The fact that most clinical cases
are also at greater risk of developing neuropathy. Electrophysiological gradually recover suggests that dysfunctional dorsal root ganglion
studies show the typical changes of distal axonopathy. Nerve biopsy neurons may regain their functional capacity despite severe sensory
shows axonal degeneration. The mechanism of toxicity is unclear but deficits early in the course of disease.
is thought to be inhibition of synthesis of acetyl-CoA by furan deriva-
tives or accumulation of metabolites such as semicarbazide, known to Suramin
cause neuropathy in experimental animals. Improvement occurs after Originally introduced as an antiparasitic agent, suramin is used cur-
the medication is discontinued, but it may be incomplete, especially if rently as an antineoplastic drug for refractory malignancies. It acts
weakness is present. by inhibiting DNA polymerase activity and displacing several growth
factors—insulin-like growth factor (IGF-1), epidermal growth fac-
Nitrous Oxide tor (EGF), transforming growth factor (TGF), and NGF—from
A predominantly sensory neuropathy and associated myelopathy their respective receptors. Suramin neurotoxicity is the dose-limit-
develop in individuals repeatedly abusing or exposed to nitrous oxide ing side effect leading to two distinct patterns of neuropathy: one a
(N2O), an inhalation anesthetic agent that is also used in the food length-dependent axonal polyneuropathy and the other a subacute
industry as whipping cream propellant. Neurological symptoms occur demyelinating polyradiculoneuropathy (Chaudhry et al., 1996). The
following intentional abuse or, rarely, through contamination in oper- distal sensorimotor neuropathy that occurs in 30%–55% of patients
ating rooms or pediatric dental offices with faulty N2O scrubbers. Sharp manifests with paresthesias and mild distal leg weakness. About 15%
radicular pains are common symptoms, along with numbness and dis- of patients develop a subacutely evolving, demyelinating polyradic-
tal sensory loss. A Lhermitte or reverse Lhermitte sign (neck flexion uloneuropathy. Severe generalized flaccid weakness with bulbar and
induces an electrical shock sensation traveling from the feet upward), respiratory involvement, nerve conduction studies consistent with
increased reflexes, and extensor plantar signs may be present. Nerve demyelination, increased CSF protein levels, and perivascular inflam-
conduction studies show decreased SNAP amplitudes. N2O inhibits mation and increased macrophage numbers on sural nerve biopsy are
the vitamin B12-dependent enzyme methionine synthase, producing a typical features, making this neuropathy virtually indistinguishable
clinical syndrome indistinguishable from vitamin B12 deficiency. N2O from GBS or CIDP. The severe neuropathy occurs predominantly
anesthesia may even precipitate subacute combined degeneration in at peak plasma suramin concentrations above 350 μg/mL. Suramin
patients with unrecognized cobalamin deficiency. Serum methylmalo- may induce inflammatory demyelination by its many immunomod-
nic acid and homocysteine can be significantly elevated. Prognosis fol- ulatory effects. Patients improve after drug discontinuation and with
lowing cessation of exposure is good unless the myelopathy is severe. plasmapheresis.
Vitamin B12 supplementation appears to be of no benefit in treating
N2O myeloneuropathy. Tacrolimus
Tacrolimus, a macrolide antibiotic, has a potent immunosuppressive
Perhexiline effect and is used in organ transplantation. In about 30% of patients,
Perhexiline maleate, now used infrequently in a few countries (but not adverse effects including seizures, leukoencephalopathy, occipital
the United States) for treatment of angina pectoris, causes a reversible headaches, tremor, and akinetic mutism may develop. Rarely, it may
demyelinating neuropathy mimicking an inflammatory demyelinating also cause one of the two types of peripheral neuropathy: a reversible
polyneuropathy. but severe axonal neuropathy that occurs days after treatment; and a
demyelinating neuropathy similar to CIDP, 2–10 weeks after treat- of neuropathy, preventing severe disability (Cavaletti et al., 2004;
ment. Electrophysiological and nerve biopsy, as well as CSF findings, Plasmati et al., 2007).
are those usually observed in demyelinating neuropathies. The cause Lenalidomide, an analog of thalidomide, is a more potent immu-
of the axonal degeneration is unknown, but the demyelinating variety nomodulator and causes neuropathy less frequently or severely.
may be caused by an immune-mediated process, since some patients Glutethimide, a structurally related old hypnotic compound, may
improve following plasmapheresis or IVIG administration. produce a similar sensory polyganglionopathy in patients taking high
doses for many months.
Taxanes
Two taxanes, paclitaxel (Taxol) and docetaxel (Taxotere), have L-Tryptophan
played a significant role in the treatment of a variety of malignan- An unusual syndrome called eosinophilia-myalgia syndrome was
cies. They, as well as the newer antitumor agents, epothilones, bind recognized in 1989 in individuals taking preparations containing
to β-tubulin of microtubules, thereby interfering with the dynamic a contaminated L-tryptophan. A severe axonal sensorimotor poly-
assembly and disassembly of the microtubules of the mitotic spindle neuropathy, at times associated with inflammation and vasculopa-
and leading to aborted cell division and cell death. Axonal microtu- thy, was a prominent feature in some patients. The syndrome was
bules also contain β-tubulin, and binding of these drugs to microtu- to a large extent similar to Spanish “toxic oil syndrome.” Recovery
bules results in disruption of axonal transport. Paclitaxel may also from the neuropathy was slow and sometimes incomplete. Since
cause axonal mitochondrial damage, further contributing to the the elimination of contaminated tryptophan, the syndrome is no
neuropathy (Flatters and Bennet, 2006). A dose-related sensory gan- longer seen.
glionopathy results with doses above 250 mg/m2 body surface area.
Cumulative dosages of greater than 1000 mg/m2 invariably result Tumor Necrosis Factor-α Blockers
in a sensory and motor neuropathy. Burning paresthesias, sensory Adalimumab (Humira), etanercept (Enbrel), and infliximab
loss affecting all sensory modalities, and areflexia are followed by (Remicade) are immunosuppressive medications used to treat rheu-
sensory ataxia and mild distal weakness. Disabling weakness is rare matoid arthritis, inflammatory bowel disease, and other rheuma-
except in the presence of additional risk factors such as preexisting tological conditions by blocking TNF-α. They have been shown to
diabetic neuropathy, hereditary neuropathy, or combination ther- trigger a demyelinating disease in the CNS similar to multiple scle-
apy with other neurotoxic chemotherapeutic agents such as cispla- rosis. Additionally, demyelinating peripheral neuropathies, which
tin. Rarely, cranial neuropathies or autonomic dysfunction are also can resemble MMN with conduction block or CIDP or its variants,
observed. The neuropathy generally improves when the dose of the may follow the use of antagonists to TNF-α (Alshekhlee et al., 2010;
drug is reduced or following the completion of therapy. This may Stübgen, 2008). Clinically, the neuropathy is typically sensorimotor
take several months. For painful symptoms, the usual symptomatic but may be purely sensory or purely motor. CSF protein may be nor-
treatment is offered. Several neuroprotective agents, including leu- mal to moderately elevated. Nerve conduction studies show findings
kemia inhibitory factor, amifostine (a free-radical scavenger), gluta- typical of a sensorimotor or purely motor demyelinating polyneurop-
mine, and vitamin E, have been tested experimentally and in trials. athy, with relative preservation of amplitudes distally accompanied by
Of these, only the latter two provided a mild protective effect from focal slowing and conduction blocks at non-entrapment sites. IVIG
neuropathy (Lee and Swain, 2006). and plasma exchange typically are effective in treating the neuropathy,
Docetaxel, used in metastatic breast and ovarian cancer, causes a similar to other forms of demyelinating neuropathies. The decision of
dose-dependent sensory neuropathy similar to its parent compound. whether or not to stop the offending agent should be made on a case-
Motor symptoms are present only in the most severely affected patients by-case basis (Lozeron et al., 2009). Withdrawing the offending agent
(New et al., 1996). does not always reverse the immune process, and chronic immuno-
modulating therapy (e.g., IVIG, steroids, immunosuppressive agents)
Thalidomide and Lenalidomide may be necessary to control the inflammatory process and improve
Thalidomide was introduced as a sedative-hypnotic agent in the clinical outcome (Alshekhlee et al., 2010).
1950s, but it was taken off the market when its disastrous teratogenic
properties became evident. The drug has, however, been found useful Vinca Alkaloids
in treating erythema nodosum leprosum and other rare skin condi- Vincristine, the vinca alkaloid most used in chemotherapeutic regi-
tions, graft-versus-host disease, a number of complications of HIV mens, causes a length-dependent sensorimotor polyneuropathy as its
infection, and multiple myeloma, as well as other malignancies. This dose-limiting side effect. Vinblastine and two semisynthetic deriva-
compound owes its therapeutic effects to its inhibition of TNF-α tives, vindesine and vinorelbine, are less neurotoxic. Vinca alkaloids
production and antiangiogenic properties. Thalidomide causes dor- function as mitotic spindle inhibitors. Like taxanes, their neurotoxicity
sal root ganglion degeneration with selective involvement of large-diis related to tubulin binding, which interferes with axonal microtubule
ameter sensory neurons or a length-dependent painful sensory assembly, thereby impairing axonal transport.
axonal neuropathy. Painful distal paresthesias and numbness occur, Vincristine produces a dose-dependent neuropathy with sensory
with palmar erythema and brittle nails as prominent signs. In most symptoms beginning at 5 mg and motor symptoms at cumulative doses
patients, the neuropathy is dose related, occurring after high doses or of 30–50 mg. There are several reports of vincristine-induced severe
chronic administration for more than 6 months (Bastuji-Garin et al., paralysis at conventional doses in patients with preexisting heredi-
2002; Tosi et al., 2005). In general, cumulative dosages greater than tary neuropathies. Paresthesias and pain, often starting in the fingers
100 g result in significant neuropathy, and the neuropathy is rare at before the feet, and loss of ankle jerks are common initial findings.
cumulative doses less than 20 g. After discontinuation of the drug, Distal muscle weakness and sensory impairment follow. Autonomic
symptoms and signs improve slowly, though coasting is often seen. dysfunction—particularly gastroparesis, constipation, occasionally
Because thalidomide produces neurotoxicity in a dose-dependent paralytic ileus, urinary retention, impotence, and orthostatic hypo-
manner, monitoring for peripheral neuropathy with clinical exam- tension—may occur and is an early manifestation. Weakness, often
ination and sensory conduction studies allows for early detection accompanied by muscle pains, may evolve rapidly to severe motor
impairment. Occasionally, isolated mononeuropathies have been measured by the QSART or thermoregulatory sweat testing. Sural
