Professional Documents
Culture Documents
Guest Editor: Susan H. Fox, MBChB, MRCP(UK), PhD Denotes Supplemental Digital Content
REVIEW ARTICLES
Diagnosing Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
Christopher W. Hess, MD; Michael S. Okun, MD, FAAN
Treating the Motor Symptoms of Parkinson Disease . . . . . . . . . . . . . . . . . . . . . 1064
John C. Morgan, MD, PhD; Susan H. Fox, MBChB, MRCP(UK), PhD
Neuropsychiatric Issues in Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Jennifer G. Goldman, MD, MS, FAAN
Treatment of Advanced Parkinson Disease and Related Disorders . . . . . . . 1104
Janis M. Miyasaki, MD, MEd, FRCPC, FAAN
Diagnostic Approach to Atypical Parkinsonian Syndromes . . . . . . . . . . . . . . 1117
Nikolaus R. McFarland, MD, PhD
Diagnosis and Management of Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143
Elan D. Louis, MD, MS, FAAN
Movement Disorders Presenting in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . 1159
Manju A. Kurian, MBBChir, MRCPCH, PhD; Russell C. Dale, MBChB, MRCP, PhD
Chorea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
Tiago A. Mestre, MSc, MD
Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208
Tetsuo Ashizawa, MD, FAAN; Guangbin Xia, MD, PhD
Diagnosis and Management of Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
Vicki Shanker, MD; Susan B. Bressman, MD, FAAN
Wilson Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246
Ronald F. Pfeiffer, MD, FAAN
ETHICAL ISSUES
Ethics of Preclinical Dopamine Transporter Imaging . . . . . . . . . . . . . . . . . . . . 1262
Thomas I. Cochrane, MD, MBA
PRACTICE ISSUES
Chemodenervation Coding for Neurologists . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266
Allan D. Wu, MD; Dawn Eliashiv, MD, FAAN; Marc Nuwer, MD, PhD, FAAN
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover
Nonrigid Approach to
Movement Disorders
and addresses how their distinctive with a family history of PD who is re-
(although overlapping) clinical features questing such testing. Drs Allan D. Wu,
can help distinguish them from PD. Dawn Eliashiv, and Marc Nuwer pres-
Dr Elan D. Louis next discusses the clin- ent two cases to illustrate their discus-
ical approach to the categorization, di- sion of the various considerations
agnosis, and management of patients neurologists need to be aware of with
with any of the various tremor disorders regard to diagnostic coding for
who may present for our care. chemodenervation procedures.
Drs Manju A. Kurian and Russell C. As with every issue of Continuum,
Dale provide an overview of the a number of opportunities exist for
diagnosis and management of the CME. By taking the Postreading Self-
multitude of acquired and genetic Assessment and CME Test, written by
movement disorders that may present Drs James W. M. Owens Jr and Joseph
in childhood. Turning back toward E. Safdieh, after reading the issue, you
adults, Dr Tiago A. Mestre reviews the may earn up to 12 AMA PRA Category 1
approach to the diagnosis and manage- CreditsTM toward self-assessment and
ment of patients with disorders CME. The Patient Management Prob-
manifesting with chorea as a clinical lem, written by Dr Fox, describes the
sign, including Huntington disease case of a 70-year-old woman who pre-
and the many other genetic and ac- sents with a 6-month history of abnor-
quired choreic syndromes. Drs Tetsuo mal mouth and truncal movements
Ashizawa and Guangbin Xia next dis- and vocalizations. By following her
cuss their approach to the clinical as- case and answering multiple-choice
sessment, classification, diagnosis, and questions corresponding to diagnostic
laboratory investigation of patients with and management decision points along
ataxia. In the subsequent article, Drs the course of her disorder, you will
Vicki Shanker and Susan B. Bressman have the opportunity to earn up to 2
review the clinical phenomenology, AMA PRA Category 1 CME Credits.
classification, and the diagnosis and I want to sincerely thank Dr Fox for
treatment of patients with dystonia. her thoughtfulness, dedication, re-
In the final review article of the sponsiveness, collegiality, and hard
issue, Dr Ronald F. Pfeiffer discusses work beginning from the develop-
the most current approaches to the ment and organization of this issue
diagnosis and treatment of Wilson and culminating in its publication.
disease, a disorder that is so important Thanks also to each of the expert
to keep in mind when seeing any authors in this issue for providing the
patient with unexplained neurologic readers of Continuum with the bene-
or psychiatric (or hepatic) dysfunction fit of their clinical experience and
since it is treatable and reversible if expertise so that we can use their
caught early but progressive and irre- insights to inform our own individual-
versible if not. ized approaches to the clinical diag-
In the Ethical Issues article, Dr nosis and treatment of our patients
Thomas I. Cochrane dissects the eth- with movement disorders.
ical considerations involved in the
decision whether to order preclinical
dopamine transporter imaging in the VSteven L. Lewis, MD, FAAN
hypothetical case of a 52-year-old man Editor-in-Chief
Diagnosing Parkinson
Address correspondence to
Dr Christopher W. Hess,
University of Florida Health
Center for Movement
KEY POINTS
h Parkinsonism is a clinical TABLE 1-1 Classification of Parkinsonism
syndrome that can have a
variety of possible causes, b Idiopathic parkinsonism (Parkinson disease, including sporadic and
only one of which is genetic cases)
Parkinson disease.
b Atypical parkinsonian syndromes (eg, multiple system atrophy, progressive
h There are no clinically supranuclear palsy, corticobasal syndrome)
available biomarkers to
b Heredodegenerative parkinsonism (usually other additional neurologic
indicate the presence of
symptoms are present) (eg, PLA2G6-associated neurodegeneration,
Parkinson disease or track
aceruloplasminemia, X-linked dystonia-parkinsonism, spinocerebellar ataxias)
disease progression.
b Secondary parkinsonism (drug-induced, vascular, structural, infectious,
h The diagnosis of immunologic, toxic, traumatic, metabolic)
Parkinson disease
during the patient’s
lifetime is based on the
clinical examination. putamen) and modulate corticostriatal American Academy of Neurology (AAN),
h Core criteria, exclusion transmission. PD must be distin- the most common clinical criteria used
criteria, and supportive guished from many other forms of to establish the diagnosis of idiopathic
criteria have been parkinsonism.6 Additional or atypical PD is the UK Parkinson’s Disease Society
established that can neurologic symptoms as well as key Brain Bank (UKPDSBB) clinical diag-
assist in the diagnosis aspects of the reported history can nostic criteria (Table 1-2).8 These cri-
of Parkinson disease. help point to the correct diagnosis. teria provide essential clinical findings
Despite a concerted and continued as well as supportive and exclusion-
effort to develop a biomarker that can ary criteria for diagnosing PD.
accurately confirm or refute the pres-
ence of PD and monitor disease pro- Bradykinesia
gression, none has been found. Thus, The first and most important step in
the diagnosis of PD during the patient’s diagnosing PD is to establish the pres-
lifetime is based on a careful clinical ence of bradykinesia, or slowness of
examination. Practically speaking, this movement. While akinesia (the failure
is the most important criterion as few or delay in execution of a purposeful
patients diagnosed with PD undergo movement) and hypokinesia (a de-
postmortem neuropathologic evalua- crease in movement size) are distinct
tion.7 Recently, the use of clinical criteria entities from the motor control stand-
as the practical gold standard for the point, for the purposes of the clinical
diagnosis of PD has been questioned, examination they are often included
and the manner in which PD is best under the umbrella term of bradykinesia,
defined continues to be a current topic especially when describing the de-
of interest, as the clinical diagnosis of crease and slowing of movements as
PD does not always match the patho- well as the loss or decrease of automatic
logic diagnosis (especially in genetic movements that occur in PD.9 With
forms of PD, in which the presence of continued movement, true bradykinesia
pathologic gene mutations is compli- typically gets worse (movements be-
cated by incomplete penetrance).7 come progressively smaller or decre-
These detailed discussions and debates mental), a feature that is required for
are outside the scope of this review, the UKPDSBB criteria and more recent
and this article focuses on diagnosing European guidelines.8,10 Common early
PD for the practicing clinician. manifestations of bradykinesia in PD
Although no clinical diagnostic include decreased facial expression
criteria are formally endorsed by the (hypomimia), soft speech (hypophonia),
KEY POINTS
h Rigidity giving rise and small handwriting (micrographia). presenting symptoms of PD. Prominent
to decreased range of The latter can be tested by asking pa- axial rigidity early in the course of symp-
motion and shoulder tients to write the same sentence at toms is not typical and is commonly
pain (often misdiagnosed least three times sequentially, observing observed in progressive supranuclear
as orthopedic or the possibility of a progressive decrease palsy (PSP).
arthritic) and difficulty in sentence length and the size of the
turning over in bed at characters. Although bradykinesia is Resting Tremor
night are common required to make the diagnosis of PD, The classic parkinsonian resting tremor
presenting symptoms of it can sometimes be difficult to elicit in is present in approximately 70% of
Parkinson disease. strongly tremor-predominant patients patients with PD.13 It is typically 4 Hz
h Parkinson tremor can with PD, especially early in the PD course. to 6 Hz and starts unilaterally and distally
fluctuate significantly in In addition to bradykinesia, at least one and, over time, progresses more proxi-
amplitude with mental additional cardinal symptom of rigidity, mally and often to the contralateral side.
activity or voluntary resting tremor, or postural instability The resting tremor can variably involve
movements of other oscillations around the wrist and finger
must be present as a second step to
limbs, and, thus, it is
make the clinical diagnosis of PD.8 joints, although a pronation/supination
not unusual to be
axis at the wrist and a pill-rolling qual-
initially described as
Rigidity ity to finger tremor are classic in PD.14
intermittent. It often has
a reemergent quality Rigidity refers to the resistance of mus- Parkinson tremor can fluctuate signifi-
such that it can reappear cles to passive movement around a cantly in amplitude with mental activity
with postural sustention joint. While rigidity is a clinical sign or voluntary movements of other limbs,
after a variable delay, and detected by the examiner, it is experi- and, thus, it is not unusual to be initially
patients may report enced and often described by patients described as intermittent.14 It often has
noticing it for the first as stiffness.9 When absent or mild on a reemergent quality such that it can
time with sustained examination, rigidity can be augmented reappear with postural sustention after
postures, such as holding by asking the patient to perform volun- a variable delay, and patients may
a telephone or newspaper. tary movements of the contralateral report noticing it for the first time with
limb. In evaluating rigidity, it is impor- sustained postures, such as holding a
tant to distinguish true parkinsonian telephone or newspaper (Case 1-1).15
rigidity from both paratonia (involuntary This manifestation can sometimes lead
variable and proportional resistance in to confusion as it can be reported as an
response to passive movement [also action tremor. Some patients also re-
known as gegenhalten]) and the cog- port a sensation of ‘‘inner tremor’’ that
wheel phenomenon that can be ob- does not involve oscillations around a
served with essential and other types of joint.16 A jerky quality to tremor can
tremor without any underlying in- sometimes be observed in younger
creased tone (Froment sign, which is patients, but in older patients this can
the increase in resistance to passive signal the presence of multiple system
movement about a joint with voluntary atrophy (MSA). Although more charac-
action in another part of the body).11 teristic of essential tremor, kinetic
Similarly, reduced arm swing on one tremor (occurring during active move-
side can be misleading without the ment) is not unusual in PD, and
appropriate clinical context, as some amelioration of tremor with alcohol
degree of arm swing asymmetry can be (due to its relaxing effects) can also be
observed in healthy adults.12 Rigidity reported in PD, emphasizing the im-
giving rise to decreased range of motion portance of the clinical examination.17
and shoulder pain (often misdiagnosed Parkinsonian tremor does not uniformly
as orthopedic or arthritic) and difficulty respond to levodopa, so occasionally
turning over in bed at night are common patients, in whom the other cardinal
KEY POINT
h Nonmotor symptoms and cognitive task completion are Since the initial publication of the
such as hyposmia, common early reported symptoms, while UKPDSBB criteria, the inclusion of a
erectile dysfunction, a progressively flexed posture, freezing strong family history (more than one
constipation, and rapid phenomenon, gait initiation difficul- affected relative) has been challenged
eye movement sleep ties, postural deformities, and swal- as an exclusionary criterion and is
behavior disorder can lowing difficulties tend to appear later often overlooked in the appropriate
precede the onset of in the disease. clinical context. Other features (such
motor symptoms of as hyposmia, rapid eye movement [REM]
Parkinson disease Exclusionary and Supportive sleep behavior disorder, and constipa-
by years. Criteria for Diagnosing tion) that are known to be strongly
Parkinson Disease associated with the diagnosis of PD
The exclusionary criteria for PD listed have been proposed as additional
in Table 1-2 need to be practically formal supportive criteria, especially as
considered on an individual basis, as they often precede the motor symp-
some criteria reflect confounders in toms of the disease.8,21Y23 Although
attributing symptoms to PD while early severe dementia is an exclusion
others suggest the presence of other criterion in the UKPDSBB criteria, more
diseases. For example, a history of than 15% of patients with PD can have
multiple concussions that preceded at least mild cognitive impairment at
the onset of parkinsonism is a poten- the time of diagnosis.24 However the
tial confounder in diagnosing PD, but presence of visual hallucinations at the
it does not exclude the diagnosis of time of presentation and especially in
PD or specifically suggest an alterna- untreated patients is suggestive of
tive diagnosis. However, cerebellar dementia with Lewy bodies, which
signs or a supranuclear gaze palsy de- some argue should be considered a
veloping simultaneously with progres- subtype of PD.7
sive parkinsonism would strongly
suggest an alternative diagnosis of an NONMOTOR SYMPTOMS
atypical parkinsonism such as MSA or The function of the basal ganglia was
PSP, respectively. traditionally thought to be limited to
Supportive criteria (of which three the modulation and processing of in-
or more are required) are all charac- formation related to motor control,
teristics that commonly are observed with projections solely to motor corti-
in PD. Patients with PD usually pres- ces.25 However, it is now accepted
ent with a clear asymmetry of symp- that the basal gangliaYthalamocortical
tom onset and respond well to trials of circuits consist of multiple subcircuit
levodopa when appropriate, but this loops projecting cortically to diverse
is not always the case. Resting tremor targets.26,27 These circuits are largely
is absent in 30% of patients with PD, parallel, somatotopically arranged, and
and patients without resting tremor functionally specific, and are organized
can experience a longer delay in into motor, oculomotor, associative,
diagnosis due to physician familiarity and limbic circuits. They are involved
with the association between resting in a variety of activities including emo-
tremor and PD.19 Patients with path- tion, reward behavior and habit forma-
ologically confirmed PD can go many tion, time estimation, attention, working
years from the onset of resting tremor memory, and learning.28 Thus, it would
before developing other symptoms and be expected that the basal ganglia
might never develop unequivocal dysfunction that occurs in PD would
bradykinesia.20 produce a more complicated clinical
1052 www.ContinuumJournal.com August 2016
KEY POINTS
h Parkinson disease more information, refer to the article commonly referred to as early PD in
results in a variety of ‘‘Treatment of Advanced Parkinson Dis- clinical trials (in which motor symptoms
nonmotor symptoms ease and Related Disorders’’ by Janis M. are just beginning to manifest) is a point
that can sometimes be Miyasaki, MD, MEd, FRCPC, FAAN,35 in in time that is actually relatively later
more disabling than the this issue of Continuum. In the patient in the disease course. Therefore, it has
motor symptoms, and
presenting with PD, nonmotor symp- been recognized by many experts that a
studies suggest that the potential window for disease-modifying
toms often precede or present with
nonmotor symptoms and neuroprotective treatments exists,
have a greater effect motor symptoms but are not commonly
but that earlier diagnosis and a bio-
on quality of life. reported unless uncovered by the clini-
marker are necessary. Many current
h At least two subtypes cian during the encounter.36
neuroprotective and disease-modifying
(tremor-predominant strategies are being tested in patients
PARKINSON DISEASE SUBTYPES
Parkinson disease and where presumably a large proportion
postural instability and One of the most remarkable aspects of
PD is the degree of clinical heterogeneity of neurodegeneration has already
gait difficulty Parkinson
that exists across patients, to such a de- occurred.47 A variety of terms have
disease) have been
gree that some have questioned whether been proposed, including prephys-
identified, and both of
these entities manifest PD can be considered a unified disease.7 iologic, preclinical, prodromal, premotor,
different rates of It has long been recognized that and prediagnostic, to describe the
progression, disability, considerable variability exists between various stages that can be identified
nonmotor symptoms, patients with PD in the expression of prior to the diagnosis of PD.7,48 From
and complications clinical symptoms, the rate of disease the practical and clinical standpoint, it
of therapy. is most important to remember two
progression, and the response to
main points. First, the vast majority of
therapies.37 The approaches that have
patients with PD already manifest one
been used to try to organize this het-
or more nonmotor symptoms of the
erogeneity into distinct and useful clin-
disease at the time of diagnosis and
ical subtypes have largely been based
often years prior. 23 Evaluation of
on specific clinical or demographic
nonmotor symptoms in PD is a critical
features (empirical approach) or on
part of the history at the initial presen-
methods of statistical clustering (data-
tation and should be uncovered, if
driven approach) with a variety of
present, in all patients. Second, some
classifications proposed.38 The obser- patients may have nonmotor symp-
vation that a predominance of tremor toms and mild soft signs of parkinson-
in PD portends a slower disease pro- ism, but not enough clinical findings to
gression was one of the earliest indi- confer the diagnosis of PD. In these
cators of the existence of PD subtypes patients, monitoring symptom stability
and dates back more than 45 years.39 A and progression over time is impor-
tremor-predominant phenotype has tant, especially prior to labeling the
been associated with a slower disease patient as having PD.