reported. Cranial nerve involvement occurs infrequently and includes SNAPs are preserved if small fibers are involved exclusively, but they
trigeminal sensory loss, ocular motility disorders, facial weakness, and are frequently reduced or absent in sensory polyneuropathies affect-
recurrent laryngeal nerve palsies. ing both large and small fibers. Reduced IENFD on punch skin biopsy
EDX studies reflect the degeneration of distal axons. SNAPs are provides objective evidence of involvement of distal small nerve fibers
reduced in amplitude, whereas NCVs are preserved. EMG shows in these patients (Terkelsen et al., 2017; Zhou, 2014), without identify-
denervation in distal muscles. The predominant pathological features ing the specific cause. IGT may be associated with chronic axonal sen-
are axonal degeneration and myopathic changes, with spheromembra- sory polyneuropathies of presumed unknown cause (Hoffman-Snyder
nous inclusions in the muscle fibers evident on electron microscopy. et al., 2006; Smith et al., 2001). Among 73 patients referred for distal
Reduction in dose or withdrawal from therapy at an early stage usually idiopathic sensory neuropathy and screened with glucose tolerance
leads to eventual, though delayed, recovery. In up to 60% of patients, testing, 56% had abnormal results, either IGT (36%) or frank diabetes
residual sensory symptoms and absent tendon reflexes may persist, (Sumner et al., 2003).
and electrophysiological abnormalities continue. Co-administration Both idiopathic sensorimotor and sensory polyneuropathies pur-
of glutamic acid or ORG 2766, an adrenocorticotropic hormone-de- sue a very slowly progressive course or reach a stable plateau. Even
rived synthetic peptide, has shown promising results in reducing the after a course of more than 10 years, severe disability rarely occurs.
severity of vincristine neuropathy in preclinical trials, but there was no Independent ambulation is almost always maintained.
benefit in a clinical trial. Neurotrophins have neuroprotective effects Management of these common neuropathies centers on treating
in experimental studies as well, although there is reticence to use these neuropathic pain, providing ankle braces in some cases, and patient
compounds in patients with established neoplasms because of the fear education about the favorable long-term outcome (Wolfe and Barohn,
that growth factors may stimulate tumor growth. 1998). Periodic re-evaluation of patients in search of a possible under-
lying cause cannot be overemphasized.
NEUROPATHIES ASSOCIATED WITH INFECTIONS
PAIN IN PERIPHERAL NEUROPATHY
Neuropathies associated with infection, including viral, bacte-
rial, and parasitic infections, are discussed in the online version Pain is one of the cardinal symptoms of peripheral nerve disorders.
of this chapter, available at http://www.expertconsult.com. Estimates of the population prevalence of chronic pain with neuro-
pathic components range between 6% and 10%. The liability for pain
appears to vary from person to person, from nerve to nerve, between
CHRONIC IDIOPATHIC AXONAL POLYNEUROPATHY male and female, and even with age. Neuropathic pain may occur
Despite all efforts, a group of acquired polyneuropathies remains spontaneously without provocation (i.e., is stimulus independent) or
idiopathic. Acquired chronic sensorimotor and sensory polyneurop- be provoked by noxious or non-noxious stimuli. Hyperalgesia is an
athies are common in individuals older than 50 years of age, with an increased pain response to noxious stimuli. Allodynia is the sensation
estimated prevalence of more than 3%, and a male/female ratio of of pain elicited by non-noxious stimuli (e.g., from contact with cloth-
3/2. A chronic idiopathic axonal polyneuropathy with either mixed ing, bed sheets, or air flow).
sensorimotor features or pure or predominant small sensory man- The sensation of pain in peripheral neuropathies is generated by
ifestations afflicts patients starting the sixth decade of life and may nerve impulses triggered when free nerve endings (nociceptors) in
accounts for up to 30% of all polyneuropathies (Zis et al., 2016). sensitive tissues, particularly the skin, respond to noxious stimuli. A
Patients with sensorimotor peripheral polyneuropathy complain of number of neurophysiological studies have determined that both small
tingling, prickling, numbness or burning of the feet, and often stiff- myelinated Aδ fibers and unmyelinated nociceptive C fibers mediate
ness of the toes. There is stocking loss of pinprick and temperature the afferent impulse of pain stimuli (Campbell and Meyer, 2006).
sensation in the feet, together with mild loss of vibratory sensation, Intraneural microstimulation of human sensory nerves has shown
absent ankle reflexes, and sometimes mild toe-extensor weakness. that stimulating Aδ nociceptors evokes an acute sensation of sharp
EDX and nerve biopsy studies in patients with cryptogenic polyneu- and well-localized pain. In contrast, the stimulation of polymodal C
ropathy are compatible with a length-dependent axonal polyneu- nociceptors evokes a sensation of delayed, more diffuse burning pain.
ropathy. These abnormal signs must be distinguished from normal Peripheral nerve injury results in the upregulation of sodium channels
manifestations of aging in the PNS. Loss of vibratory sense that is in nociceptive terminals and unmyelinated axons that leads to ectopic
restricted to the toes or absent ankle reflexes may be a normal finding activity in sensitized C fibers and spontaneous firing in nociceptive pri-
in healthy elderly controls (present in about a third of individuals mary sensory neurons. The increase in peripheral activity generates a
>65). Absent lower extremity SNAPs may also be seen in healthy cascade of secondary changes in the dorsal horn, with the end result of
elderly subjects. However, absent sural SNAPs combined with fibril- central sensitization in second- and third-order neurons. The periph-
lation potentials in the anterior tibialis muscle support the diagno- eral and central sensitization involves a number of recently recognized
sis of polyneuropathy, since such combined abnormalities are rarely neurobiological events involving altered expression of sodium chan-
found in healthy older individuals (Vrancken et al., 2002). nels, increased glutamate activity at N-methyl-d-aspartate (NMDA)
Idiopathic small-fiber neuropathy presents with painful burning feet, receptors, and downregulation of γ-aminobutyric acid (GABA) recep-
with or without numbness. The condition also occurs in older patients tors and opioid receptors. Reorganizational changes can occur at the
without associated systemic diseases or exposure to identifiable toxins level of the dorsal horn and dorsal root ganglion. These include the
(Lauria et al., 2014). Epidemiological studies have shown that this dis- sprouting of sympathetic axons into the dorsal root ganglion, form-
order is not rare, with an incidence of 12 cases per 100,000 inhabitants ing baskets around nociceptive neurons, and the sprouting of non-
per year and a prevalence of 53 cases per 100,000 in the Netherlands nociceptive Aβ central axon terminals into the superficial dorsal horn
(Terkelsen et al., 2017). Most patients have elevated thermal thresholds (Woolf and Mannion, 1999). For a more detailed discussion of neuro-
on quantitative sensory examination and impaired distal sweating, pathic pain mechanisms, see Chapter 52.
Peripheral neuropathy occurs in a number of infectious diseases— eTABLE 106.17 Neuropathies Associated
viral, prion, bacterial, and parasitic—making this group of neuropa-
with Human Immunodeficiency Virus
thies the largest in the world. Their recognition is important because
they are often preventable or treatable (Said, 2007).
Infection
Human
Viral Infections and Neuropathy Immunodeficiency
Human Immunodeficiency Virus Type 1 Neuropathies Clinical Features Virus 1 Stage
HIV-1 infection is associated with a wide variety of peripheral neurop-
Distal symmetrical Pain, sensory loss Late: CDC IV, AIDS, ARC
athies, with onset from the time of seroconversion to the late stages of
polyneuropathy
AIDS (see Chapter 77) (Cornblath and Hoke, 2006; Ferrari et al., 2006)
Autonomic neuropathy
(eTable 106.17). Few of these neuropathies are specific to HIV infection
Treatment-induced ddC, ddl, 3TC, d4T, FIAU
and most resemble the neuropathies seen in non-HIV patients. It is not
Lumbosacral polyradic- Cauda equina syndrome Late: CDC IV, AIDS
entirely clear why some patients infected with HIV-1 develop neuropa-
uloneuropathy
thy while others do not. The possibility of more frequent mitochondrial
CMV radiculopathy CSF pleocytosis (poly-
haplogroup T in those who develop neuropathy has been raised (Hulgan
morphonuclear cells)
et al., 2005). The neuropathies of HIV-1 infection are divided into neu-
Lymphoma CSF cytology (malignant
ropathies occurring early and late in the course of disease. The CD4 count
cells)
inversely parallels the frequency of neuropathy, with normal counts in the
Diffuse infiltrative lym- CD8 lymphocytosis
inflammatory demyelinating neuropathies and low counts in distal axo-
phocytosis syndrome
nal symmetrical polyneuropathies and lumbosacral polyradiculopathy.
Multiple mononeurop- Limited to extensive CDC III-IV; ARC, AIDS
The estimated prevalence of peripheral neuropathy in patients with
athies mononeuropathies
HIV-1 infection ranges from 15% to 30%, based on the clinical find-
Vasculitis
ings, and increases substantially if electrophysiological variables are
CMV
used for inclusion. More than 75% of patients with AIDS have patho-
Lymphoma
logical evidence of peripheral nerve involvement at autopsy. Although
Inflammatory demye- Guillain-Barré syndrome Early: CDC I-III
the incidence of HIV neuropathy has declined in recent years since the
linating polyneurop- or CIDP; CSF pleocy-
introduction of highly active antiretroviral therapy (HAART), its prev-
athies tosis
alence has increased because these patients are now living longer. It
Cranial mononeurop- Facial palsy Early: CDC I-III
is emphasized that the neuropathic manifestations of HIV-1 infection
athy
rarely occur in isolation and are often associated with CNS or muscle Sensory neuropathy Sensory ataxia Early: CDC I-III
involvement, making the precise diagnosis even more difficult.
Herpes zoster radi- Dermatomal vesicular Early and late
Acute and chronic inflammatory demyelinating polyradic culitis eruption
uloneuropathies. Of the neuropathies that occur in HIV-1 infection,
AIDP and CIDP predominate during the seroconversion and the early AIDS, Acquired immunodeficiency syndrome; ARC, AIDS-related com-
stages of disease. plex; CDC I-IV, Centers for Disease Control and Prevention classification
An AIDP, clinically and electrodiagnostically indistinguishable system for human immunodeficiency virus infection stages I-IV; CSF, cere-
from GBS, is seen in individuals who are positive for HIV-1. Its clin- brospinal fluid; CMV, cytomegalovirus; ddC, ddI, 3TC, d4T, FIAU, dideox-
ycytidine, dideoxyinosine, lamivudine, stavudine, fialuridine, respectively.
ical course, spontaneous recovery, or response to plasmapheresis and
IVIG therapy are similar to that seen in non-HIV-1-related GBS. The
main differences between the acute polyradiculoneuropathy of HIV-1
and non-HIV-1-related GBS are CSF pleocytosis, ranging from 10–50 Mononeuropathy and multiple mononeuropathies. Although
cells/μL, and HIV-1 seropositivity. CSF protein is elevated (>100 mg/ isolated involvement of single cranial nerves, particularly the facial
dL), and demyelination or mixed demyelination and axonal degen- nerve, may occur in the asymptomatic or early stages of symptomatic