progression and less cognitive impair-
ment, depression, and apathy when DIFFERENTIAL DIAGNOSIS
defined empirically in data-driven stud- A myriad of diseases and syndromes can
ies and retrospective clinicopathologic be mistaken for PD, including other
studies.40Y46 forms of parkinsonism (Table 1-1)
as well as nonparkinsonian mimics.
PREDIAGNOSTIC PARKINSON Table 1-4 lists the commonly consid-
DISEASE ered differential diagnoses in the ini-
In the field of PD research, it is be- tial presentation of PD. Atypical
coming increasingly clear that what is parkinsonism can sometimes initially
1054 www.ContinuumJournal.com August 2016
KEY POINT
h Laboratory testing can Case 1-2
sometimes be useful in
A 56-year-old woman with a past medical history of hypertension,
ruling out metabolic
hyperlipidemia, and refractory major depressive disorder presented for
abnormalities that may
a neurologic evaluation because of a 4-month history of difficulty walking.
present as parkinsonism.
She reported problems with handwriting due to tremor and micrographia
and difficulty getting in and out of her car. She denied any sleep
disturbances, constipation, changes in her sense of smell, or urinary dysfunction.
A CT scan of her brain ordered by her primary care doctor 1 year previously
after an episode of acute dizziness was remarkable only for mild chronic
microvascular ischemic changes. She had been tried on multiple antidepressants
but denied ever taking a neuroleptic, and none was uncovered following
inspection of her current medication bottles. Her neurologic examination
was remarkable for decreased facial expression and blink rate, bilateral
rigidity, and low-frequency resting and action tremors. Perioral tremor was
noted as well. Since she had used the same pharmacy for the last 5 years, the
pharmacy was called and a list of all recently prescribed medications was
reviewed. The list included an atypical neuroleptic that had been prescribed
for depression 2 weeks prior to the onset of her neurologic symptoms. This
medication had been discontinued the month prior to her presentation, and
her symptoms gradually improved over the next few weeks and resolved
completely within 2 months.
Comment. Although features such as a subacute onset and relative
symmetry of symptoms can suggest a secondary cause of parkinsonism
such as drug-induced parkinsonism, it may not be possible to distinguish
these entities on a clinical basis alone. An accurate history of current and
recently prescribed medications is critical in establishing the accurate
diagnosis when a patient presents with parkinsonism.
levels, and 24-hour urine copper excre- the diagnosis of PD recommends con-
tion should be considered. For more sideration of specific gene testing in
information, refer to the article ‘‘Wilson patients without a family history of PD
Disease’’ by Ronald F. Pfeiffer, MD, but onset before the age of 40, patients
FAAN,54 in this issue of Continuum. with a strong family history of either a
recessive pattern of inheritance (espe-
GENETIC TESTING cially with onset before the age of 50)
Most patients (approximately 90%) or an autosomal dominant pattern of
diagnosed with PD do not have a family inheritance, and patients who belong
history of the disease and are, there- to ethnic groups associated with foun-
fore, considered to be sporadic cases.55 der mutations.10 These recommenda-
While monogenic forms of PD have tions are very similar to those put forth
been identified and may provide insight by the Consortium on Risk for Early-
into the pathophysiology and genetic Onset Parkinson Disease (CORE PD) in
heterogeneity of PD, they constitute a 2010.58 In such patients, genetic test-
very small portion of patients with PD.56 ing can be helpful in family and finan-
Recently, alleles that are more com- cial planning, aiding in prognosis, or in
mon in the general population and patients with a strong personal desire
that may increase the risk for PD have for testing.
been identified.57 No formal guidelines Clinicians also need to be aware that
exist regarding which patients with PD the first direct-to-consumer genetic
should be considered for genetic test- tests have been approved by the US
ing. A recent European guideline for Food and Drug Administration (FDA)
KEY POINT
h While the research and may become available for PD.59 diseases, FDG-PET is currently lim-
utility of dopamine These tests can potentially mislead ited to the differentiation of Alzheimer
transporter single-photon asymptomatic patients into thinking disease and frontotemporal dementia.
emission computed they are sure to develop the disease if FDG-PET may be especially useful in
tomography is universally they are positive for an allele that the differentiation of atypical parkin-
agreed upon, its use increases the risk of PD, or that they sonism in the future as the research in
in the clinical setting are no longer at increased risk when this area evolves.64
for differential diagnosis a single gene or a limited number of In 2011, ioflupane I-123 single-
in the individual genes are tested. Any decision to pur- photon emission computed tomogra-
remains controversial. sue clinical genetic testing should be phy (SPECT) was approved in the
preceded by genetic counseling and United States as an adjunctive evalua-
family discussions to ensure patients tion tool for use in the diagnosis of
are aware of the implications for them- suspected parkinsonian syndromes.
selves and their families. This compound binds to the presyn-
aptic dopamine transporter (DAT) and
NEUROIMAGING acts as a marker for dopamine levels in
The clinical utility of structural neuro- the striatum. While the research utility
imaging in the evaluation of PD has of DAT-SPECT is universally agreed
traditionally been limited to ruling upon, its use in the clinical setting for
out secondary causes of parkinsonism, differential diagnosis in the individual
such as vascular parkinsonism or nor- remains controversial.65
mal pressure hydrocephalus, as MRI It is generally agreed on by experts
and CT are largely unremarkable in PD that DAT-SPECT does not currently
beyond generalized cortical atrophy. have a role in the differentiation of PD
Most experts make a bedside decision from other neurodegenerative forms
on the need for structural neuroimag- of parkinsonism as DAT binding will
ing on a case-by-case basis, and the most be reduced in all of these entities
recent AAN practice parameter on diag- (Case 1-3). Further, progression of
nosing PD did not render a recommen- PD cannot yet be followed by DAT-
dation regarding the need for structural SPECT as it has not been shown to
imaging prior to making the diagnosis define a clear and reliable relationship
of PD. However, structural imaging is between DAT binding and disease
often recommended to rule out sec- severity.66 Therefore, DAT-SPECT is
ondary causes of parkinsonism.60 Novel currently limited to the differentiation
techniques of diffusion, perfusion, and of a neurodegenerative parkinsonian
functional MRI (fMRI) continue to be syndrome from entities such as essential
developed and show promise as po- tremor, dystonia, or secondary causes
tential biomarkers of PD.61,62 of parkinsonism. Yet even in these
Metabolic imaging with fludeoxyglu- populations, findings are not always
cose positron emission tomography straightforward. DAT binding would be
(FDGYPET) measures regional differ- expected to be normal in essential
ences in glucose metabolism, and these tremor and thus useful for ruling out a
studies have uncovered patterns of dopamine deficiency in the long-
activity that are characteristic for the standing patient with essential tremor
motor and cognitive symptoms of PD, who has developed a superimposed
as well as patterns specific to atypical slowing of movement speed beyond
forms of parkinsonism such as MSA or that which can be seen in essential
PSP.17,63 Although approved in the tremor.11 It should also be normal in
United States for neurodegenerative dystonia, which is believed to account
1058 www.ContinuumJournal.com August 2016
KEY POINT
h If dopamine transporter reduce DAT binding (potentially can emerge over time, it is important for
single-photon emission resulting in a false-positive interpreta- the clinician to continue to follow the
computed tomography tion). The duration of discontinuation patient long-term, monitor the exami-
imaging is pursued, it is recommended for some of these agents nation, and document the response to
important to note that a is significant (such as for some of the dopaminergic therapy. In many cases,
number of commonly selective serotonin reuptake inhibitors the diagnosis may be revised based on
prescribed medications [SSRIs]), and the decision to stop medi- the emergence of a pattern of symp-
can interfere with cations needs to be considered on an toms suggesting an atypical parkinso-
dopamine transporter individual basis. In contrast, dopami- nian syndrome or other diagnosis.
binding and produce nergic medications such as levodopa and
erroneous results.
dopamine agonists are generally not held REFERENCES
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Variable expression of Parkinson’s disease:
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46. Selikhova M, Williams DR, Kempster PA, Newsroom/PressAnnouncements/
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2009;132(pt 11):2947Y2957. doi:10. 60. Pahwa R, Lyons KE. Early diagnosis of
1093/brain/awp234.
Parkinson’s disease: recommendations from
47. Lang AE, Melamed E, Poewe W, Rascol O. diagnostic clinical guidelines. Am J Manag
Trial designs used to study neuroprotective Care 2010;16(suppl implications):S94YS99.
AAV2 = adeno-associated type-2 vector; GDNF = glial cell line-derived neurotrophic factor;
GM-CSF = granulocyte-macrophage colony-stimulating factor; MAO-B = monoamine oxidase type B;
PPAR = peroxisome proliferator-activated receptor.
a
See Kalia et al, 20154 for a full review on this subject.
TABLE 2-2 Medications Used in the Initial Therapy of Early Parkinson Disease
Maintenance
Generic Name Mechanism Initial Dosage Dosage Major Side Effects
Amantadine Multiple 100 mg 100 mg 2 to Nausea, confusion,
(N-methyl-D-aspartate 2 times a day 3 times a day hallucinations, leg edema,
[NMDA] receptor livedo reticularis
antagonist, potentiates
dopamine release)
Benztropine Anticholinergic 0.5 mg every 1 mg 2 to Dry mouth, reduced
night at 3 times a day cognition, urinary
bedtime retention, hallucinations,
blurry vision, constipation
Bromocriptine Dopamine agonist 1.25 mg 5Y10 mg 2 to Nausea, impulse control
(ergot derived) 2 times a day 3 times a day disorders, hallucinations,
orthostatic hypotension,
fibrosis, sleep attacks
Carbidopa/levodopa Aromatic amino 25 mg/100 mg Variable Nausea, orthostatic
acid decarboxylase 2 times a day hypotension, confusion,
inhibitor/dopamine hallucinations, dizziness
precursor
Carbidopa/levodopa Converted to 23.75 mg/95 mg Variable Nausea, orthostatic
extended release dopamine 3 times a day hypotension, confusion,
capsules hallucinations, dizziness
Pramipexole Dopamine agonist 0.125 mg 2 to 0.5Y1.5 mg 2 to Nausea, hallucinations,
(nonYergot derived) 3 times a day 3 times a day impulse control disorders,
orthostatic hypotension,
sleep attacks, leg edema
Pramipexole Dopamine agonist 0.375 mg/d 1.5Y4.5 mg/d Nausea, hallucinations,
extended release (nonYergot derived) impulse control disorders,
orthostatic hypotension,
sleep attacks, leg edema
Rasagiline Monoamine oxidase 0.5Y1 mg/d 1 mg/d Dizziness, flu syndrome,
type B inhibitor arthralgia
Ropinirole Dopamine agonist 0.25 mg 2 to 2Y8 mg 2 to Nausea, hallucinations,
(nonYergot derived) 3 times a day 3 times a day impulse control disorders,
orthostatic hypotension,
sleep attacks, leg edema
Ropinirole Dopamine agonist 2 mg/d 8Y24 mg/d Nausea, hallucinations,
extended release (nonYergot derived) impulse control disorders,
orthostatic hypotension,
sleep attacks, leg edema
Rotigotine Dopamine agonist 2 mg/d 6 mg per 24 hours Nausea, hallucinations,
(nonYergot derived) (maximum dose) impulse control disorders,
orthostatic hypotension,
sleep attacks, leg edema,
and may have patch
application site reactions
Continued on page 1069
Maintenance
Generic Name Mechanism Initial Dosage Dosage Major Side Effects
Selegiline Monoamine oxidase 5 mg 1 to 5 mg 2 times Confusion, hallucinations,
type B inhibitor 2 times a day a day orthostatic hypotension,
insomnia, nausea, benign
cardiac arrhythmias
Trihexyphenidyl Anticholinergic 2 mg/d 2 mg 2 to Dry mouth, reduced
3 times a day cognition, urinary
retention, hallucinations,
blurry vision, constipation
is also falling out of favor by many agonists are also available as once-daily
clinicians given that untreated patients extended-release (pramipexole ex-
have a worse self-rated quality of life over tended release, ropinirole extended
time compared to those who receive release) and patch (rotigotine) formu-
treatment around the time of diagnosis.11 lations. Currently, for the patient with
Of the many options, the patient in early PD, no evidence exists of differ-
Case 2-1 chose monoamine oxidase ences in efficacy or in the propensity
type B (MAO-B) inhibitor therapy with to induce motor complications or side
rasagiline 1 mg/d. In practice, this med- effects with longer-acting dopamine
ication is well tolerated, is taken once agonists versus regular release.