eration with prominent inflammation is present in nerves and nerve HIV-1 infection, multiple mononeuropathies associated with HIV-1
roots. The intensity of inflammation is more pronounced than is usu- disease occur more frequently late in the course of the illness. These
ally observed in the non-HIV-related GBS. may be associated with superimposed infection (including herpes
A CIDP-like syndrome similar to that seen in HIV-seronegative zoster, CMV, hepatitis C, and syphilis), lymphomatous infiltration, or
patients may be seen in association with HIV-1 infection. CSF pleo- necrotizing vasculitis.
cytosis and prominent inflammatory infiltrates consisting primarily of Unilateral or bilateral facial neuropathy may accompany HIV-1
cytotoxic-suppressor T lymphocytes and macrophages in sural nerve seroconversion. Patients with involvement of one or two cranial or
biopsy specimens separate these patients from those with non-HIV- spinal nerves in association with CD4 counts greater than 200/μL often
related CIDP. Although the neuropathy is often symmetrical, it may have a good prognosis, and many recover spontaneously. Multiple
predominate on one side or prominently involve one or more of the mononeuropathies with severe deficits, on the other hand, are more
spinal nerve roots. Spontaneous pain and paresthesias, at times severe, likely to occur in immunocompromised AIDS patients with CD4
may also be experienced. IVIG is the preferred treatment for HIV- counts below 200/μL. This mononeuropathy multiplex may be due to
related CIDP if the illness is sufficiently severe to warrant intervention. CMV infection or represent a peripheral nerve vasculitis. Peripheral
It is advisable to test for the presence of HIV-1 antibodies in all patients nerve biopsy in multiple mononeuropathies associated with HIV-1
with acquired demyelinating neuropathies who have conceivable HIV-1 infection demonstrates multifocal decreased density of myelinated
risk factors or suspicious laboratory test results such as CSF pleocytosis, fibers, degenerating fibers, and interstitial abnormalities dominated
positive hepatitis B serology, or polyclonal hypergammaglobulinemia. In by epineurial mononuclear cell infiltrates and vessel wall necrosis.
fact, in one series from a large urban center, 8% of patients with such Schwann cells may be infected directly by HIV-1 particles (Mahadevan
inflammatory demyelinating neuropathies tested positive for HIV-1. et al., 2001).
When CMV is confirmed or even suspected clinically, treatment another group of patients, a disabling autonomic neuropathy may
should begin immediately with ganciclovir. Other therapies that are develop with sudomotor and pupillary dysfunction, sphincter abnor-
also likely effective include corticosteroids, plasmapheresis, IVIG, and malities, syncope, and labile blood pressure, with or without features
foscarnet. Use of corticosteroids might seem theoretically risky but is of sensorimotor polyneuropathy.
surprisingly well tolerated. Lumbosacral polyradiculoneuropathy. Even though uncommon,
Distal symmetrical polyneuropathy. The most common acute lumbosacral polyradiculoneuropathy (cauda equina syndrome),
neuropathy related to HIV-1 infection, especially in late stages of often associated with CMV infection, is among the most devastating
the disease, is painful distal symmetrical polyneuropathy. The onset neurological complications in AIDS, usually occurring in the late stages
occurs often with burning feet, painful paresthesia, and distal sensory of the disease. CMV infection is the most common opportunistic viral
loss combined with mild distal weakness and autonomic dysfunction. infection in AIDS, affecting up to 35% of patients. It is often associated
Ankle reflexes are usually depressed or absent, but in some patients, with bilateral visual impairment due to retinitis or involvement of
other tendon reflexes may be exaggerated. In patients with symptomatic other organs such as colon and pancreas. The usual neurological
distal symmetrical polyneuropathy, nerve conduction studies presentation is rapidly progressive flaccid paraparesis, sphincter
show borderline to low-amplitude sensory and motor responses, dysfunction, perineal sensory loss, and lower-limb areflexia.
often accompanied by denervation changes in distal muscles. EDX EDX studies show low-amplitude CMAPs and prolonged or absent
evaluations of patients with HIV-1 infection demonstrate that as many F-wave latencies. SNAPs are normal, consistent with a cauda equina
as two-thirds may have peripheral nerve involvement. Sural nerve lesion, but may be reduced or absent if there is a concomitant poly-
biopsy shows loss of myelinated fibers and unmyelinated fibers, with neuropathy. Within a few weeks of onset, needle EMG signs of active
no distinctive inflammatory or interstitial abnormalities. Although denervation become apparent. CSF examination in CMV-related
skin biopsy demonstrates reduction in epidermal nerve fiber density, lumbosacral polyradiculoneuropathy shows pleocytosis (>50/μL; typ-
increased frequency of fiber varicosities, and fiber fragmentation ically with > 40% polymorphonuclear cells), elevated protein levels,
(Keswani et al., 2002), it does not have specific diagnostic value. The and low glucose concentrations. MRI with gadolinium may demon-
severity of neuropathic pain and elevation of distal cold threshold strate enhancement of cauda equina nerve roots. With this clinical
values in distal symmetrical polyneuropathy appears to correlate with and CSF profile, a presumptive diagnosis of CMV polyradiculoneu-
plasma HIV-1 RNA levels (Simpson et al., 2002). The risk of developing ropathy should be made, prompting empirical therapy even before
polyneuropathy may be related to age, White race, presence of the demonstration of positive CSF PCR results. Empirical treatment
diabetes, low CD4 count, increased viral load, and exposure to protease with IV ganciclovir should be started promptly in AIDS patients with
inhibitor drugs (Pettersen et al., 2006). However, the progression of polymorphonuclear CSF pleocytosis and progressive flaccid parapa-
polyneuropathy appears to be independent of these factors and is often resis. Foscarnet alone or in combination with ganciclovir may be an
slow (Simpson et al., 2006). alternative for patients who develop this syndrome during ganciclovir
The cause of distal symmetrical polyneuropathy in HIV-1 infection treatment for systemic CMV infection. Although early antiviral ther-
is unknown, but direct infection of peripheral nerves is thought to be apy may preserve neurological function, long-term prognosis is poor.
unlikely. Although a macrophage response induced by low levels of Along with polyneuropathy and polyradiculoneuropathy, severe
HIV-1 in the dorsal root ganglia may play a role, macrophage infil- CNS manifestations of CMV infection such as necrotizing myelitis and
tration and the release of proinflammatory cytokines appear to be the encephalitis may also be present. Other rare causes of lumbosacral poly-
primary mediators of the dying-back axonal degeneration. The HIV-1 radiculoneuropathy in AIDS include syphilis, mycobacterial infections,
envelope protein gp120 may cause upregulation of TNF-α, leading to toxoplasmosis, and leptomeningeal lymphomatosis. Also, herpes zoster
apoptosis of sensory neurons. It may also cause direct axonal dam- radiculitis occurs in perhaps 10% of HIV-1-infected patients.
age by binding to the axonal chemokine receptors and activating the Another condition associated with HIV-1 infection, diffuse infiltrative
caspase pathway, with subsequent distal axonal degeneration. Specific lymphocytosis syndrome, is a nonmalignant CD8 lymphocytosis that may
treatment of distal symmetrical polyneuropathy of HIV-1 infection affect multiple viscera as well as peripheral nerves and may respond to
has been disappointing. Although symptomatic approaches may be either corticosteroid or antiretroviral treatment (Gherardi et al., 1998).
helpful, clinical trials of NGF, peptide T, plasmapheresis, and acu-
puncture have not proved effective. Current interest in such agents as Cytomegalovirus
L-acetylcarnitine and prosaptide may lead to further therapeutic trials CMV commonly causes an asymptomatic infection. In immunocom-
(Simpson, 2002). promised individuals, however, a life-threatening disseminated illness
A significant proportion of patients with HIV-1-related distal may result, often with fatal meningoencephalitis. Antecedent CMV
symmetrical polyneuropathy also have antibodies to human T-cell infection has been associated with AIDP. Late-stage HIV-1-infected
lymphotropic virus 2, suggesting coinfection (Zehender et al., 1995). patients are at risk of developing fulminant severe lumbosacral
Nutritional deficiencies (chiefly vitamin B12 and folate deficiencies) polyradiculoneuropathy.
have also been implicated, as have neurotoxic drugs including vin-
cristine, dapsone, INH, and nucleoside analog reverse transcriptase Epstein-Barr Virus
inhibitors. Mounting evidence supports the observation that sev- Although most well known as the chief cause of infectious mononucle-
eral nucleoside analogs used in HAART have contributed to both osis, the Epstein-Barr virus is associated with a variety of neurological
improved survival and an increase in toxic neuromuscular disorders complications. Those with peripheral nerve manifestations include
in individuals infected with HIV-1 (Brinley et al., 2001). Among these cranial neuropathies with rhombencephalitis, myelitis with spread to
agents, zidovudine (AZT) may lead to myopathy; zalcitabine (ddC), adjacent nerve roots, multiple mononeuropathies, and brachial and
didanosine (ddI), and lamivudine (3TC) have been linked to neurop- lumbosacral plexopathy.
athy; and stavudine (d4T) and fialuridine (FIAU) cause neuropathy
or myopathy and lactic acidosis (Dalakas, 2001). A subset of HlV-1- Herpes Simplex Virus
positive patients with distal symmetrical polyneuropathy has been The herpes simplex viruses are a group of neurotropic DNA viruses
found to have necrotizing vasculitis (Bradley and Verma, 1996). In that colonize primary sensory neurons. In the case of herpes simplex
virus 1, the gasserian ganglion is most often affected, and repeated cutaneous vasculitis, arthralgias, renal dysfunction, and peripheral
eruption of oral and labial ulceration ensues. With herpes simplex nerve involvement due to vasculitis of small vessels. Vasculitic neu-
virus 2, a sexually transmitted disease, sacral dorsal root ganglion cells ropathy may manifest as multiple mononeuropathies and, rarely, a
are the site of infection, leading to the periodic appearance of genital chronic sensorimotor neuropathy or a purely sensory neuropathy.
ulcers. Although segmental recurrence is most common, more wide- Vasculitic neuropathy may be associated with chronic hepatitis C
spread disease may result in disseminated eruptions in immunocom- infection with or without the presence of cryoglobulinemia (Nemni
promised hosts. Antiviral treatment with acyclovir (200 mg five times et al., 2003). Although no controlled clinical trials have been carried
daily for 10 days) or famciclovir (125 mg twice daily for 5 days) can out, individual patients have been observed to respond to plasma
reduce the duration of eruption and prolong the time to subsequent exchange and immunomodulatory therapy followed by antiviral treat-
outbreak. ment of the underlying HCV infection (see Cryoglobulinemia, earlier).
Herpes Zoster Virus Human T-Cell Lymphotropic Virus Type 1 and 2