daily, and provides mild symptomatic Anticholinergics (benztropine,
improvement. Many patients taking ra- trihexyphenidyl) have largely fallen out
sagiline may not notice obvious benefit of favor due to potential adverse cog-
after several weeks, and it may take nitive effects, but they may be useful in
8 to 12 weeks to notice full benefit.12 younger, cognitively intact patients with
Selegiline 5 mg 2 times per day would tremor.15 Side effects can also include
also be expected to provide similar be- dry mouth, blurry vision, worsened con-
nefit. Patients on rasagiline or selegiline stipation, and urinary retention.
will eventually need additional therapy Amantadine would also be useful as a
after 6 months to 2 years, depending potential therapy for the young patient
on the patient. with early PD, as in Case 2-1. Dosing is
Other options (outside of levodopa) typically 100 mg titrated to 2 or 3 times
in the early, young patient include do- daily. Side effects with this medication
pamine agonists, anticholinergics, and include leg edema, livedo reticularis,
amantadine. All of these medications and, rarely, corneal edema. It also has
could provide some benefit. Dopamine mild anticholinergic properties and can
agonists (bromocriptine, pramipexole, lead to hallucinations and negative
ropinirole, rotigotine) are more apt to cognitive effects as well.
cause neuropsychiatric issues such as A younger patient with early PD is
hallucinations, impulse control disor- very different from an older, retired
ders, and somnolence as potential side patient. Physicians should try to un-
effects.13 In addition to motor benefit, derstand where the patient is in his or
there is some benefit of additional anti- her life with regard to children, career,
depressant effects.14 Some dopamine and concerns about long-term financial
KEY POINTS
h Exercise, if safe for the issues, and should consider the fears Therapeutic Options in Older,
patient, should be a part a patient might have for a future living Cognitively Intact Patients
of every patient’s with PD. One of the most important With Parkinson Disease
regimen to battle against tasks for the clinician and the care In most patients with a typical age of
Parkinson disease. This team is to help the patient accept his onset (late fifties to early sixties), there
not only includes physical or her diagnosis and decide to battle are numerous pharmacologic and
exercise, but cognitive against the disease through all means nonpharmacologic treatments that can
exercise such as reading, at their disposal. improve motor symptoms and quality
crossword puzzles, and of life (Case 2-3).
current events. Complementary and Data indicate that dopamine ago-
h Many younger patients Alternative Therapies nists of all types are effective in the
with Parkinson disease Be aware that many younger patients treatment of motor symptoms of early
embrace alternative with PD may want to pursue alternative PD. Ropinirole, pramipexole, and
therapies, and it is therapies and modalities for treat- rotigotine are nonYergot-derived dopa-
important, as a clinician, ment of their PD motor and non- mine agonists with multiple clinical trials
to work within the
motor symptoms. In many series of supporting their use in untreated PD.20
patient’s framework as
patients with PD throughout the world, Ergot-derived dopamine agonists were
much as possible. At the
same time, discouraging
use of alternative therapies has been previously used in practice but have
use of unproven, as high as 75% in some cohorts.16 The fallen out of favor given potential fi-
expensive therapies that data supporting the use of most alter- brosis of pleuropulmonary tissues and
are highly unlikely to native therapies such as vitamins and heart valves.21 Pergolide is now off the
provide any subjective or nutritional supplements, acupuncture, market in the United States, but bro-
objective benefit is key. or manual therapies are scant, how- mocriptine remains available, although
ever.17 Some more promising therapies it is used extremely rarely for treating
that have emerged with better study PD today.
design and data are speech therapy for Some data offer evidence of an
hypophonia in PD and physical and antidepressant effect with dopamine
occupational therapy focused on inten- agonists (especially pramipexole), and
sity and amplitude of movement. Tai they clearly improve quality of life.14,22
chi for gait and balance, tandem cycling, While sudden onset of sleep is a black
and other therapies have also proven box warning for dopamine agonists,
to be useful in recent work.18,19 sudden onset of sleep does not occur
Many patients with PD embrace commonly in practice.23 However, pa-
exercise and alternative therapies, and tients with PD who are driving need
as a clinician, it is important to work to be advised about sleep risks of all
within the patient’s framework as much drugs. Lower extremity edema is not
as possible to improve quality of life. uncommon in longer-term therapy with
Discouraging use of unproven, expen- dopamine agonists and is often unrec-
sive therapies that are highly unlikely ognized as a side effect by neurologists
to provide any subjective or objective and primary care physicians alike.24 The
benefit, however, is also very important. major issue with these medications is
impulse control disorders that can
Therapeutic Options in Older emerge at any stage, although generally
Patients With Parkinson Disease occur early on in treatment.25 Often,
and Cognitive Impairment changes in behavior are subtle and do
In an older patient with significant co- not necessarily fulfill the impulse con-
morbidities and significant motor dis- trol disorder criteria of the Diagnostic
ability, therapeutic options are usually and Statistical Manual of Mental
more restricted (Case 2-2). Disorders, Fifth Edition (DSM-5).26
KEY POINT
h When possible, the dose
Continued from page 1071
Remember that levodopa provides the most effective motor benefit for
of levodopa should be
PD, and while there are risks of motor fluctuations and dyskinesia with this
kept lower to reduce
medication, it should be used in any patient with PD regardless of age
the risk of wearing off
or other factors when a patient experiences significant disability (in activities
and dyskinesia.
of daily living or occupation) due to motor symptoms. When possible,
keeping the dose of levodopa lower, however, reduces risk of developing
dyskinesias and motor fluctuations. In many cases, when motor complications
do initially arise, they are not severe, and there are numerous adjunctive
therapies that can ameliorate wearing off and reduce dyskinesia.
Case 2-3
A 62-year-old right-handed man with hypertension and hyperlipidemia
presented for slowness and stiffness of his left side. He had not noticed much,
if any, tremor on either side of his body, but his wife had noticed an occasional
lower lip tremor. He was somewhat bothered in his daily life (work and
running) by the left-sided slowness and stiffness. He worked as a teacher and
did research as a biologist at the local college; he had been doing well in his
daily function and had received great reviews by students and his superiors.
He was taking two medications, hydrochlorothiazide and atorvastatin.
He was active and ran 15 to 20 miles per week. He had noticed that it took
him longer to run 4 miles than it did before. His handwriting did not appear
to be affected yet, and he wanted to keep teaching until he reached 68,
when his mortgage on his house would be paid off.
Examination demonstrated normal cognition with a score of 29 out of
30 on the Montreal Cognitive Assessment (MoCA) and exquisite recall of
current news events. He had mild bradykinesia and cogwheel rigidity of the
left upper extremity and left lower extremity that worsened with contralateral
distraction. He did have a mild occasional lower lip tremor. His gait was
steady with great turns, reduced arm swing on the left, and a normal pull
test. There were no signs of ataxia, and his orthostatic blood pressures were
normal. The patient was diagnosed with Parkinson disease (PD). After
discussing the options with the patient and his wife, the patient decided to
start a dopamine agonist, pramipexole, titrating from 0.125 mg 2 times a day
to 0.75 mg 2 times a day over 3 weeks. He was counseled about potential
side effects, including nausea, hypersomnolence (including sudden onset of
sleep), edema, hallucinations, and impulse control disorders. Screening for
impulse control disorders (eg, hypersexuality, gambling, overshopping) at
baseline was negative.
The patient returned 6 weeks later and noted significant improvement
in his left-sided slowness and rigidity. He had noticed some nausea and
somnolence within an hour after each dose of pramipexole, but it was
mild and did not affect his ability to drive, perform activities of daily living,
or work. These side effects improved over time. His wife noted that his
lip tremor had improved somewhat as well. He had not had symptoms of
an impulse control disorder or hallucinations.
Two years later, his symptoms had gradually progressed, and he was
interested in further therapy for slowness and tremor that had become
apparent and more bothersome in his left hand.
Continued on page 1073
Case 2-4
A 66-year-old man with a 3-year history of Parkinson disease (PD) presented
with uncomfortable curling of the toes in his right foot on waking up
several mornings per week. This was often associated with feeling anxious.
During the day he managed reasonably well, but reported that he
experienced more right hand tremor and slower dexterity midafternoon
and at bedtime. He was on carbidopa/levodopa 25 mg/100 mg 1 tablet
every 4 to 5 hours (total of 4 tablets per day), plus selegiline 10 mg/d. He had
anxiety and was also on citalopram 10 mg/d. Examination 2 hours
postYcarbidopa/levodopa revealed a good ‘‘on’’ response with some mild,
nonbothersome neck chorea.
He was advised to take carbidopa/levodopa 30 minutes before meals, and
the fourth dose was switched to a controlled-release carbidopa/levodopa
25 mg/100 mg taken at bedtime. He had no known risk factors for impulse
control disorders, apart from gender, and pramipexole was cautiously
started and titrated up to 0.5 mg 3 times a day with better overall
symptom control.
He was reassessed 4 months later and had less off symptoms but was noted
to be spending more time at night on the computer on an online gambling
site. His family expressed concern, although he was not aware of the change
in behavior. Pramipexole was tapered and stopped, with resolution of his
gambling. Carbidopa/levodopa dosing was increased to 5 tablets per day,
with 1 tablet every 3.5 to 4 hours, and the fifth dose at bedtime of
controlled-release carbidopa/levodopa. Although he had more neck chorea
in the evening, this was not bothersome, and he was happy with his PD control.
Comment. The patient had developed early-morning off-period dystonia
of the foot with nonmotor off symptoms as well as wearing off midafternoon,
which may have been due to effect of food on lunchtime dosing. Evaluating
issues related to poor absorption of the levodopa (eg, timing of medications
in relation to food and constipation) can help. He had head chorea
already (a common issue in managing these patients) and so adding in a
catechol-O-methyltransferase inhibitor, entacapone, will increase dyskinesia.
Dopamine agonists are helpful for reducing wearing off and can also help
depression but must be used with caution due to impulse control disorders, as
occurred in this patient.
b Motor Symptoms
Off State
Predictable wearing off: Reemergence of Parkinson disease (PD) symptoms before next dose
of medication
Unpredictable off: Random, sudden return of PD symptoms, not related to timing of levodopa
Dose failure/partial response: A dose of levodopa that has a delayed effect (delayed on) or no effect
or a reduced effect (dose failure)
Off freezing: A transient difficulty in initiating or continuing a movement (eg, when starting to walk
[start hesitation], while turning [turning hesitation], when going through a narrow doorway, or due
to sudden stress or anxiety [startle hesitation])
Off-period dystonia: Usually painful affecting distal leg, foot, toes with abnormal postures
On State
Peak-dose dyskinesia: Mixed chorea and dystonia of neck and limbs; increases with mental and
physical activity
On freezing: Rare but may occur
Transitional state
Diphasic dyskinesia: Legs, dystonic and high amplitude; stereotypic kicking, ‘‘funny’’ gait
Beginning-of-dose worsening and end-of-dose rebound: A transient worsening of symptoms at the
beginning of dose or end of a dose, often presenting as an increase in tremor
b Nonmotor Symptoms
Off State
Neuropsychiatric: Anxiety, depression, irritability, panic attacks, apathy, fatigue, verbal fluency,
attention, executive functions
Autonomic: Sweating, facial flushing, pallor, hyperthermia, cold limb extremities (hands and feet),
urinary disturbances, bloating, abdominal discomfort, drooling, dyspnea (air hunger)
Pain/sensory: neuropathic, dysesthesia, numbness, paresthesia, restlessness/akathisia
On State
Neuropsychiatric: Euphoria, agitation, illusions, hallucinations, delusion, paranoia, distracted, impulsive
timing of levodopa doses is essential, ment to improve efficacy.34 In prac- KEY POINT
such as reducing the time between tice, a lower dose of levodopa more h Wearing off is generally
each levodopa dose to 4 hours or less frequently becomes the best option more bothersome to
patients than on-period
so that subjects take 4 or 5 doses per for managing motor complications.
dyskinesia, so clinicians
day (as in Case 2-4). The longer-acting Gastrointestinal factors can be very
should focus on
carbidopa/levodopa, recently approved important in some individuals. Sub- strategies to improve
by the US Food and Drug Administra- jects may notice an effect after eating, off symptoms.
tion (FDA), may also be useful to im- especially after consuming meat pro-
prove duration of action.33 Other novel tein, which reduces the efficacy of
levodopa preparations are in develop- levodopa action (Case 2-4). Such
a
TABLE 2-4 Drug Therapies for Levodopa-Induced Complications
individuals may also notice fluctuations Thus, delayed effects or even no effect
in benefit that are unrelated to the of a dose can be due to food in-
timing of the medications (termed teractions. Levodopa competes with
unpredictable offs and sudden offs). protein amino acids for transport across
KEY POINTS
h Clinicians should assess after a few years of levodopa therapy. side or upgaze eye movements) or res-
the timing of movements Most commonly, levodopa-induced piratory muscles (breathlessness). Many
in relation to the dose of dyskinesia will start on the side of the patients with PD are unaware of such
levodopa as high dose body initially affected by PD. Managing peak-dose dyskinesia, unless severe,
(peak-dose of levodopa dyskinesia involves identifying the time and it is often family members who will
action) or low dose when the movements occur in relation comment on the presence of dyskine-
(onset and end of to a dose of levodopa (Table 2-3). sia. Thus, treating peak-dose levodopa-
levodopa dose, or in the Thus, one simple classification relates induced dyskinesia should be targeted
off periods) to help to the level of levodopa: high-dose to patient disability, and clinicians
classify and then treat the dyskinesia occurs when levels of dopa- should only treat dyskinesia that is inter-
type of dyskinesia.
mine stimulation are at their highest fering with daily life. Many patients,
h Often, patients with and is the classic peak-dose dyskinesia. even when aware of involuntary move-
Parkinson disease are The opposite is low-dose dyskinesia, ments, prefer to be on with some dys-
unaware of the which occurs when the levels of dopa- kinesia than off without any dyskinesia.
movements, especially
mine are low. The most common type Dyskinesia occurring toward the
chorea, and as such do
of high-dose dyskinesia occurs at the end of a dose of levodopa or between
not report any disability.
Painful dystonia is more
peak level of levodopa action (ie, 1 to doses (off periods) tends to be pre-
likely to be reported. 2 hours post dose), called peak-dose dominantly dystonic and affects the legs
dyskinesia (Case 2-5), and is a mixture and feet. Patients often experience a
h Not all dyskinesia needs
of chorea and dystonia affecting the more fixed posture (eg, ankle intorsion
to be treated. Rather,
focus on reducing only
neck, limbs, and trunk, with rarer high- with toe flexion or extension), especially
disabling, bothersome amplitude limb ballism. Rarely, myoclo- in the early morning (early-morning
dyskinesia with medical/ nus or even dyskinesia can occur dystonia). As off-period dystonia can be
surgical strategies. affecting the eyes (including side-to- painful and disabling, patients are more
Case 2-5
A 62-year-old woman with Parkinson disease (PD) presented for a follow-up
visit with neck pain. She had a history of PD for 6 years, which started with
left hand tremor, and was on carbidopa/levodopa 25 mg/100 mg 1.5 tablets
every 4 hours, 4 doses a day, with 1 tablet of entacapone with each dose,
and ropinirole 3 mg 3 times per day. She worked as a teacher, and her
students reported that she moved her head when talking to them. She
otherwise managed well throughout the day, but had some nighttime
insomnia and felt sleepy in the afternoons. On examination, 2 hours after
her last dose of levodopa, she had neck chorea and mild finger chorea
and dystonia in the left hand but with no tremor, and her gait was normal.
The entacapone was tapered and stopped with reduced neck chorea
and less pain. She did not want to reduce ropinirole, as she had tried this
previously but felt anxious and had more tremor, including an inner sense
of tremulousness. She was aware of a slightly increased appetite, especially
for sweets.
Comment. The patient’s pain was likely due to the involuntary movements
in her neck on a background of some mild degenerative spine disease.
Rarely, some patients can develop spinal cord lesions from severe involuntary
neck movements. Patients often prefer to put up with some mild dyskinesia
rather than the PD symptoms. Ropinirole is likely exacerbating sleep
disturbances and causing increased eating, but she had previously had a
mild dopamine agonist withdrawal syndrome on trying to stop taking the
drug. Inner tremor is common in PD and often associated with anxiety.
KEY POINTS
h Early referral for deep disease progression.42 With STN DBS, taking levodopa-carbidopa gel possibly
brain stimulation in patients can reduce medication by linked to low vitamin B levels.46 Sup-
subjects not yet about 50%, with less reduction in plementation with vitamin B12 may be
optimized on medication following GPi DBS. The useful, although not yet proven. Infusion
medical therapies main concerns of surgery are cognitive of apomorphine has been available in
remains controversial. impairment and, as such, younger many countries as another means of
h Infusional therapies patients are more suitable. The clinical continuous dopaminergic stimula-
require nursing and care advantage of early referral for DBS tion. This method is not currently
support for patients with (average of 7.5 years disease duration) available in the United States and, to
advanced Parkinson remains unclear; in general, subjects date, there appears to be no advantage
disease and their need to have optimized medical thera- over levodopa infusion.
families, and pies prior to considering surgery.43
device-complications Advanced Parkinson Disease
Significant depression is also a contra-
are common. With Levodopa-Resistant
indication due to higher risk of suicide.
h Counseling patients that Motor Symptoms
Too-rapid reduction of medications
some symptoms postsurgery can also induce apathy Disease progression in PD involves
(eg, falling, dysphagia) and mood issues. A prior history of structures beyond the dopamine sys-
will not respond to a visual hallucinations can be a red flag for tem, including brainstem and cortical
higher dose of levodopa pending cognitive impairment, and pa- regions. As such, some symptoms are,
is important, and tients with reversible drug-induced vi- or can become, resistant to dopamine
nondrug management replacement therapy. Motor symp-
sual hallucinations should be carefully
strategies are far
evaluated. Rarely, lesioning, including toms that are often harder to treat due
more effective.
newer techniques under development, to poor response to levodopa include
such as focused ultrasound of the tremor, gait and balance with falling,
thalamus for tremor-dominant PD, is and speech issues. Thus, part of
used in certain clinical scenarios, such managing such symptoms includes
as in elderly patients in whom DBS is education of patients and families of
considered too high risk.44 limited benefit of current drugs and
Infusional levodopa/carbidopa in- the use of nonpharmacologic strate-
testinal gel. Infusional levodopa may
gies (eg, physical therapy and occu-
be useful in patients with advanced
pational and speech therapy).
PD who are considered poor surgical
Falls. Falls are common and fre-
candidates because of age constraints
quently multifactorial. A careful history,
or cognitive or behavioral concerns.45
Carbidopa/ levodopa (5 mg/mL/ with good collateral history, is therefore
20 mg/mL) in a stable methylcellulose always important.47 The major cause
gel is pumped through a gastrostomy of falls is postural instability, a disor-
tube with a jejunal extension. The pa- der of balance that becomes increas-
tient carries the pump. The infusion is ingly common with advancing disease
commenced during waking hours but duration. This can be tested in clinic
can be extended overnight if required with the pull test. A normal pull test is
for nocturnal symptoms. Additional one to two steps of retropulsion after
bolus doses can also be used. Technical a brief tug backward; always warn the
hardware complications associated with patient what you are going to do and
gastrostomy tube placement and its be prepared to catch them if they fall.48
chronic use are common (eg, infection, Slow, shuffling gait with short strides,
occlusion, or displacement). More re- reduced or absent arm swing, start
cently, there have been reports of hesitation, and freezing of gait often
Guillain-Barré syndromeYtype sub- accompany postural instability. Some
acute peripheral neuropathy in subjects patients fall because of dystonia/chorea
to antipsychotics. All these postural ab- monly used, such as Lee Silverman
normalities have a poor response to Voice Treatment.51 Simple measures
levodopa. The cause is unclear and may such as reading out loud and singing
be due to postural lean implicated in ab- can help patients with PD.
normal postural reflexes from PD, rigidity Refractory tremor. Drug-resistant
combined with dystonia, or a secondary tremor can be an issue throughout
myopathic process. Use of dopamine the course of PD. Levodopa may help
agonists has also been suggested as a but often high doses are required. Im-
cause, as improvements in posture have portantly, unlike all other parkinsonian
been reported when dopamine ago- features, the absence of a levodopa
nists have been stopped (Table 2-5). response does not predict a poor op-
Speech. The characteristic speech erative outcome if DBS is planned. A
disturbance in PD is low volume, mo- number of medical strategies using
notonous pitch, loss of prosody, impre- nondopaminergic therapies have
cise consonants, variability of rate, and been suggested (Table 2-5).
occasional bursts of rapid, unintelligible
speech (tachyphemia). Early in the CONCLUSION
disease, some features may improve Treatment of the motor symptoms of
with levodopa but over time become early PD is relatively straightforward given
less responsive. Speech therapy is com- the choices of medications available in
12. Parkinson Study Group. A controlled 22. Holloway RG, Shoulson I, Fahn S, et al.
trial of rasagiline in early Parkinson disease: Pramipexole vs levodopa as initial
the TEMPO Study. Arch Neurol 2002 treatment for Parkinson disease: a 4-year
Dec;59(12):1937Y1943. doi:10.1001/ randomized controlled trial. Arch Neurol
archneur.59.12.1937. 2004;61(7):1044Y1053. doi:10.1001/
13. Connolly BS, Lang AE. Pharmacological archneur.61.7.1044.
treatment of Parkinson disease: a review. 23. Hobson DE, Lang AE, Martin WR, et al.
JAMA 2014;311(16):1670Y1683. doi:10.1001/ Excessive daytime sleepiness and
jama.2014.3654. sudden-onset sleep in Parkinson disease: a
survey by the Canadian Movement Disorders
14. Barone P, Poewe W, Albrecht S, et al.
Pramipexole for the treatment of Group. JAMA 2002;287(4):455Y463.
depressive symptoms in patients with doi:10.1001/jama.287.4.455.
Parkinson’s disease: a randomised, 24. Kleiner-Fisman G, Fisman DN. Risk factors for
double-blind, placebo-controlled trial. the development of pedal edema in patients
Lancet Neurol 2010;9(6):573Y580. using pramipexole. Arch Neurol 2007;64(6):
doi:10.1016/S1474-4422(10)70106-X. 820Y824. doi:10.1001/archneur.64.6.noc60158.
15. Katzenschlager R, Sampaio C, Costa J, Lees A. 25. Weintraub D, David AS, Evans AH, et al.
Anticholinergics for symptomatic Clinical spectrum of impulse control
management of Parkinson’s disease. Cochrane disorders in Parkinson’s disease. Mov
Database Syst Rev 2003;(2):CD003735. Disord 2015;30(2):121Y127. doi:10.1002/
doi:10.1002/14651858.CD003735. mds.26016.
16. Wang Y, Xie CL, Wang WW, et al. Epidemiology 26. American Psychiatric Association. Diagnostic
of complementary and alternative medicine and statistical manual of mental disorders,
use in patients with Parkinson’s disease. J Clin fifth edition. Washington, DC: American
Neurosci 2013;20(8):1062Y1067. doi:10.1016/ Psychiatric Publishing, 2013.
j.jocn.2012.10.022. 27. Storch A, Schneider CB, Wolz M, et al.
17. Suchowersky O, Gronseth G, Perlmutter J, Nonmotor fluctuations in Parkinson disease:
et al. Practice parameter: neuroprotective severity and correlation with motor
strategies and alternative therapies complications. Neurology 2013;80(9):800Y809.
for Parkinson disease (an evidence-based doi:10.1212/WNL.0b013e318285c0ed.
review): report of the Quality Standards 28. Ahlskog JE, Muenter MD. Frequency of
Subcommittee of the American Academy levodopa-related dyskinesias and motor
of Neurology. Neurology 2006; fluctuations as estimated from the cumulative
66(7):976Y982. doi:10.1212/01.wnl. literature. Mov Disord 2001;16(3):448Y458.
0000206363.57955.1b. doi:10.1002/mds.1090.
18. Ni X, Liu S, Lu F, et al. Efficacy and safety 29. Cilia R, Akpalu A, Sarfo FS, et al. The modern
of Tai Chi for Parkinson’s disease: a pre-levodopa era of Parkinson’s disease:
systematic review and meta-analysis of insights into motor complications from
randomized controlled trials. PLoS One sub-Saharan Africa. Brain 2014;137(pt 10):
2014;9(6):e99377. doi:10.1371/journal. 2731Y2734. doi:10.1093/brain/awu195.
pone.0099377. 30. Scott NW, Macleod AD, Counsell CE. Motor
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Active-assisted cycling improves tremor and disease cohort. Eur J Neurol 2016;
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Neuropsychiatric Issues
Address correspondence to
Dr Jennifer G. Goldman, Rush
University Medical Center,
Department of Neurological
Sciences, 1725 W Harrison St,
Suite 755, Chicago, IL 60612,
Jennifer_Goldman@rush.edu.
in Parkinson Disease
Relationship disclosure: Jennifer G. Goldman, MD, MS, FAAN
Dr Goldman has received
personal compensation for
serving as a consultant for
Acadia Pharmaceuticals Inc, ABSTRACT
Pfizer Inc, and Teva
Pharmaceutical Industries Ltd. Purpose of Review: This article reviews the recognition and management of
Dr Goldman receives research neuropsychiatric issues in Parkinson disease (PD), including mood disorders,
support from Acadia cognitive impairment, and behavioral disturbances.
Pharmaceuticals Inc, Biotie
Therapies, the Michael J. Fox Recent Findings: Patients with PD frequently develop neuropsychiatric issues, and
Foundation, the National these issues can greatly affect their quality of life. In recent years, mood, cognitive, and
Institute of Neurological behavioral issues in PD have received greater recognition, with increasing atten-
Disorders and Stroke/National
Institutes of Health, and Teva tion directed toward improved screening and therapeutic interventions for symptom-
Pharmaceutical Industries Ltd. atic treatment. Taken together as a group, neuropsychiatric issues can be found
Unlabeled Use of throughout the whole course of PD, from early in the disease, potentially even in
Products/Investigational
Use Disclosure:
a premotor stage, to the time of diagnosis and later in the course with more
Dr Goldman discusses the advanced disease.
unlabeled/investigational use Summary: In the comprehensive care of patients with PD, recognition of
of antidepressants,
antipsychotics, anxiolytics,
neuropsychiatric issues is critical. Advances in therapeutics for the different neuropsy-
and cognitive impairment chiatric symptoms are still needed, although several pharmacologic and
medications for the treatment nonpharmacologic options are available. Patient management frequently requires a
of Parkinson disease, none of
which are approved by the US
multidisciplinary approach, with collaboration of neurologists with neuropsychologists,
Food and Drug Administration psychologists, psychiatrists, and other health professionals.
except rivastigmine.
* 2016 American Academy Continuum (Minneap Minn) 2016;22(4):1086–1103.
of Neurology.