The most common symptomatic peripheral nerve viral infection is with Although the majority of patients infected by human T-cell lympho-
the neurotropic VZV. It has been estimated that for patients older than tropic virus type 1 (HTLV-1) present with a progressive spinal cord
age 70, the lifetime percent probability of segmental VZV infection syndrome of spastic paraparesis, sphincter disturbances, and impo-
approximates the years of life. The spectrum of peripheral neurolog- tence, many affected patients have dysesthesias and mild distal sensory
ical involvement in VZV includes cranial zoster (chiefly affecting the loss, implicating additional involvement of peripheral nerves (Leite
trigeminal or, less often, the geniculate ganglion), radicular zoster (also et al., 2004). The terms tropical spastic paraparesis (TSP) and HTLV-1-
called segmental zoster, zoster radiculopathy, or shingles), and polyradic- associated myelopathy (HAM) are used. CSF examination is essentially
uloneuropathy. Although sensory pathways are most affected, in cases normal but may show a mild lymphocytic pleocytosis. Somatosensory
with radicular zoster affecting one or two spinal root levels, there is an evoked potential studies are abnormal in more than half of patients.
approximate 5% probability of significant motor involvement, lead- NCVs are minimally slowed in roughly a third of those studied. Sural
ing to the designation segmental zoster paresis. Segmental zoster paresis nerve biopsy shows a combination of demyelination with remyelin-
with motor weakness in the same distribution of the rash was found in ation and axonal degeneration with regeneration (Kiwaki et al., 2003).
19% of cases of VZV involving the limbs, while in 43% of patients with Progression is slow, although most patients eventually become severely
limb zoster, abnormal spontaneous activity on needle EMG was found disabled 10 years or more after the onset of symptoms.
in a muscle of at least one myotome corresponding to the affected der- Tropical ataxic neuropathy is a predominantly sensory syndrome
matome. In 15%, abnormal spontaneous activity was found in contig- occurring in middle age that manifests with burning feet, distal sensory
uous unaffected dermatomes (Mondelli et al., 2002). The motor lesion loss, gait ataxia, and lower-limb areflexia. Mild distal lower motor neu-
may localize to radiculopathy, plexopathy, or multiple mononeu- ron signs, optic atrophy, and sensorineural hearing loss may be pres-
ropathies (Alshekhlee et al., 2011). A neurogenic bladder caused by ent. Although nutritional, toxic (cassava), and infectious causes have
involvement of motor or sensory nerves innervating the bladder or been considered, some evidence suggests that infection with HTLV-2
sacral segments of the spinal cord can develop after cutaneous eruption may play a significant role.
of sacral dermatomes. Gastrointestinal visceral motor complications
manifesting as paralytic ileus, colonic pseudo-obstruction, or localized West Nile Virus
colonic spasm may also occur after lumbar or sacral segment involve- West Nile virus infection may manifest with symmetrical or asymmet-
ment. Careful needle EMG studies show as many as 50% of segmental rical flaccid limb and facial weakness without sensory deficits and with
zoster patients have active denervation in muscles innervated by the few or no signs of encephalitis; this motor neuronopathy picture is
myotome corresponding to the affected dermatome and sometimes in compatible with acute poliomyelitis (Li et al., 2003). The EDX studies
myotomes contiguous to affected dermatomes (Alshekhlee et al., 2011; are consistent with anterior horn cell damage, supported by normal
Haanpää et al., 1997; Mondelli et al., 2002). In severe segmental zoster SNAPs, low-amplitude CMAPs recorded from weak muscles, active
infection, inflammation may spread into the spinal cord, resulting in denervation including the paraspinal muscles, and generalized or focal
myelitis of variable severity, and be responsible for long-tract signs. loss of motor units. Recovery of the neurological deficit is often slow
Occasional patients present with unilateral dermatomal pain and CSF and may be incomplete.
evidence of VZV DNA or antibody to VZV (Fox et al., 2001), but no
cutaneous vesicular eruption (zoster sine herpete). Treatment with fam- Prion Diseases and Neuropathy
ciclovir (500 mg three times daily for 7 days) or acyclovir (800 mg five Creutzfeldt-Jakob disease is a transmissible neurodegenerative disor-
times daily for 10 days) is indicated at the onset of symptoms. der caused by prions, proteinaceous infectious particles. Prions inter-
act with a normal host protein to produce clinical Creutzfeldt-Jakob
Hepatitis Viruses disease. Although the CNS is the main target, rarely a demyelinating
Hepatitis B virus infection has been reported in association with the peripheral neuropathy may precede the cognitive and intellectual dete-
demyelinating form of GBS: that is, AIDP. It also may trigger a nec- rioration (Antoine et al., 1996). In fact in some cases, prion protein
rotizing vasculitis of the polyarteritis nodosa predominantly affecting deposition in peripheral nerves, nerve roots, and dorsal root ganglion
medium-size vessels with multiorgan involvement (gastrointestinal, cells has been demonstrated (Favereaux et al., 2004; Ishida et al., 2005).
kidney and skin).
Infection with HCV is transmitted by sexual contact, through Bacterial Infections and Neuropathy
blood transfusion, or IV drug abuse and may be particularly common Mycobacterium leprae (Leprous Neuropathy)
in urban populations. HCV has been associated with essential mixed Hansen disease (leprosy) is a major cause of neuropathy worldwide,
cryoglobulinemia and is its most common cause. In fact, a detectable especially in tropical and subtropical regions (Walters and Jacobs,
cryoglobulinemia is present in as many as 50% of hepatitis C patients. 1996). As improvements in public health and use of multidrug ther-
The syndrome of HCV infection associated with cryoglobulinemia is apy have advanced, the prevalence of Hansen disease in the world, as
a systemic disease characterized by recurrent cold-sensitive purpura, estimated by the World Health Organization (WHO), is 0.2 cases per
10,000 people. The number of registered cases has dropped from 5.1 trauma, ulcerations, and trophic changes. Preserved tendon reflexes
million in 1987 to less than 500,000 in 2004, and to 176,176 cases in are an important differential diagnostic sign, in contrast to the loss of
2015. India accounted for 60% of the cases, followed by Brazil and reflexes seen in most polyneuropathies.
Indonesia having 13% and 8% of cases, respectively. The Centers for In tuberculoid Hansen disease, sensory loss initially affecting pin-
Disease Control and Prevention (CDC) reported 144 new cases in the prick and temperature is detected within sharply demarcated hypopig-
United States in 1995 and that the total number of active cases in the mented skin lesions. Adjacent cutaneous nerves or mixed nerve
United States was about 7500. Of new cases, approximately 20% orig- trunks are apt to become involved. The body folds, being warmer
inate in this country (mainly Hawaii, Florida, Louisiana, and southern than exposed areas, are not affected. The focal areas of sensory loss
Texas), with the balance occurring in immigrants mainly from Asia also become anhidrotic. The associated intense inflammatory response
or the South Pacific. Leprosy remains a major challenge in the field of can affect underlying nerve trunks and cause a mononeuropathy or
microbiology, pathology, immunology, and genetics, as M. leprae can- mononeuropathy multiplex in the distribution of those nerves, which
not be cultivated in the laboratory, generates an extraordinary range may become indurated and palpable because of fusiform swelling.
of cellular immune responses, and only a small portion of any given Thickening and nerve enlargement are the sine qua non in leprosy,
population is susceptible to its infection (Scollard et al., 2006). clinically perceived in one-third of patients. This is detected by pal-
M. leprae is thought to be transmitted through the upper respiratory pation, which is often painful, of peripheral nerves that course close
tract. The nasal secretions of those with lepromatous leprosy may con- to the skin surface, including the great auricular, dorsal ulnar, ulnar,
tain up to 2 × 108 M. leprae in a single nose blow. However, 50%–70% superficial radial, superficial fibular, and sural nerves (Gourie-Devi,
of patients with leprosy have no history of contact with another known 2002). The predominant sensory loss and anesthesia can lead to pain-
leprosy patient. Nonhuman sources of infection, such as infected less trauma with acrodystrophic deformities and autoamputations.
wild armadillos, have also been suggested as the source of leprosy. Involvement of the nerves of the face leaves patients at risk of corneal
Approximately 5%–10% of wild nine-banded armadillos (Dasypus abrasion and blindness.
novemcinctus) in Louisiana, Mississippi, and eastern Texas have lep- Lepromatous Hansen disease is characterized by symmetrical bac-