KEY POINTS
h It is important to ask and daily function. Neurobiological and ing overlapping symptoms (PD versus
patients with Parkinson epidemiologic data support the hypoth- depression, depression versus apathy),
disease about esis that depression, along with anxiety, difficulty in assessing cognitively im-
depressive symptoms, may represent a prodromal feature of paired patients with PD, differences in
even when mild in PD. Consistent with the hypothesized depression in PD versus the general
severity, as well as about pathologic Braak staging of PD, de- population, different purposes of the
symptoms pression and anxiety may reflect brain- scales, lack of collateral information re-
of hopelessness stem degeneration affecting the locus quired, and failure to specify the timing
and suicidality. coeruleus and dorsal raphe nuclei and of the assessment, in particular in rela-
h Depression in Parkinson resultant noradrenergic and seroto- tion to PD medications. Despite these
disease may also occur nergic dysfunction, which may occur concerns, the task force recommended
as a nonmotor even prior to motor dysfunction. Epi- the Hamilton Depression Scale, Beck
fluctuation or off period demiologic studies support an over two- Depression Inventory, Hospital Anxiety
phenomenon, which fold increased prevalence of depression and Depression Scale, MontgomeryY
necessitates management
diagnosis in patients later diagnosed )sberg Depression Rating Scale, and
strategies that target
with PD.9 Depression is also commonly Geriatric Depression Scale for screen-
cyclical fluctuations.
reported in early, de novo, or untreated ing purposes and the Hamilton Depres-
h Treatment of Parkinson patients with PD, along with other non- sion Scale, Beck Depression Inventory,
disease depression, as
motor symptoms and neuropsychiatric MontgomeryY)sberg Depression Rat-
well as several other
issues, with de novo PD patients expe- ing Scale, and Zung Self-Rating Depres-
neuropsychiatric issues
in Parkinson disease,
riencing significantly more depression, sion Scale for severity measurements.
involves both fatigue, apathy, and anxiety than healthy Treatment of PD depression involves
pharmacologic and controls at baseline and over 2 years of both pharmacologic and nonpharma-
nonpharmacologic follow-up.10 Depression may be associ- cologic approaches. The pharmacologic
strategies. ated with a number of PD-related fac- rationale is rooted in neurochemical al-
tors, such as longer disease duration, terations of serotonin, norepinephrine,
younger age at onset, worsened motor and, to some degree, dopamine, which
severity and motor complications, more are associated with depression. The
advanced disease stage, greater disabil- evidence base, however, is limited for
ity, and the postural instability gait antidepressants in PD because few large
disturbance phenotype, as well as other randomized double-blind placebo-
neuropsychiatric comorbidities affect- controlled studies have been con-
ing cognition, psychosis, and sleep.11 ducted.13,14 Selective serotonin reuptake
The clinical assessment for PD de- inhibitors (SSRIs) are frequently used
pression may incorporate interview since they are better tolerated than
questions, diagnostic clinical examina- other antidepressant classes, such as
tions and criteria, and self- or clinician- tricyclic antidepressants (TCAs). In the
administered depression rating scales Study of Antidepressants in Parkinson’s
for screening or measuring severity. An Disease comparing paroxetine, venlafax-
International Parkinson and Movement ine, and placebo, both drug treatment
Disorder Society (MDS) task force re- groups showed similar improvement
viewed depression rating scales in PD, in Hamilton Depression Scale scores
critiquing the scales’ psychometric prop- at 12 weeks.15 Two other randomized
erties, validation in PD populations, controlled trials compared SSRIs and
availability of cutoff scores for patients TCAs (one with desipramine versus
with and without PD, sensitivity to citalopram, the other with paroxetine
change, and inclusion of somatic and controlled release versus nortripty-
psychological items.12 Several problems line); in both studies, the drug treat-
with the scales were identified, includ- ment groups did better than placebo,
1088 www.ContinuumJournal.com August 2016
the disease course, from premotor An MDS task force reviewed anxiety
phases to advanced stages (Case 3-1). rating scales in PD, critiquing six scales
Anxiety also has been proposed as a risk in a similar manner to those reviewed
factor for PD, with a 1.5-fold increased for depression.25 None of the reviewed
risk of PD associated with phobic scales met the task force’s criteria for
anxiety and antianxiety medication pre- “recommended” but a few scales were
scriptions. The concept of a “PD per- classified as “suggested.” Among those
sonality type” that is more anxious, were the Beck Anxiety Inventory, Hos-
lower novelty seeking, and higher in pital Anxiety and Depression Scale,
harm avoidance has been proposed Zung Self-Rating Anxiety Scale, Anxiety
over the years.22 Compared to healthy Status Inventory, Spielberger State-
controls, early and de novo PD patients Trait Anxiety Inventory, and Hamilton
had more anxiety and worse health- Anxiety Rating Scale. Problems identi-
related quality of life.23 Anxiety symp- fied with the anxiety rating scales
toms have been endorsed by over 50% included substantial overlap (anxiety
of patients with PD on nonmotor symp- versus depressive symptoms, anxiety
tom surveys.24 versus motor and other PD symptoms)
Evaluations for anxiety in PD may and failure to capture episodic anxiety
incorporate interview questions, self- disturbances and the heterogeneity of
report or clinician-rated scales, and diag- anxiety disorders in PD (eg, general-
nostic clinical examinations and criteria. ized anxiety, panic attacks).
Case 3-1
A 68-year-old man presented with a 2-year history of a left hand resting
tremor, small handwriting, and shuffling gait. He reported having
increased anxiety that was unusual for him for several years prior to the
onset of motor symptoms. He also had developed insomnia and lost about
9 kg (20 lbs) over the past 3 years. He denied depressed mood or loss of
interest. Both he and his wife felt that he could not handle stress at work
as well as previously. His tremor was worse when he was anxious. He did
not take any medications. His examination revealed an anxious man with
normal cognition, moderate left hand resting tremor, mild postural and
action tremors (more so on the left), mild to moderate bradykinesia (more
so on the left), and a mildly slow gait with decreased left arm swing but no
postural instability.
Comment. This case demonstrates the typical features of early
idiopathic Parkinson disease (PD). This patient described new-onset anxiety
and stress prior to the onset of his motor symptoms. He did not endorse
depressive symptoms, although the clinician should inquire further about
depressed mood, loss of interest, and somatic and vegetative symptoms. Several
epidemiologic studies, along with Braak staging of PD neurodegeneration and
neurochemical alterations in brainstem areas, suggest that anxiety and
depressive symptoms may precede the onset of motor symptoms of PD. In some
patients with PD, such as this de novo PD patient, motor and mood symptoms
may respond to dopaminergic treatment. Selective serotonin reuptake
inhibitors (SSRIs) and judicious use of benzodiazepines may be used to
treat PD anxiety and may be needed in conjunction with dopaminergic
replacement therapies. It is not uncommon for a patient’s tremors to
worsen with anxiety or when under stress.
KEY POINTS
h In contrast to the (eg, executive function, visuospatial reasoning, visuospatial abilities, and
definition for Parkinson function) are affected, including be- praxis). Cognitive tests vary in their
disease dementia in the havioral problems (eg, psychosis, sleep sensitivity to PD cognitive deficits and
Diagnostic and Statistical disturbances, mood disturbances), optimal use (eg, screening, response to
Manual of Mental which are common in PD dementia. Pa- change or intervention). To date, no
Disorders, Fourth Edition, tients with parkinsonism who develop consensus exists regarding specific neu-
the International an early dementia (within 1 year of the ropsychological test batteries or even
Parkinson and Movement motor symptoms) are diagnosed as global tests, although the MDS PD-MCI
Disorder Society criteria having dementia with Lewy bodies, and PD dementia diagnostic criteria,
for Parkinson disease although this condition has overlap of along with reviews and literature, pro-
dementia propose that
neuropathology with PD dementia. vide recommendations for global and
memory does not have
Cognitive impairment in PD is associated domain-specific tests.
to be impaired in
Parkinson disease and
with poor outcomes, negatively impact- In the evaluation of patients with PD
that dementia can be ing patients’ quality of life, contributing to who have acute or new-onset cognitive
present if other cognitive morbidity and mortality, and increasing issues, infections (eg, urinary tract infec-
domains (eg, executive nursing home placement. Cognitive tion, pneumonia), metabolic derange-
function, visuospatial deficits, including PD-MCI, occur in de ments, dehydration, new neurologic
function) are affected novo PD patients with estimates of problems (eg, stroke, subdural hema-
and include behavioral about 20%.32Y34 Thus it is important toma), new medical problems (eg,
problems (eg, psychosis, to ask patients and caregivers about vitamin B12 deficiency, thyroid disor-
sleep disturbances, cognitive symptoms even at this early ders), and medication effects (eg, pain,
mood disturbances), stage. Neurochemical abnormalities in bladder, sedating medications) should
which are common
cholinergic, dopaminergic, serotoner- be excluded. It is important to inquire
in Parkinson
gic, and noradrenergic systems; neuro- about other comorbid neuropsychiat-
disease dementia.
pathologic changes with cortical, ric problems, including poor nighttime
h Patients with limbic, and brainstem Lewy bodies; sleep, excessive daytime sleepiness,
parkinsonism who
comorbid AD pathology and vascular psychosis, depression, anxiety, and ap-
develop an early
disease; biological markers including ge- athy, which may influence cognitive
dementia (within 1 year
of the motor symptoms)
netics such as "-synuclein duplication/ function. Medications, including PD
are diagnosed as having triplication, MAPT, GBA and APOE *4 medications such as anticholinergics
dementia with Lewy mutations; and comorbid nonmotor and dopamine agonists, should be care-
bodies, although it symptoms may influence phenotypic fully reviewed so that agents that may
has overlap differences and rates of cognitive de- contribute to impaired cognition, con-
of neuropathology cline.35 Risk factors for PD cognitive fusion, or sleepiness can be reduced or
with Parkinson impairment include older age, ad- discontinued. Clinical, laboratory, and
disease dementia. vanced disease, longer disease duration, imaging investigations should be or-
h Parkinson disease baseline cognitive impairment, and dered, as indicated. Management also
cognitive impairment is neuropsychiatric comorbidities (eg, includes addressing safety and driv-
associated with poor hallucinations and depression). ing issues.
outcomes, negatively Cognitive function in PD can be ex- Treatment trials for cognitive im-
impacting patients’ amined in numerous ways, ranging pairment in PD have primarily focused
quality of life, contributing from bedside tests by the clinician to on PD dementia but in recent years
to morbidity and
formal evaluations by a neuropsycholo- have also addressed PD-MCI or exec-
mortality, and increasing
gist. Cognition can be assessed globally utive dysfunction. Many of the trials
nursing home placement.
and with tests targeting individual have studied drugs developed for AD,
cognitive domains and functions (eg, such as cholinesterase inhibitors (eg,
orientation, attention, working mem- rivastigmine, donepezil, galantamine)
ory, processing speed, executive func- and the N-methyl-D-aspartate (NMDA)
tion, memory, language, abstract antagonist memantine.36 To date, only
1092 www.ContinuumJournal.com August 2016
KEY POINTS
h Apathy in Parkinson cortex).43 These include a reward Evaluation Scale, Apathy Scale, Apathy
disease may manifest as deficiency syndrome, depression, dys- Inventory, and Lille Apathy Rating Scale,
decreased goal-directed executive syndrome, and an auto- as well as single-item questions from
behaviors, loss of activation deficit in which patients lack the Unified PD Rating Scale and Neuro-
motivation, decreased spontaneous activation of mental pro- psychiatric Inventory.49 Of these, the
interest, or blunted cesses without external stimulation. Apathy Scale and Lille Apathy Rating
emotional responses. The prevalence of apathy ranges Scale were specifically developed for
h Proposed subdomains or from 15% to 75% depending on the PD and validated in PD populations,
types of apathy in PD population studied, with lower rates but only the Apathy Scale was recom-
Parkinson disease in early PD (20% to 36%) and higher mended by the task force. Problems
include: (1) a reward rates (over 60%) in more advanced PD. identified with apathy rating scales
deficiency syndrome in Apathy is also associated with poor out- included substantial overlap of apathy
which patients lack comes, decreased quality of life, and symptoms with depression, cognitive
emotional resonance, increased caregiver burden, similar to decline, and PD symptoms; lack of clear
(2) depression, (3)
many of the other neuropsychiatric definitions; failure of the scales to ad-
dysexecutive syndrome
symptoms encountered in PD. Thus it dress motor or nonmotor fluctuations
of cognitive deficits, and
(4) auto-activation deficit
is important to ask about apathy at all in PD; and limited clinimetric testing
in which patients stages of PD. In several de novo PD in PD.
lack spontaneous cohorts, apathy has been reported and, The pharmacologic treatment of
activation of mental in some, depressive symptoms, anhe- apathy has been anchored in medica-
processes without donia, and fatigue have also been tions for depression, dementia, or PD,
external stimulation. reported.46,47 In patients with more despite a limited evidence base.13 In
h Apathy is also associated advanced PD, apathy co-occurs with the context of comorbid depression or
with poor outcomes, cognitive impairment and dementia.45 dementia, management strategies may
decreased quality of life, Apathy may occur after DBS, often in need to address these issues. The use
and increased caregiver the first months to 1 year, and with- of antidepressants for PD apathy has
burden, similar to drawal of dopamine agonists may con- been reported mostly in case reports
many of the other tribute to postoperative apathy.48 with mixed outcomes. In a small
neuropsychiatric Several versions of diagnostic criteria randomized double-blind placebo-
symptoms encountered for apathy have been proposed over controlled trial of transdermal riva-
in Parkinson disease.
the years, with some defining a “pure” stigmine versus placebo in PD apathy
apathy syndrome distinct from de- without depression and dementia
pression or dementia. Others cover a (n = 31), a significant improvement
broader context, including comorbid in the Lille Apathy Rating Scale was
neuropsychiatric features; spanning seen after 6 months.50 Dopamine ago-
multiple neurodegenerative diseases; nists, particularly those with D2 and D3
or integrating apathy’s behavioral, receptor stimulation and involved in
cognitive, and emotional features.43 the “reward system,” have been studied
Recognition of apathy can also be chal- in PD apathy. In a randomized double-
lenging because of a lack of consensus blind placebo-controlled trial of
for diagnosis and its overlapping fea- piribedil in patients with PD with
tures with anhedonia, depression, and apathy who had DBS of the subtha-
cognitive impairment. Moreover, in the lamic nucleus (n = 37), significant
clinic, symptoms often are brought to improvement was shown in the
attention by the caregiver rather than Apathy Scale in the piribedil group
reported by the patient. Using method- with a trend toward improvement of
ology similar to other rating scale re- quality of life.51 Other dopamine ago-
views, an MDS task force reviewed nists have been studied in PD apathy
scales for apathy, including the Apathy in open-label studies or as secondary
1094 www.ContinuumJournal.com August 2016
neurobiology of PD. Patients with PD diction, and mood disorders, with one
who have impulse control disorders study detecting genetic polymorphisms
may have impaired decision making, in the D3 dopamine receptor (DRD3)
altered risk-reward processing, and cog- and glutamate ionotropic receptor
nitive and executive function deficits. NMDA type subunit 2B (GRIN2B) in
Neuroimaging studies suggest altered patients with PD with impulse control
dopaminergic binding, structural ab- disorders compared to those without
normalities, or disrupted networks in impulse control disorders.55
regions involved with cognitive pro- Impulse control disorders in PD are
cesses and reward (eg, ventral striatum, underrecognized, partly because of lack
orbitofrontal, anterior cingulate, and of routine screening; stigma or embar-
dorsolateral prefrontal cortex regions). rassment of symptoms; and limited
Genetic susceptibilities to impulse con- awareness of impulse control disorders
trol disorders have been considered and their association with dopami-
given their association with positive nergic medications by patients, care-
family histories of alcoholism, drug ad- givers, and health care providers.