rosy. Once the nasal mucosa is colonized, the organism spreads slowly illary infiltration of the skin with a predilection for cooler areas of the
to other regions, with an estimated incubation period of 3–10 years. body, avoiding the scalp, palms, soles, and midline of the back. The
Particularly vulnerable tissues are those with mean daily temperatures skin may have multiple nodules, papules, macules, and ulcerations,
in the 27°C–30°C range, as this promotes more rapid bacterial growth. or there may be diffuse cutaneous involvement with a waxy myxede-
The tendency of M. leprae to grow in cooler temperatures is the main ma-like appearance. Similarly, the distribution of sensory loss is related
reason for the susceptibility of armadillos to this mycobacterium, as to the local skin temperature, the coolest parts such as the pinna of the
these animals typically have a body temperature of 30°C–35°C. The ear, tip of the nose, malar areas of the face, dorsal surfaces of the hands,
skin and superficial nerve trunks of patients with leprosy are particu- forearms, and feet, and dorsolateral surfaces of the lower legs being
larly vulnerable, leading to cutaneous lesions, anesthesia, and paraly- affected first. Because of the minimal inflammatory response, nerve
sis of face and limb muscles. The Hansen bacillus has a proclivity for trunk involvement occurs late in this form. Commonly affected nerves
Schwann cells, which may serve as a sequestered reservoir of infection include the ulnar, fibular, and superficial branches of the facial and
with relative protection from host defenses. The neuropathy arises not median nerves, in that order. Selective involvement of small branches
only from the infection of peripheral nerves but also from the inflam- of the facial nerve leads to the typical patchy nature of facial paralysis,
matory and immunological responses to this mycobacterium. Exactly with early weakness of medial forehead elevators.
how the M. leprae enters the Schwann cells and why these cells are Either spontaneously or during the course of treatment, acute
incapable of destroying it remain unknown. One model for the early leprosy reactions may complicate the insidious course of the disease.
interaction of M. leprae with peripheral nerve suggests that the bacillus Such reactions, affecting 30%–50% of all leprosy patients, are acute
activates α-dystroglycan receptors on Schwann cells via the G domain inflammatory complications often presenting as medical emergencies
of laminin-2 (LNa2G), a major component of Schwann cell basal lam- that occur because of a sudden alteration in the host immune response.
ina, allowing the bacillus entry to the cell (Rambukkana, 2000). The brunt of these reactions occurs in the peripheral nerves, result-
The vigor of host cell-mediated immunity appears to dictate the ing in severe and rapid nerve injuries. In the reversal reaction, which
course of events. The disease is classified by host reaction to infection is usually seen in the borderline lepromatous stage, patients develop
into two polar forms, tuberculoid and lepromatous, with three interme- a spontaneous and poorly understood enhancement in cell-medi-
diate forms termed borderline tuberculoid, intermediate borderline, and ated immunity and delayed hypersensitivity to M. leprae antigens.
borderline lepromatous. Tuberculoid Hansen disease is characterized This reaction is identified clinically by swelling and exacerbations
by active cell-mediated immunity, intense delayed hypersensitivity of existing skin and nerve lesions. Marked reversal reactions can be
response to lepra antigens such as lepromin, localized destruction of associated with intensely painful nerve trunks, and total loss of sen-
infected nerves by intense inflammatory lesions, and rare organisms sory and motor functions may develop within hours because of the
detected in skin and nerve. Lepromatous Hansen disease, on the other pronounced inflammatory damage of the affected nerves. These acute
hand, is typified by unopposed proliferation of organisms, complete reactions appear most commonly during the first year of therapy and
anergy to lepra antigens, and disseminated skin and nerve lesions with require immediate treatment with systemic corticosteroids and other
minimal inflammatory response. Intermediate forms share features of antiinflammatory agents to prevent further nerve damage. In another
the two extremes. reaction called erythema nodosum leprosum occurring in multibacillary
Clinical features. The unique propensity of M. leprae to invade patients, there is an abrupt onset of diffuse erythematous nodules in
cutaneous nerves and nerve trunks causes the cardinal symptom of the skin, associated with fever and malaise. Inflammation of muscles,
sensory loss. Negative symptoms of loss of pain and touch sensation joints, testes, and eyes may also develop.
without positive sensory symptoms of paresthesia, dysesthesia, or pain Nerve conduction studies show reduced amplitudes of CMAPs
dominate the earlier symptoms of leprous neuropathy. Proprioception and SNAPs, together with focal conduction slowing at sites of nerve
and motor function are largely unaffected in the early stages, so enlargement. Dorsal ulnar and greater auricular SNAPs are frequently
patients can still use their anesthetic limbs, which leads to painless abnormal in many patients with leprous neuropathy (Gourie-Devi,
is now very rare in the United States with less than five cases reported
to CDC in the past decade. However, the disease continues to cause
illness globally. In 2016, countries reported about 7100 cases of diph-
theria to the WHO. There was, however, a resurgence of diphtheria
in central and Eastern Europe in adults (Logina and Donaghy, 1999).
The most common sites of diphtheria infection are the pharynx and
the tonsils. Following a prodrome of malaise, anorexia, and low-grade
fever, sore throat and pharyngitis emerges insidiously within 2–3 days and
manifests with a bluish-white pseudomembrane covering the tonsils and
soft palate. This becomes greyish green, or black if bleeding has occurred,
and is firmly adherent to the tissue. The pharyngeal forms of diphthe-
ria are usually associated with substantial systemic absorption of toxin.
Cutaneous-onset diphtheria is much less common, but may be seen in
eFig. 106.32 Tuberculoid Leprosy. Biopsy of enlarged sural nerve
tropics and homeless population. Skin infections may be manifested by
demonstrates extensive epineurial inflammatory granuloma consisting a scaling rash or by ulcers with clearly demarcated edges and membrane.
of epithelioid and mononuclear inflammatory cells; adjacent nerve fas- The most frequent complications of diphtheria are myocarditis
cicle (arrow) is devoid of myelinated fibers. (Hematoxylin and eosin; bar and polyneuropathy. Myocarditis may present as cardiac arrhythmias
= 300 μm.) or heart failure or both. Early-onset myocarditis is often fatal. Death
occurs in 5%–10% of patients, mostly in children less than 5 years old
or adults older than 40.
2002). For diagnosis and accurate classification, a skin punch biopsy Neurological complications occur in approximately 15% of patients
is necessary and should be taken from the active borders of the lesions. with diphtheria. Neurological symptoms begin with paralysis of the soft
The architecture of cutaneous nerves is destroyed by an intense granu- palate, impaired pharyngeal sensation, and paralysis of pupillary accom-
lomatous inflammation in tuberculoid Hansen disease (eFig. 106.32). modation. Occasionally, the diaphragm becomes weak at this stage
In lepromatous disease, multiple acid-fast organisms are found in (Logina and Donaghy, 1999). A local limb neuropathy may appear adja-
Schwann cells, foamy macrophages, and axons of involved nerves, cent to cutaneous diphtheria. The focal palatal-pharyngeal neuropathy
together with recurrent demyelination and progressive nerve fiber loss. may progress 3–15 weeks after the infection to a generalized mixed sen-
Treatment. Management consists of specific chemotherapy sorimotor polyneuropathy, or less frequently to a sensory polyneuropa-
and prevention and treatment of deformities. The current thy manifesting with ataxia in approximately 10% of patients.
recommendation for paucibacillary infections (those classified as Culture of C. diphtheriae from the pharynx or the cutaneous ulcer
indeterminate, tuberculoid, or borderline tuberculoid Hansen disease) establishes the diagnosis. CSF protein may be normal or elevated to
is the combination of dapsone, 100 mg/day, and rifampin, 600 mg/ more than 100 mg/dL. Mildly increased distal motor latencies and
day. Patients with multibacillary infections (borderline or lepromatous decreased conduction velocities are seen in most patients 2 weeks after
leprosy) receive the same combination therapy, with the addition of the onset of neurological symptoms. However, maximal slowing, with
clofazimine (50 mg/day). Treatment is continued for a minimum conduction velocities ranging from 15 to 35 m/sec, tends to occur later
of 2 years or until skin smear results are negative. Sometimes, this is when clinical recovery has already begun. The brunt of the pathologi-
followed by dapsone monotherapy for 3–5 years. For dapsone-resistant cal changes, segmental demyelination with sparing of axons, is seen in