Case 3-2
A 54-year-old woman with a 5-year history of Parkinson disease (PD)
with right arm and leg tremor and slowness came with her husband for
her clinic visit. She had been started on carbidopa/levodopa 25 mg/100 mg
initially since she was having marked tremor and difficulty at work, and
this dose was gradually increased to 8 tablets daily. She began to
develop wearing off between doses and then was started on ropinirole,
which helped her tremor, cramping, and slowness. She experienced some
anxiety when her medications were wearing off. However, she had
developed some sleepiness during the daytime and began to shop
compulsively in stores and online. She also bought lottery tickets. Her
husband was very concerned that she had exceeded their credit card limits
and that she could not focus on anything else. She felt embarrassed
about it but could not stop. Her examination revealed that she was very
mildly bradykinetic, without tremors or rigidity, and had mild to
moderate dyskinesia.
Comment. This case demonstrates a young-onset patient with PD who
has developed an impulse control disorder on high-dose levodopa and
a dopamine agonist. The impulse control disorder symptoms of compulsive
shopping and purchasing lottery tickets are disruptive and bothersome,
having personal and financial consequences in this patient. The patient was
embarrassed to discuss this. It is important for clinicians to educate patients
and caregivers about impulse control disorders and their association with
dopaminergic medications, particularly dopamine agonists, and to
inquire about these symptoms at clinic visits. Management strategies for
this patient involved reducing her ropinirole dose while monitoring for
reemergence of motor and neuropsychiatric symptoms. In addition, the
patient and her husband agreed to limit her access to money, computer time,
and lottery ticket stores. After discontinuation of her ropinirole, her
impulse control disorder symptoms resolved. She was managed on
carbidopa/levodopa with entacapone for several more years without
recurrence of her impulse control disorder before considering surgical
interventions for her PD motor symptoms.
KEY POINTS
h Illusions or studies, represent an important part of Simple hallucinations in PD lack form
misperceptions of real the PD psychosis spectrum. (eg, photopsia, flashes of light or color).
stimuli include the Most hallucinations in PD are visual, Complex hallucinations include clearly
interpretation of although they also can occur in audi- defined or formed visions that may take
inanimate objects as tory, tactile, olfactory, and gustatory the shape of animals, humans, or other
living beings (eg, a chair modalities. Illusions or mispercep- objects. Common complex visual hallu-
mistaken for a dog, a tions of real stimuli include the inter- cinations may include mice scurrying
lamppost mistaken pretation of inanimate objects as living on the floor; children playing in the
for a tree). beings (eg, a chair mistaken for a dog, house; or sometimes distorted, gro-
h Many, but not all, visual a lamppost mistaken for a tree). tesque, or bizarre figures. Many visual
hallucinations in “Presence” hallucinations evoke the hallucinations in PD are nonthreaten-
Parkinson disease are sense that someone is nearby when no ing, brief (lasting seconds to minutes),
nonthreatening, brief one is really there, whereas “passage” and worse at night or in instances of
(lasting seconds to hallucinations involve the sensation compromised or low vision.
minutes), and worse
of a person or animal passing in the Hallucinations in nonvisual modali-
at night or in instances
person’s peripheral visual field. These ties are frequently accompanied by
of compromised or
low vision.
minor hallucinations may not be trou- visual hallucinations and occur in
blesome for the patient or caregiver more advanced PD (Case 3-3). Once
and, thus, may not necessitate treat- present in multiple sensory modali-
ment interventions with antipsychotics. ties, a high risk exists of multimodal
Case 3-3
A 72-year-old man with a 6-year history of Parkinson disease (PD), with
bradykinesia, right hand resting tremor, occasional imbalance and
falls, and mild dyskinesia, reported the feeling of someone standing
behind him. He kept looking behind him, but found no one was there.
He was somewhat disturbed by this as it first began at night, but now also
occurred during the day. He had had fleeting shadows in his peripheral
vision for 1 year and intermittently saw furry animals scurrying across
the kitchen floor, which bothered him, as he kept his house neat and tidy.
He tried to reason with himself as he knew that the animals were not
really there. He was treated with five tablets of carbidopa/levodopa
25 mg/100 mg a day, pramipexole 1 mg 3 times a day, and amantadine
100 mg 3 times a day.
Comment. This case demonstrates psychosis in PD with illusions, passage
and presence hallucinations, and formed visual hallucinations. In this
case, the hallucinations initially occurred only at night but progressed to
daytime occurrence and more involved visual hallucinations. Hallucinations
in PD are often worse in settings of reduced sensory stimulation (eg,
low light, evening). This patient’s features suggest a progressive nature to
his course of hallucinations and are a potential harbinger of further
hallucinations. Since he is bothered by the hallucinations, an intervention
may be considered. The first consideration would likely be reducing or
discontinuing his amantadine or pramipexole dose. The timing of his
carbidopa/levodopa doses may also be adjusted to minimize doses in
the evening hours when psychosis may be worse. Adjustments to
dopaminergic medications may require careful balancing of motor and
nonmotor effects. Nonpharmacologic strategies, such as night-lights
in the house, may be helpful.
KEY POINT
h Causes of Parkinson psychosis may require cautious short- receptor 2A (5-HT2A) receptor inverse
disease psychosis may term use of low-dose benzodiazepines. agonist, recently demonstrated improve-
include dopaminergic Specific medical causes, such as infec- ment on the Scale for Assessment of
medication effects, but tions, should be treated. Non-PD med- Positive Symptoms for PD without wors-
other causes, such as ications with centrally acting properties ened parkinsonism in patients with PD
toxic-metabolic (eg, anticholinergics for bladder hyper- psychosis and was approved by the FDA
encephalopathy, urinary activity, TCAs for depression, benzodi- for treatment of PD psychosis in 2016.64
or pulmonary infections, azepines for anxiety or sleep, hypnotics Once antipsychotic therapy is initiated,
stroke, subdural for sleep, and opioids for pain) should continued treatment may be necessary
hematoma, or be reduced or stopped. Dopaminergic to maintain control of psychosis. Cho-
medication interactions,
medications for PD motor symptoms linesterase inhibitors may play a role in
should be excluded.
may need to be reduced or discon- the treatment of patients with PD who
tinued, in some cases while monitoring have dementia and hallucinations.
for worsened motor function.
Antipsychotic medications may be CONCLUSION
required for acute and chronic PD Neuropsychiatric issues in PD repre-
psychosis, particularly if dopaminergic sent a growing area of focus in the
medications cannot be reduced without multidisciplinary care of patients with
worsening parkinsonism. To date, few PD at all stages of their disease. While
randomized double-blind placebo- increased recognition of neuropsychi-
controlled trials of atypical antipsy- atric symptoms exists, there remains a
chotics in PD have been conducted.11 great need for patient, caregiver, and
Clozapine is supported by double- health care provider education; inquiry
blind placebo-controlled trials in about these symptoms at clinical visits;
PD demonstrating improvement in and development of assessment tools
psychosis without worsening of motor and rating scales. Advances are needed
function. However, its use requires for symptomatic treatment and disease-
blood count monitoring given the rare modifying agents.
idiosyncratic risk of agranulocytosis
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Treatment of Advanced
Address correspondence to
Dr Janis M. Miyasaki, 7-133
Clinical Sciences Building,
11350 83rd Ave, University of
Alberta, Edmonton, AB T6G
2G3, Canada,
miyasaki@ualberta.ca.
Parkinson Disease and
Relationship Disclosure:
Dr Miyasaki received personal
compensation as a consultant
Related Disorders
for Merz Pharma Group and
as a lecturer for Teva Janis M. Miyasaki, MD, MEd, FRCPC, FAAN
Pharmaceuticals Industries
Ltd, has received research/
grant support as principal
investigator of studies for
ABSTRACT
Parkinson Alberta and Purpose of Review: Parkinson disease often spans decades of a patient’s lifetime.
Patient-Centered Outcomes Over time, nonmotor symptoms predominate and may limit dopaminergic therapy.
Research Institute, and
receives royalties from Neurologists continue to play a vital role in treatment. In addition to balancing
UpToDate Inc. neurobehavioral complications of Parkinson disease with motor benefit, addressing
Unlabeled Use of nonmotor symptoms common in the advanced stage may improve quality of life
Products/Investigational
Use Disclosure:
and reduce symptom burden. Symptoms such as dysphagia, constipation, urinary
Dr Miyasaki reports dysfunction, orthostatic hypotension, and pain respond to nonpharmacologic and
no disclosure. pharmacologic therapies.
* 2016 American Academy Recent Findings: Evidence for treatment of many nonmotor symptoms is weak or
of Neurology.
lacking. The evidence for treatment of the atypical parkinsonian syndromes (pro-
gressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration) in
advanced stages is even more scant.
Summary: Engaging palliative care physicians in the joint care of patients can provide
patients with access to expertise in end-of-life issues. Neurologic illnesses have specific
hospice criteria to guide clinicians for referrals. Evidence supports that assisting patients
with advance directives can result in improved satisfaction with care and improved
quality of life in the last weeks of life. Neurologists can remain engaged in their
patients’ care throughout the course of illness.
a
TABLE 4-1 Stages of Hoehn and Yahr Scale
Follow-up Living
Study N= Period Alive Mortality Rate Independently Psychosis Choking
Hely et al, 136 20 years 36 3.1 times that of 3% 74% 48%
20087 age-matched controls
Auyeung 171 10 years 121 1.1 times that of 32% 60% 60%
et al, 20128 age-matched controls
Forsaa et al, 230 12 years 25 60%
20109
skilled nursing facility when a person patients’ needs, the available re-
is wheelchair dependent. Another con- sources in the system to support them
sideration is whether patients feel utility (eg, home care, hospice, day pro-
exists in continued connection. grams), and improve the safety and
Qualitative studies confirm that quality of patient care.
patients and caregivers feel alone in What does this mean for neurolo-
their struggle with PD, find the health gists caring for patients with PD?
care system confusing, and care is Giving information regarding what to
often provided in silos without com- expect in the next stage of illness is
munication between segments of the important for patients as they prepare
health care system, which is challeng- for their work, home, and family lives.
ing to navigate and financially For instance, patients with postural
straining.15Y17 One group proposed instability will require adjustments to
four stages for physicians to follow their home to reduce the risk of falls,
(Table 4-3).18 This framework empha- may require the use of a walker for
sizes the role of physician as educator safe ambulation, and may require a
and advocate and requires integration wheelchair for unpredictable or longer
of systems-based practice. That is, distances, which can be facilitated by a
neurologists need to be aware of their home safety assessment. The home
a
TABLE 4-3 Four Stages of Information Sharing in Parkinson Disease
a
Data from Liao YC, et al, J Neurosci Nurs.18 journals.lww.com/jnnonline/pages/articleviewer.aspx?
year=2013&issue=12000&article=00007&type=abstract.
Case 4-1
A 59-year-old man presented for an evaluation of his Parkinson disease
(PD). He had been diagnosed with PD 8 years ago and had retired from his
occupation as a store clerk 2 years ago due to disability from his PD. He
had difficulty giving the details of his medication history. He was
dyskinetic during the visit but described that he was in the “off” stage for
much of the day and wanted his medications significantly increased since
this had worked for him in the past. His wife stated that her husband was
often confused, did not seem to take his medications in a predictable
manner, often forgot doses, acted impulsively, and was very dyskinetic to
the point that he was off balance due to dyskinesia. She expressed that her
husband had not wanted her to accompany him to appointments in the
past, but she wanted information and to ensure that the information
given to the new neurologist was accurate.
Comment. It is possible to engage family members or spouses in the
interview process and maintain patient autonomy and dignity. Patients
may not have insight to their illness. Obtaining collateral history from
family members is important. Asking the patient’s permission to get the
spouse’s or family member’s viewpoint can allow valuable information to
surface. This can strengthen the physicianYfamily caregiver bond and
improve patient and caregiver care.
KEY POINT
h Assessing caregiver will observe and report dyskinesia or as advocates for patients remaining at
burden with the Zarit dystonia. Insights to cognitive func- home with support programs in place.
Burden Interview will tion, behavioral changes, or hopeless-
help identify those ness often originate from caregiver PALLIATIVE CARE APPROACH
caregivers requiring reports. In later stages, caregivers add The scenario in Case 4-2 is a common
assistance. Small care coordination to their role. They representation of patients who have
changes may enable must often assume decision making had PD for more than 10 years.3,4
patients to remain at and, therefore, are responsible for Cognitive decline and dementia can
home longer by engaging outside help, community result in antiparkinsonian medication
providing respite to organizations, and medical care for reduction. The presence of nonmotor
the caregiver.
the person with PD. Added to these symptoms presents a challenge to the
organizational tasks is the physical practitioner at this stage of illness.
burden of caring for someone requir- Explaining to families that neuro-
ing increasing assistance with activities behavioral symptoms are frequent
of daily living. Often, family caregivers consequences of neurodegenerative
are either spouses of a similar age with disease can help family members link
their own health and cognitive prob- patients’ inexplicable behavior to a neu-
lems or adult children with families to rologic diagnosis. Including spouses
raise in addition to providing care for and other family members as an impor-
their parent. Assessing caregiver strain tant part of the care team by eliciting
can help identify those patient- their observations and care goals can be
caregiver dyads requiring assistance. valuable in management of the disease.