strains or patients with glucose-6-phosphate dehydrogenase deficiency, the dorsal root ganglia and nerve roots, which lack an effective blood–
clofazimine and rifampin are used together, with consideration of a nerve barrier to the toxin because of fenestrated capillaries.
third agent, either ofloxacin (400 mg/day), clarithromycin (250 mg Prompt administration of antitoxin within 48 hours of the onset
twice a day), or minocycline (100 mg/day). Reactions must be treated of the primary infection reduces the incidence and severity of neu-
immediately with high doses of corticosteroids. For erythema nodosum ropathy but is ineffective if administered later in the course of disease.
leprosum, thalidomide is the treatment of choice and is extraordinarily Respiratory support may be needed for severe cases. Recovery takes
effective. Readers are encouraged to consult WHO or CDC publications place over a period of weeks and is usually complete if antitoxin is
for the latest recommendations on the treatment regimen (WHO: www. given within 48 hours of symptom onset. In one series of 50 adults
who.int/lep/disease/en/, CDC www.cdc.gov/leprosy/index.html). with diphtheritic polyneuropathy, identical rates of death (18%) and
peak severity of neuropathic deficits (25% in the severe category) were
Corynebacterium diphtheriae (Diphtheric Neuropathy) recorded in those who received antitoxin on days 3–6 and those who
Diphtheria is a localized infection of the upper respiratory tract or did not receive it at all (Logina and Donaghy, 1999).
skin, produced by C. diphtheriae. The organism elaborates a protein
exotoxin responsible for the delayed systemic manifestations includ- Borrelia burgdorferi (Lyme Neuroborreliosis)
ing cardiomyopathy and segmental demyelination of nerve roots and Lyme disease is a multisystem illness caused by the tick-borne spiro-
peripheral nerves. Diphtheria toxin is used as an experimental model chete B. burgdorferi sensu lato, with characteristic early and late neu-
of PNS demyelination. Local injection of the toxin produces focal rological manifestations. Most cases (97%) in the United States have
demyelination of nerve fibers without inflammation. The toxin enters been reported from nine states in the Northeast, upper Midwest, and
the susceptible cells by binding to a specific receptor known as heparin Pacific coastal regions. Endemic foci occur in northern and central
binding-epidermal growth factor (HB-EGF). It is known that Schwann Europe. It is now recognized that Lyme disease is widely distributed in
cells, as well as myocardial and kidney cells, have a much higher num- temperate zones worldwide (see Chapter 79). Certain differences occur
ber of HB-EGF receptors than other cells, explaining the vulnerability between American and European isolates of B. burgdorferi in terms of
of these cells to diphtheria toxin. morphology, outer surface proteins, plasmids, and DNA homology.
The disease is now rare except in poor socioeconomic conditions From the initial appearance of the pathognomonic dartboard-like
where immunization is inadequate (Bisgard et al., 1998). The disease skin lesion known as erythema migrans, a distinctive early neurological
syndrome develops in approximately 15% of patients (Halperin, 2019). million individuals, of whom approximately 5 million develop clin-
This consists of cranial neuropathy (usually facial palsy and often bilat- ical symptoms attributed to the disorder. Chagas disease is a para-
eral), radiculoneuropathy, or lymphocytic meningitis, often in combi- sitic infection caused by the flagellate protozoan Trypanosoma cruzi.
nation. These conditions usually abate without intervention over weeks The parasite is transmitted to humans by reduviid bugs of the order
to months, but they improve more rapidly with appropriate antibiotic Hemiptera when the proboscides (sucking mouth parts) pierce the
treatment. Months to years after the initial infection, a late neurological skin of their host to feed. The microorganism is not introduced with
syndrome may emerge. This consists of a predominantly sensory poly- the insect bite, but rather it is passively deposited in reduviid feces and
radiculoneuropathy that may present with distal sensory symptoms or subsequently penetrates the bite wound into the bloodstream. Other
proximal radicular pain and does not often resolve on its own, but rather means of transmission are through broken skin or mucous mem-
regresses only after use of efficacious antibiotics (Logigian, 1997). branes, contaminated food, blood transfusion, laboratory accidents,
Laboratory investigations helpful in the diagnosis of early Lyme dis- and organ transplantation.
ease include CSF analysis, which shows a lymphocytic pleocytosis and Once the protozoon gains access to the host circulation, three stages
mild elevation of the total protein. Intrathecal production of anti-B. of disease ensue. The acute phase is marked variably by either no symp-
burgdorferi antibodies can usually be documented in these cases. EDX toms or alternatively by malaise, local inflammation, gastrointestinal
study results in patients with chronic Lyme polyradiculoneuropathy symptoms, and lymphadenopathy. The second phase, typically occur-
confirm a multifocal or widespread axonal process, with borderline ring approximately 3 months after initial inoculation, may last for years
to low-amplitude distal responses, greater involvement of sensory and is an asymptomatic period. During this time, serological test results
than motor fibers, and little or no slowing of velocities. Needle EMG for trypanosomiasis become positive. The third or chronic stage affects
often shows signs of chronic partial denervation in distal and proximal about a third of patients and usually begins 10–20 years following the
muscles, including fibrillation potentials and neurogenic motor unit original reduviid bite. This phase is characterized by gastrointesti-
potential changes. Sural nerve biopsy confirms axonal degeneration as nal, cardiac, and neurological manifestations. Approximately 10% of
well as interstitial alterations with perivascular and perineurial mono- patients with chronic Chagas disease develop a predominantly sensory
nuclear inflammation. The diagnosis of Lyme disease must depend on neuropathy.
appropriate exposure in endemic regions and a plausible clinical con- Most patients with neuropathy complain of paresthesias in the
text. Serological confirmation of Lyme disease documents prior expo- distal lower limbs. On examination, distal hypoesthesia and hypore-
sure, although seropositivity alone is not sufficient to establish a causal flexia are found, usually limited to the lower limbs, occasionally
relationship because, in endemic areas, up to 18% of asymptomatic involving all four extremities, and rarely only in the distal upper
individuals are seropositive (Mygland et al., 2006). Serological tests limbs. EDX findings include low-amplitude sensory and motor
for Lyme disease have not been well standardized and confusion about responses, mild slowing of conduction velocities, and distal neu-
tests interpretation is common. There may be false-negative, and more rogenic motor unit potential changes on needle EMG. Sural nerve
commonly, false-positive tests. A screening ELISA is useful but should biopsy demonstrates decreased density of large and small myelin-
be confirmed by Western blots; this may be replaced by second ELISAs ated fibers, axonal clusters indicating regeneration, and para-
(Halperin, 2019). High titers of anti-B. burgdorferi antibody in CSF are nodal and segmental demyelination on teased-fiber preparations
helpful in linking the peripheral neurological manifestations to Lyme (Sica et al., 1995). Involvement of the autonomic ganglia may be
disease. PCR assays to identify spirochetal DNA in CSF are promising prominent, resulting in gastrointestinal and cardiac dysfunction.
techniques (Schmidt, 1997). Megaesophagus, megaduodenum, and megacolon due to destruc-
Most patients treated with IV ceftriaxone, 2 g daily for 2–4 weeks, tion of ganglia and myenteric plexuses result in progressive dyspha-
improve slowly over 3–6 months. Oral antibiotic therapy with doxycycline gia and constipation. Other parts of the gastrointestinal tract may
or amoxicillin may be effective in mild cases without CSF abnormalities. also be similarly affected. Cardiovascular autonomic involvement,
with and without congestive heart failure, may manifest as ortho-
Parasitic Infections Associated with Peripheral static hypotension, bradycardia, impaired heart rate response to
Neuropathy exercise or Valsalva maneuver, conduction blocks, complex arrhyth-
Trypanosoma cruzi (American Trypanosomiasis, Chagas mias, and even sudden death. Although both itraconazole and allo-
Disease) purinol have been shown to improve ECG abnormalities in Chagas
American trypanosomiasis (Chagas disease) occurs from the southern disease, there is little information regarding the efficacy of such ther-
United States to southern Argentina and is known to have affected 17 apy for the neuropathy (Apt et al., 2003).
analgesics, and topical agents (Attal et al., 2006). In general, once an