A useful tool is the Zarit Burden In the author’s experience with the first
Interview.19,20 Items in the scale in- interdisciplinary neurologist-led pallia-
clude caregiving burden, anger, rela- tive care program for PD and related
tionships with others, fear for the disorders, families often were unaware
future, health of the caregiver, impact that in advanced stages they had a
on social life, privacy, financial strain, choice between optimal motor function
and other items reflecting strain. Care- or cognitive clarity or that this balancing
givers score items as never, sometimes, act would dominate future care conver-
quite frequently, and nearly always. sations. Additional discussion of the
Even minimal changes such as in- diagnosis and treatment of neuropsy-
home care by paid caregivers can chiatric complications of PD is discussed
provide welcome respite for the family. in the article “Neuropsychiatric Issues in
Continued contact with patients and Parkinson Disease” by Jennifer G.
families even when improvement is no Goldman, MD, MS, FAAN21 in this issue
longer the treatment goal can be valu- of Continuum.
able, and neurologists often have the Recently, palliative care approaches
best insights into the nature and degree to late-stage PD and parkinsonian
of disability of neurodegenerative dis- disorders have been implemented in
eases and can help educate the home earlier stages.20,22,23 Previous studies
care providers about the patients. have examined place of death and
Day programs can be helpful, partic- cause of death in PD.24,25 In brief, these
ularly if transportation to the program is studies demonstrate that the majority
available. Volunteer organizations can of patients die in an acute care hospi-
provide friendly visitors to intellectually tal, and few patients have discussions
challenge patients and provide care- with their physician regarding prefer-
givers with time away from the patient. ences for care delivery or place of
Neurologists can provide a valuable role death. Establishing palliative care for
PD can help treat patients and families tive is further affected by the admitting
in a holistic manner, focus on non- service for in-hospital care, with at least
motor symptoms, and establish pa- one study finding that surgical services
tients’ goals of care and their wishes were more likely to have an advance
regarding place of death. A formal directive determined at admission.27
palliative care team consists of physi- However, the correct documentation
cians, social workers, nurses, and spiri- of the presence of an advance directive
tual or pastoral care. However, many was zero out of 100 reviewed charts,28
aspects of palliative care can be incor- and another study indicated that phy-
porated into individual practice. Neu- sicians would disregard the patient’s
rologic follow-up does not need to end wishes in the face of a request by a
upon admission to a long-term care relative to continue resuscitation ef-
facility (Case 4-3). forts or intensive care treatment.29 A
Studies demonstrate that physicians’ further study found that of 306 study
initiation of the conversation, the pa- participants, only 25% had a durable
tient’s higher education level, and ex- power of attorney, and 15% had an
posure to advance directive campaigns advance directive.30 Although 74% of
positively influence patients to com- study participants felt that it was
plete an advance directive.26 Despite important to make their wishes
this, among those over 65 years of age known to their doctor, only 16% had
attending a tertiary care hospital, only done so. Discussing their wishes with
63% had completed an advance direc- family was important to 87% of par-
tive. Completion of an advance direc- ticipants, and 60% had done so.
KEY POINTS
h Advance care planning
or advance directives are Case 4-3
often completed by the A 79-year-old woman with a 6-year history of Parkinson disease presented
patient without a for follow-up. Her response to levodopa had been definite but modest and
physician providing complicated by dementia. She was on a complicated regimen of levodopa,
context for interventions quetiapine, midodrine, polyethylene glycol (PEG) 3350, and senna glycoside.
or the likelihood that an Her husband had recently passed away and her children were overwhelmed
intervention will help with her care. She was on a list for placement in a long-term care facility. Her
the patient meet their family asked if the patient could continue to see the neurologist for
care goals. Neurologists follow-up visits.
have the information Comment. This scenario is common. Although families may be willing
that can help patients and able to bring patients to appointments, the misconception often exists
make informed choices that visits to specialists must stop upon admission to long-term care facilities.
to complete their If the physician is willing, continuing to provide care for these patients offers
advance directives. the skilled nursing facilities or long-term care facilities with the opportunity to
h Advance directives learn about Parkinson disease and related disorders, the nuances of behavior
should be reviewed
changes, and how to appropriately manage medication changes. Patients
periodically. They are a
often speak of giving up their neurologist as the last of a long series of losses
living document that
for them and is one that they associate with abandonment and the time to
requires revision
give up hope.
according to the
patient’s condition Although some patients may fear related disorders are admitted to hos-
and experiences “death panels,” a study found that pital, and our experience of outcomes
with hospitalizations. patients with do not resuscitate orders from intensive care unit interven-
had better quality of life in the last tions is important to give perspec-
weeks of life than those requesting tive to patients and their families. An
intensive or invasive treatment.31 A advance directive or goals of care
study specifically for those with PD document should be viewed as a
found that patients consistently “living document” so that the conver-
overestimated the effectiveness of sation is reviewed periodically. Follow-
interventions such as cardiopulmo- ing recent hospitalizations, aspiration
nary resuscitation (CPR) and resusci- pneumonia or change in functional
tation and ventilation.32 If patients status are often good opportunities to
discussed advance directive planning reflect with the patient about their
with their physician, 72% chose pain goals of care.
and symptom management compared Beyond the role of helping patients
to 47% wishing CPR, 16% wishing with advance care planning, neurolo-
ventilator support, and 20% wanting gists can also play a role in their pal-
a feeding tube. Proxy decision makers liative care. Although palliative care is
often opted for more intensive in- often equated with imminent death,
terventions if the patient had not recent evidence demonstrates that
discussed wishes with them. The early palliative care in oncology pa-
authors of the study concluded that tients results in improved quality of
coordinating advance care planning life and prolonged survival.33 A trial of
with patients and families is more palliative care in patients with PD,
effective. Neurologists can and leaving referral open to those Hoehn
should play an active role in their and Yahr scale stage 3 or greater, with
patients’ decision making. Neurolo- caregiver strain or expressed desire to
gists are often the specialists called talk about advance directives, showed
upon when patients with PD and improved symptom burden using the
KEY POINTS
h Orthostatic hypotension hypotension are: first thing in the 600 mg 3 times a day. Common side
can lead to falls, morning, following meals, following effects include changing color of the
confusion, fatigue, sitting or lying for prolonged periods, urine; difficult, burning, or painful uri-
and shoulder pain in 30 minutes to 1 hour after levodopa or nation; and urinary frequency.
addition to syncope. dopaminergic medication dose, higher If patients develop supine hyperten-
h Appropriate goals for ambient temperatures, and following a sion at bedtime, first elevate the head
blood pressure are at warm or hot bath or shower. Appropri- of the bed at 30 degrees (ie, 4 inches)
least 90 mm Hg systolic ate goals for blood pressure are at least at night. If unsuccessful, medication
while standing and less 90 mm Hg systolic while standing and options are losartan 50 mg in the
than 180 mm Hg less than 180 mm Hg systolic supine. evening, nifedipine 30 mg at night,
systolic supine. Physical methods for orthostatic hypo- clonidine 0.1 mg to 0.2 mg at night, or
tension treatment have not been tested hydralazine 25 mg in the evening.37
in PD or related disorders but include Aspiration and choking on food or
an abdominal binder (which is essen- liquids is a burden for patients and
tially compression of the abdomen to families, resulting in fear of meal times
increase venous return and reduce and weight loss. Detecting aspiration
splanchnic-mesenteric pooling and is is challenging. A study of 35 patients
easier than compression stockings), with PD found 40% had swallowing
water bolus (two 8-oz glasses of cold complaints and 20% of patients had
water in rapid succession will raise airway food penetration on video-
systolic blood pressure by 20 mm Hg fluoroscopy.38 Of those without swal-
for 1 to 2 hours), contracting bilateral lowing complaints, 22% had evidence
groups of muscles for 30 seconds of aspiration on videofluoroscopy.
(crossing their legs and squeezing, Respiratory parameters for patients
standing on their toes or squeezing were impaired compared to controls.
their buttocks), and avoiding lying flat. Behavioral steps to improve swal-
If these fail, medications may be used. lowing include: removing distractions
Midodrine is a selective agonist at during meals (do not watch television
peripheral !1 receptors with a duration while eating), not talking while eating,
of 2 to 4 hours. The maximum dose is putting the fork or spoon down be-
10 mg 3 times a day (often 1 hour prior tween bites to reduce rushing food,
to meals, and no later than 6:00 PM). and clearing the mouth with small
Midodrine tablets come in 2.5 mg, amounts of water between each mouth-
5 mg, and 10 mg dosages. Fludrocor- ful. Mincing or pureeing foods can help,
tisone expands plasma volume and in- and patients should avoid foods with
creases sensitivity of !-adrenoceptors. multiple consistencies (soup or stews
Typical dose is 0.1 mg to 0.2 mg daily, with large solids), and ensure the chin
usually given in the morning. Potassium and neck are in a neutral position. Swal-
should be monitored as hypokalemia lowing exercises have been studied in
and constipation are common with flu- PD.39 These exercises focused on in-
drocortisone. At higher doses, corti- creasing the strength and range of
costeroidlike complications may occur. motion of the mouth, larynx, and
The newest addition to the arma- pharyngeal structures and coordination
mentarium of orthostatic hypotension between breathing and swallowing.
treatment is droxidopa, an oral norepi- Exercises were to be performed twice
nephrine precursor. Starting droxidopa a day, 5 days a week. Fifteen subjects
dose is 100 mg 3 times a day (avoiding demonstrated improved bolus control
3 hours prior to bedtime to reduce and swallow as well as reduced residue
supine hypertension) to a maximum of on structures following a swallow.
1112 www.ContinuumJournal.com August 2016
Disorder Guideline
Dementia Stage 7C or higher on the Functional Assessment Staging Test (FAST) scale
AND
One or more of the following in the past year: aspiration pneumonia,
pyelonephritis, septicemia, stage 3 or 4 pressure ulcers, recurrent fevers, other
conditions suggesting limited prognosis, or inability to maintain sufficient fluid/
caloric intake in past 6 months (10% weight loss or serum albumin G2.5 g/dL)
Stroke or coma Palliative Performance Scale score e40%
AND
Poor nutritional status with inability to maintain sufficient fluid/caloric
intake (10% weight loss in 6 months, 7.5% weight loss in 3 months,
serum albumin e2.5 g/dL, or pulmonary aspiration resistant to speech
therapy interventions)
Other neurologic disease Critically impaired breathing including dyspnea at rest, vital capacity
including amyotrophic G30%, oxygen need at rest, AND refusal of artificial ventilation
lateral sclerosis, Parkinson
OR
disease, muscular
dystrophy, myasthenia gravis, Rapid disease progression (to bed-bound status, unintelligible speech,
or multiple sclerosis need for pureed diet, and/or major assistance needed for activities of daily
living) with either:
Critical nutrition impairment in the prior year (inability to maintain
sufficient fluid/caloric intake, continuing weight loss, dehydration, AND
refusal of artificial feeding methods)
OR
Life-threatening complications in the prior year (recurrent aspiration
pneumonia, pyelonephritis, sepsis, recurrent fever, OR stage 3 or 4
pressure ulcers)
Generic criteria Terminal condition (can be multiple conditions)
AND
Rapid decline over past 3 to 6 months as evidenced by progression of
disease signs, symptoms, and test results; decline in Palliative Performance Scale
score e40%, and involuntary weight loss 910%, and/or serum albumin G2.5 g/dL
a
Reprinted with permission from Boersma I, et al, Neurology.23 B 2014 American Academy of Neurology. www.neurology.org/content/
83/6/561.full.
with diet and fluid intake with or tatic hypertrophy, the use of mir-
without abdominal massage. If neces- abegron can be effective without
sary, the use of PEG 3350 or PGB lowering blood pressure or causing
bisacodyl have been shown to be effec- delirium. Dysphagia with silent aspira-
tive. Urinary dysfunction is complex in tion is common in PD. Videofluoroscopy
PD. Urodynamics may be helpful to remains the gold standard for diagno-
determine which interventions will be sis of aspiration. Beyond dietary mo-
most helpful. For those with urinary dification and effective hand feeding,
frequency and urgency without pros- there are no effective treatments for
19. O’Rourke N, Tuokko HA. Psychometric technology. Am J Hosp Palliat Care 2009;26(4):
properties of an abridged version of The 270Y276. doi:10.1177/1049909109331886.
Zarit Burden Interview within a representative
31. Garrido MM, Balboni TA, Maciejewski PK,
Canadian caregiver sample. Gerontologist 2003;
et al. Quality of life and cost of care at the
43(1):121Y127. doi:10.1093/geront/43.1.121.
end of life: the role of advance directives.
20. Miyasaki JM, Kluger B. Palliative care for J Pain Symptom Manage 2015;49(5):828Y835.
Parkinson’s disease: has the time come? doi:10.1016/j.jpainsymman.2014.09.015.
Curr Neurol Neurosci Rep 2015;15(5):26.
32. Kwak J, Wallendal MS, Fritsch T, et al.
doi:10.1007/s11910-015-0542-4.
Advance care planning and proxy decision
21. Goldman JG. Neuropsychiatric issues in making for patients with advanced Parkinson
Parkinson disease. Continuum (Minneap disease. South Med J 2014;107(3):178Y185.
Minn) 2016;22(4 Movement doi:10.1097/SMJ.0000000000000075.
Disorders):1086Y1103.
33. Zimmermann C, Swami N, Krzyzanowska M,
22. Miyasaki JM, Long J, Mancini D, et al. et al. Early palliative care for patients with
Palliative care for advanced Parkinson advanced cancer: a cluster-randomised
disease: an interdisciplinary clinic and new controlled trial. Lancet 2014;383(9930):
scale, the ESAS-PD. Parkinsonism Relat 1721Y1730. doi:10.1016/S0140-6736(13)62416-2.
Disord 2012;18(suppl 3):S6YS9. doi:10.1016/
34. Zesiewicz TA, Sullivan KL, Arnulf I, et al.
j.parkreldis.2012.06.013.
Practice parameter: treatment of nonmotor
23. Boersma I, Miyasaki J, Kutner J, Kluger B. symptoms of Parkinson disease: report of
Palliative care and neurology: time for a the Quality Standards Subcommittee of the
paradigm shift. Neurology 2014;83(6): American Academy of Neurology. Neurology
561Y567. doi:10.1212/WNL.0000000000000674. 2010;74(11):924Y931. doi:10.1212/
WNL.0b013e3181d55f24.