BOX 106.16 Peripheral Neuropathies
agent is selected for treatment, the medication is started at the lowest
Frequently Associated with Pain possible dosage and slowly titrated by increasing the dose every 3–7
Diabetic neuropathies: days until significant pain relief or intolerable side effects occur. Many
Painful symmetrical polyneuropathy treatment failures can be attributed to insufficient dosing or intoler-
Asymmetrical polyradiculoplexopathy ance caused by rapid dose escalations. The use of the following drugs
Truncal mononeuropathy is supported by the results of randomized controlled studies, most of
Brachial and lumbosacral plexopathy which have been conducted in postherpetic neuralgia and painful dia-
Vasculitic neuropathy betic neuropathy. It is not clear that the results of these studies can be
Toxic neuropathies: fully extended to other neuropathies, but in practice this is often done.
Arsenic, thallium Guidelines on pharmacological treatment of neuropathic pain have
Alcohol recently been published (Attal et al., 2006).
Vincristine, cisplatin TCAs have been established to reduce pain independent of their
Dideoxynucleosides effect on mood. These drugs block reuptake of norepinephrine and
Amyloid neuropathies: primary and familial serotonin, two neurotransmitters implicated in nociceptive modula-
Paraneoplastic sensory neuropathy tion, and also inhibit sodium channels. TCAs are effective for both
Neuropathy associated with Sjögren syndrome constant and lancinating paroxysmal pain, particularly in patients
Human immunodeficiency virus–related distal symmetrical polyneuropathy with painful diabetic neuropathy (Saarto and Wiffen, 2005; Sindrup
Uremic polyneuropathy et al., 2005). Treatment should be initiated with low-dose (10–25 mg)
Neuropathy associated with Fabry disease amitriptyline, desipramine, or nortriptyline given at bedtime and
Hereditary sensory autonomic neuropathy increased by similar increments no more than once a week. Most stud-
Cryptogenic small-fiber neuropathy ies have shown that doses of tricyclics of 75–150 mg (less for elderly
patients) are required for pain suppression. At such high-dose levels,
sedation, confusion, anticholinergic effects (constipation, dry mouth,
Neuropathic pain can be a prominent presenting symptom in a urinary retention), and orthostatic hypotension are common side
great number of peripheral neuropathies (Mendell and Sahenk, 2003; effects, particularly in elderly patients. Desipramine and nortriptyline
Box 106.16). Pain is characteristic of neuropathies with predomi- cause less sedation and less orthostatic hypotension and have fewer
nant small-fiber involvement, but even in large-fiber neuropathies, anticholinergic effects than amitriptyline. TCAs should be started with
a sufficient number of small fibers may be damaged to cause pain. caution in elderly patients and in patients with ischemic heart disease,
The poor clinical correlation between morphological changes seen narrow angle glaucoma, or prostatism.
in nerve biopsy specimens and pain is not surprising if one consid- Other antidepressants are also used for neuropathic pain. Selective
ers that ectopic impulses may arise from regenerating axonal sprouts serotonin reuptake inhibitors are less effective than TCAs in relieving
or dysfunctional fibers at more proximal or distal sites than the nerve neuropathic pain. Venlafaxine (150–225 mg/day) is a potent inhibi-
segment examined at biopsy. Neuropathic pain is of two main types. tor of norepinephrine and serotonin reuptake and has fewer side
The first, termed dysesthetic pain, usually affects distal skin and subcu- effects than TCAs, but it is likely less efficacious (Sindrup et al., 2003).
taneous structures, may be constant or intermittent (stabbing, electri- Duloxetine, a dual reuptake inhibitor of 5-HT and norepinephrine, at
cal jolts), may often have a temporal pattern of worsening at periods a dose of 60–120 mg/day has a moderate effect on neuropathic pain
of rest or bedtime, and is described as searing, burning, or icy-cold. (Wernicke et al., 2006). Bupropion (300 mg/day), a specific inhibitor
Sensory examination should use techniques to elicit abnormal positive of norepinephrine reuptake, reduced neuropathic pain by 30% in a
sensory phenomena. Allodynia can be elicited by light touch or non- small group of patients.
painful cold stimuli. When testing for hyperpathia, single and repeated Anticonvulsants (gabapentin, pregabalin, carbamazepine, oxcar-
pinpricks are used. Patients with hyperpathia may often complain of bazepine, topiramate, and lamotrigine) are frequently given to sup-
summation (pain perception increases with repeated stimulation) and press shooting or stabbing pains. Gabapentin is an anticonvulsant
after-sensations (pain continues after stimulation has ceased). Nerve with an unknown mechanism of action. Its effect may be mediated
trunk pain, a second type of neuropathic pain, is a deep-seated, sharp, by binding to voltage-dependent calcium channels expressed in the
knifelike proximal pain along nerve roots or trunks that improves with substantia gelatinosa of the dorsal horn. Controlled studies demon-
rest or optimal position but is aggravated by movement. Nerve trunk strated benefit in patients with postherpetic neuralgia and painful
pain seems to be mediated by spontaneous impulses arising from nervi diabetic neuropathy. When compared head to head with amitripty-
nervorum innervating nerve sheaths of affected nerve roots or trunks. line, gabapentin had equal efficacy but fewer side effects. Treatment
Muscle pain and tenderness may develop with acutely evolving dener- is initiated at 300 mg at bedtime, though smaller doses should be
vation of muscle, as occurs in GBS or acute poliomyelitis. considered for elderly patients and those with renal insufficiency.
The dose is escalated by 300-mg increments every 5–7 days until ade-
Management of Neuropathic Pain quate pain relief is achieved. The median effective dose ranges from
The management of neuropathic pain is similar for all painful neurop- 900 to 1600 mg, although some patients require doses of 3600 mg/
athies, although results vary substantially. Symptomatic treatment of day. Pregabalin, which is structurally similar to gabapentin, has been
neuropathic pain is effective but seldom provides complete relief, with shown to be effective at 150–600 mg/day in several trials. It should
best therapies achieving a 30%–50% reduction in pain. Simple anal- be initiated at 50–75 mg twice a day and increased every 5–7 days.
gesics (aspirin, acetaminophen, NSAIDs) are rarely beneficial. Most Carbamazepine reduces neuronal membrane excitability by block-
patients require additional pharmacotherapy. Drugs from several dif- ing sodium channels. In painful diabetic neuropathy, carbamazepine
ferent pharmacological classes have been shown to be safe and effec- (1000–1600 mg/day) was significantly better than placebo, equivalent
tive in alleviating neuropathic pain. These include antidepressants, to that of TCAs. In practice, intolerance to side effects limits its use.
anticonvulsants, sodium channel blockers, opioids and non-narcotic It is important to initiate treatment with carbamazepine at a low dose
(100 mg twice daily) and increase slowly to avoid initial symptoms oromucosal spray) is a potential treatment for neuropathic pain but its
of nausea, disequilibrium, and memory impairment. Oxcarbazepine, value requires further controlled studies (Mücke et al., 2018).
a ketoacid analog, is better tolerated, with the effective daily dose Topical agents that act through local skin absorption have the
exceeding 1200 mg (Grosskopf et al., 2006). Topiramate failed to advantage of minimal or no systemic side effects and may be useful
relieve diabetic neuropathic pain in three large controlled studies and in patients with painful, burning feet. Capsaicin, an extract of chili
had a marginal effect in one. Lamotrigine acts by blocking sodium peppers, presumably produces relief of pain through the depletion
channels and by inhibiting the presynaptic release of glutamine. of substance P in unmyelinated nociceptive fibers. Capsaicin cream
Lamotrigine (200–400 mg/day) resulted in moderate pain relief in (0.075%) is applied to the affected area of skin three to four times a
controlled studies of painful diabetic and HIV-associated neuropa- day. Its use should be continued for at least 4 weeks before rejecting its
thies (Eisenberg et al., 2001). effectiveness. An initial intense burning frequently occurs during the
Mexiletine, the oral analog of lidocaine, is the prototype of a first 1–2 weeks of application. This may be minimized by applying a
sodium channel blocker, but there have been inconsistent results in the local anesthetic cream (such as lidocaine 5% cream) prior to the appli-
use of mexiletine to control pain. Two of the studies showed a benefi- cation of capsaicin cream for the initial 2 weeks of therapy. However,
cial effect in patients with diabetic neuropathy, but four other studies even after 4 weeks, the beneficial effects of capsaicin remain marginal.
failed to demonstrate benefit. Tramadol, a centrally acting analgesic, Patches containing 5% lidocaine have been shown to reduce pain in
has proved effective in painful neuropathies related to diabetes and postherpetic neuralgia. Some patients may receive relief from burning
other causes in two clinical trials in doses ranging from 200 to 400 mg/ feet and allodynia by topical application of such patches on areas of
day (Harati et al., 1998). Low-affinity binding to μ-opioid receptors excessive pain.
and inhibition of norepinephrine and serotonin uptake contribute to It may be necessary to use drugs in combination to achieve optimal
its analgesic action. The drug is generally well tolerated, but transient pain relief. For example, if pain is still poorly controlled on a maxi-
nausea and constipation occur in about 20% of patients. High-dose mum tolerated dose of gabapentin, tramadol, an opioid, or a TCA may
dextromethorphan, a low-affinity NMDA glutamate antagonist, probe added (Gilron et al., 2005). Combined gabapentin and nortriptyline
vided partial relief in painful diabetic neuropathy but was associated is more effective than either drug given alone in treating diabetic neu-
with significant sedation and ataxia. ropathic pain and postherpetic neuralgia (Gilron et al., 2009).
Narcotic analgesics should be limited to patients who have failed Nonpharmacological treatments, including low-intensity transcuta-
adequate treatment trials of other agents. Randomized controlled neous electrical nerve stimulation, spinal cord stimulation, acupuncture,
studies of oxycodone and levorphanol have demonstrated efficacy of medical hypnosis, and meditation, may reduce the perception of pain and
opioids in postherpetic neuralgia and painful diabetic neuropathies suffering. A comprehensive multidisciplinary pain management program
(Rowbotham et al., 2003). Specific guidelines for chronic opioid ther- should be considered for patients with chronic refractory neuropathic pain.
apy in neuropathic pain have been published and should be followed.
Cannabis-based medicine (herbal cannabis, plant-derived or The complete reference list is available online at https://expertconsult.
synthetic tetrahydrocannabinol [THC], THC/cannabidiol [CBD] inkling.com/.
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95

Alzheimer Disease and Other Dementias

Mild Cognitive Impairment

Not normal for age

Yes Memory impaired? No

Amnestic MCI Nonamnestic MCI

DSM-5 Mild Neurocognitive Disorder

• Uncertain No or conflicting Aβ or MRI or FDG-PET or tau

• Intermediate Plus biomarker for Aβ OR MRI or FDG-PET or tau

• High Plus biomarker for Aβ AND MRI or FDG-PET or tau

Prodromal AD Plus biomaker for Aβ or tau/Aβ

dementia compared to MCI patients with hippocampal volumes on

TABLE 95.3 Key Parts of the History

TABLE 95.5 Cognitive Stage

Atypical Alzheimer Disease

Right Lateral Left Lateral Right Medial Left Medial

A Anterior Posterior Superior Inferior

Right Lateral Left Lateral Right Medial Left Medial

A Anterior Posterior Superior Inferior

Fig. 95.6 Timeline of Criteria and Research Frameworks for Alzhei-

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

increased from 2.7% in individuals between ages 50 and 59 years to Aβ

Early-Onset Genes Genetic Testing

Intracellular Decrease LTP Plaque formation,

Nonamyloidogenic Pathway sAPPα

Supportive Clinical Features

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

TABLE 95.9A International Consensus Criteria for Behavioral Variant FTD

TABLE 95.9B Features of Frontotemporal Dementia Subtypes

Progressive apraxia of speech is a disorder of motor speech plan-

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

Right Lateral Left Lateral Right Medial Left Medial

B Anterior Posterior Superior Inferior

PiB-PET of inclusion body myopathy, Paget disease of bone, and frontotem-

Tau-PET Frontotemporal Dementia and Parkinsonism Linked to

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

Fig. 95.21 Fluorodeoxyglucose-positron emission tomography statistical stereotactic surface projection

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

Right Lateral Left Lateral Right Medial Left Medial

Anterior Posterior Superior Inferior

TABLE 95.10 Vascular Cognitive Impairment

TABLE 95.11 Japanese Diagnostic Criteria of Idiopathic Normal Pressure Hydrocephalus

Possible iNPH Supportive Features

Diagnostic Criteria proposed for a clinical syndrome termed “traumatic encephalopathy

BOX 95.1 Partial List of Non-Degenerative Dementias

common, but when a person is older, most individuals will have a

TABLE 95.12 Young-Onset Dementia

Functional neuroimaging studies with specific radiopharmaceutical Area Area 6

TABLE 96.1 Divisions of the Striatum

Division Afferents Striatal Nucleus Ganglia Efferents Function

MC SMA PMC MC SMA PMC

glu Putamen glu

TABLE 96.3 Toxic Proteins and Neurodegenerative Movement Disorders

U U BOX 96.1 Mechanisms of

parkinsonism, and amyotrophic lateral sclerosis (ALS)-PD of Guam.

Nonmotor symptoms are increasingly recognized as a major cause

olfactory, sleep, and autonomic involvement in patients with PD, the

Treatment anticholinergics, amantadine, LD, MAO inhibitors (MAOIs), catechol-

Time Medication Meal Asleep Off On Dyskinesia

Bradley and Daroff's Neurology in Clinical Practice, 8th, V2P2

Bradley and Daroff's Neurology in Clinical Practice, 8th, V2P2