24. Walker RW, Churm D, Dewhurst F, et al.
Palliative care in people with idiopathic 35. Zangaglia R, Martignoni E, Glorioso M, et al.
Parkinson’s disease who die in hospital. Macrogol for the treatment of constipation
BMJ Support Palliat Care 2014;4(1):64Y67. in Parkinson’s disease. A randomized
doi:10.1136/bmjspcare-2012-000412. placebo-controlled study. Mov Disord 2007;
22(9):1239Y1244. doi:10.1002/mds.21243.
25. Sleeman KE, Ho YK, Verne J, et al. Place
of death, and its relation with underlying 36. Coggrave M, Norton C, Cody JD.
cause of death, in Parkinson’s disease, Management of faecal incontinence and
motor neurone disease, and multiple sclerosis: constipation in adults with central
a population- based study. Palliat Med 2013; neurological diseases. Cochrane Database
27(9):840Y846. doi:10.1177/0269216313490436. Syst Rev 2014;1:CD002115. doi:10.1002/
14651858.CD002115.pub5.
26. Alano GJ, Pekmezaris R, Tai JY, et al. Factors
influencing older adults to complete advance 37. Low PA, Tomalia VA. Orthostatic hypotension:
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jcn.2015.11.3.220.
27. Anumobi E, Detweiler MB, Sethi R, et al.
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967Y974. doi:10.1111/imj.12550.
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Diagnostic Approach to
Address correspondence to
Dr Nikolaus R. McFarland, 1149
South Newell Dr, L3-100,
PO Box 100236, Gainesville,
b Multisystem Disease
Progressive supranuclear palsy
Corticobasal syndrome
Multiple system atrophy
Dementia with Lewy bodies
ParkinsonismYdementiaYamyotrophic lateral sclerosis
b Heredodegenerative Disorders
Huntington disease
Spinocerebellar ataxias (especially types 2, 3, and 17)
Wilson disease
Hereditary ceruloplasmin deficiency
Neuronal brain iron accumulation disorders (eg, PKAN2)
X-linked dystonia-parkinsonism (Lubag disease)
Gerstmann-Sträussler-Scheinker syndrome
Neuronal ceroid lipofuscinoses
Mitochondrial cytopathies
a
Modified with permission from Jankovic J, Lang AE, Saunders.1 B 2008 Saunders, an imprint
of Elsevier.
KEY POINT
h Key features of
progressive supranuclear
palsy include early gait
instability, unexplained
falls, supranuclear gaze
palsy, axial rigidity,
dysarthric speech,
and dementia.
parkinsonism, comprising about 5% to Gait instability and early falls are key
6% of those patients presenting with features of PSP and distinguish it from
parkinsonism. The estimated preva- other parkinsonian syndromes. Relative
lence and annual incidence of PSP is to other parkinsonian syndromes, falls
about 5 per 100,000 in individuals be- occur early, within the first year or two,
tween the ages of 50 and 99 years, but and often lead to significant injury and
is likely higher due to misdiagnosis and fractures.4 Gait in PSP is characteristically
underrecognition. The average age of stiff, broad based, with knees extended
onset is typically in the sixties (average and arms abducted. It is often described
age of 63 to 66 years), and the mean as clumsy like a ‘‘drunken sailor’’ or
survival from diagnosis is reported be- ‘‘dancing bear,’’ and includes large
tween 5 to 8 years. Hallmarks of the dis- lateral deviations and step asymmetry.
ease include prominent, early postural When turning, persons with PSP tend
instability, unexplained falls, vertical supra- to pivot rather than turn en bloc as is
nuclear palsy, and progressive dementia. more typical in PD. The cause of falls is
often multifactorial and includes axial unchecked sitting (falling into their
rigidity, bradykinesia, loss of postural chair) are also common.
reflexes, freezing, a visual-vestibular com- A key feature of PSP includes inabil-
ponent, and decreased insight. ‘‘Rocket ity to perform volitional saccades and
sign’’ occurs in patients with PSP who progressive supranuclear ophthalmo-
have lost insight into their postural paresis. Although limitation of upgaze
instability and ‘‘rocket’’ out of their is often described as a sign of PSP, it is
chair without assistance, resulting in a nonspecific and can be seen in other
high risk for falling. Retropulsion and neurodegenerative disorders as well
KEY POINTS
h Early signs of as in aging. Limitation of downgaze is thria that is often spastic or hypernasal,
supranuclear gaze most sensitive, and the syndrome hypokinetic, and monotonous. Speech
palsy in patients frequently progresses to include can be slow and can include stuttering,
with progressive upgaze and lateral gaze palsies. echolalia, and occasional involuntary
supranuclear palsy Slowed saccades and reduced optoki- vocalizations. An apraxia of phonation
include slowed vertical netic nystagmusVvertical more af- has also been reported. Most concern-
saccades and reduced fected than horizontalVare also ing, however, is progressive dysphagia
optokinetic nystagmus. frequently observed and are early pre- that can lead to aspiration, pneumonia,
Square-wave jerks, or dictors of progression to supranuclear and early death. As with other parkin-
minute saccadic eye gaze palsy. Another common finding is sonisms, mood disturbance is fre-
movements, may also
square-wave jerks, characterized by quently present and characterized by
be present, representing
rapid back and forth mini saccadic apathy, depression, or both.6 Disinhi-
fixation instability.
intrusions during fixation. Complete bition, dysphoria, anxiety, and irritabil-
h To assess for the gaze palsy and involuntary ocular ity are also possible. Emotional lability
applause sign, a clinician
fixation (as well as lack of eye blink) (also called emotional incontinence),
can demonstrate three
contribute to the classic ‘‘Mona Lisa’’ referred to as pseudobulbar affect, also
claps to the patient and
ask him or her to copy.
stare or stone face. Ability to overcome can occur and cause significant distress
The applause sign is gaze limitation with vestibular or for both the patient and caregivers.
present if the patient cervical-ocular reflex maneuvers de- PSP has the highest rate of pseudo-
claps more than fines supranuclear palsy, but can be bulbar laughing or crying across all
three times and difficult to assess in patients with PSP parkinsonian syndromes.7 Cognitive
continues (perseverates). who have significant axial rigidity. Visual decline and dementia occur with dis-
concerns are also common. Blurred ease progression. A frontal subcortical
vision occurs due to a combination of dementia is typical, with slowed pro-
factors including decreased blink and cessing, or bradyphrenia, reduced
tear production, drying of the cornea, verbal fluency, and executive dysfunc-
and ocular irritation. Diplopia is com- tion. In PSP there is often perseveration
mon not only in PSP but also in other of automatic behaviors, as exemplified
parkinsonisms and is most frequently by the three-clap test or applause sign.
due to convergence insufficiency. Read- (The clinician should demonstrate to
ing is affected and may be helped by the patient three claps and ask him or
prisms in select cases. Despite visual her to copy. The applause sign is pres-
aids, patients often continue to expe- ent if the patient claps more than three
rience blurred vision and difficulty scan- times and continues [perseverates]).
ning text due to progressive gaze palsy. Grasping, imitative behaviors may also
In addition, patients may also experience be present.
photosensitivity (wearing sunglasses
inside), decreased eye blink, blepharo- Diagnosis, Heterogeneity,
spasm, and eye-opening apraxia, leading and Progressive Supranuclear
to eyebrow furrowing (procerus con- Palsy Variants
traction), and vertical wrinkling of the In 1996 the National Institute of Neuro-
forehead, referred to as procerus sign.5 logical Disorders and Stroke (NINDS)
Additional symptoms include a char- and the Society for PSP (SPSP) inter-
acteristic facial appearance from the national workshop proposed criteria
rigid bradykinesia and dystonia in facial for the diagnosis of classic PSP
musculature. The hypertonic facial mus- (Richardson syndrome).8 The criteria
cles produce facial folds and a wor- for possible or probable PSP included
ried, astonished expression. Bulbar a progressive disorder with onset after
features include a progressive dysar- the age of 40 with postural instability,
1122 www.ContinuumJournal.com August 2016
Progressive Supranuclear
Palsy (PSP) Syndrome Clinical Features Regional Pathology
Classic PSP Early gait instability, falls, supranuclear Dentate nucleus, globus pallidus,
(Richardson syndrome) gaze palsy, axial rigidity, dysarthria, striatum, midbrain, and superior
dysphagia, progressive dementia cerebellar peduncle
PSP-parkinsonism Tremor, rigid bradykinesia, levodopa Substantia nigra, subthalamic nucleus
responsive,a late cognitive decline,
longer life expectancy (9 years)
PSPYpure akinesia with Early gait difficulty, freezing of Motor cortex, pons, cerebellum
gait freezing gait/motor block, micrographia, speech
impairment, hypophonia, longer
disease duration (11Y15 years)
PSPYcorticobasal syndrome Dystonia, dyspraxia, cortical sensory Frontal and parietal cortex
loss, apraxia of speech
PSPYbehavioral variant of Predominant cognitive, personality Frontotemporal cortex
frontotemporal dementia change, late parkinsonism
PSPYprimary lateral sclerosis Bulbar, limb weakness, upper motor Frontal predominant, corticospinal tract
neuron signs/spasticity
PSP-cerebellar Cerebellar ataxia Deep cerebellar nuclei
a
Levodopa response for PSP-parkinsonism wanes later in disease.
criteria are likely in the near future. dominance types and atypical PSP var-
In 2014, because of the overlap in fea- iants is ongoing.
tures, Respondek and colleagues10 Progressive supranuclear palsyY
proposed a more comprehensive parkinsonism. PSP-parkinsonism is
approach to describing the pheno- the most common variant of PSP with
typic spectrum of PSP based on the features of tremor, early asymmetric
predominant clinical feature seen bradykinesia, and axial rigidity that
within the first 2 years of presenta- mimic PD.11 As illustrated in Case 5-1,
tion. Predominance types were de- a striking feature is relatively normal
fined including classic Richardson eye movements early on, although
syndrome, postural instability predom- slowed saccades and reduced optoki-
inant, oculomotor predominant, Par- netic nystagmus may be present, sug-
kinsonism, CBS, FTD, and those gesting atypical disease. Patients are
unclassified. Validation of these pre- also frequently levodopa responsive,
Case 5-1
A 65-year-old man presented with a 5-year history of reported Parkinson
disease. He was diagnosed 2 years ago, but had noticed onset of a mild
right hand resting tremor 3 years earlier and progressive slowing and
stiffness of his right arm and gait. After his initial diagnosis, he was started
on carbidopa/levodopa 25 mg/100 mg with initial positive response.
However, gait instability progressed with onset of falls, slurred speech, and
mild dysphagia. His wife also noticed a progressive change in his facial
expression. He seemed to stare more and rarely initiated conversation.
On examination (Supplemental Digital Content 5-1, links.lww.com/
CONT/A178), he was fully oriented. His speech was hypophonic and dysarthric,
but language and cognition were preserved. His facial expression was
masked, and he tended to squint. Vertical saccades (upgaze and downgaze)
were reduced, and horizontal saccades were slowed. Off levodopa he had
moderate bradykinesia of hand movements, finger tapping, and rigidity in
the limbs, on the right more than the left. Mild left hand dystonic posturing
was also noted. He had marked neck rigidity, and he found it difficult to
achieve full range of motion. He stood without assistance, and his gait was
stooped, slow, and his stance was narrowed and unstable with a tendency to
hold onto the examiner or walls. Pull test revealed minimal to no compensation.
He would have fallen if not caught. Brain MRI was notable for age-related
cerebral atrophy and mild prominence of basal cisterns. Further increase in
carbidopa/levodopa dose was unhelpful. A year later, he continued to slow
in all of his movements, his dysarthria worsened, and his vertical gaze
palsy became more apparent. A diagnosis of progressive supranuclear
palsyYparkinsonism was suspected.
Comment. This case illustrates several features suggestive of probable
progressive supranuclear palsyYparkinsonism. Early on, the patient’s
features were typical of Parkinson disease, including tremor, asymmetric
rigid bradykinesia, and response to levodopa. Later, he developed
oculomotor abnormalities, bulbar features (eg, dysarthria, mild dysphagia),
increased postural instability, and waning levodopa response. There is an
increased awareness of levodopa-responsive cases of progressive supranuclear
palsy, especially early in the disease course.
microtubules. The protein has six Brain imaging such as MRI, however,
isoforms based on splice variants, in- remains most helpful. In PSP, atrophy
cluding three or four microtubule bind- of the midbrain and superior cerebel-
ing repeat (R) domains. In PSP the 4R:3R lar peduncles can help distinguish PSP
tau ratio in brain is increased (lower in from other neurodegenerative disor-
PSP-parkinsonism) compared to con- ders. Measurement of suprapontine an-
trols. By contrast, the opposite is ob- teroposterior diameter with MRI has
served in FTD. Although MAPT is not been used for analyzing midbrain atro-
mutated in sporadic PSP, it is closely phy, but remains controversial. Another
linked to parkinsonisms including PSP. proposed method of assessing mid-
Mutation in MAPT is most commonly brain atrophy is by measurement of
associated with FTD with parkinsonism the midsagittal area of the midbrain
linked to chromosome 17 (FTDP-17). tegmentum and ratio to area of the
A recent genome-wide association study pons, which is significantly reduced in
was performed and identified three ad- PSP compared to that in PD, MSA-
ditional putative genes associated with parkinsonism, and healthy controls.22
PSP: STX6 (encodes syntaxin 6), EIF2AK3 As a result, the brainstem is often
(PERK, which involves the endoplasmic beaked and takes on the appearance
reticulum unfolded response pathway), of a hummingbird or penguin body
and MOBP (myelin-associated oligoden-
(Figure 5-4). The width of the supe-
drocytic basic protein, which is concen-
rior versus the middle cerebral peduncle
trated in pathologic regions).21
has also been used.23 Diffusion-tensor
Diagnostics imaging (DTI) shows both gray and
To date there is no available blood, CSF, white matter reduction, with predilec-
or single imaging marker for PSP. tion for the anterior and medial thalamic
KEY POINTS
h Levodopa therapy be carefully approached and discussed antidepressant, or an SSRI may be help-
should be tried in most as it raises ethical, cultural, and personal ful. Treatments for other symptoms are
progressive supranuclear considerations regarding quality of summarized in Table 5-5.
palsy cases, with a life. A social worker or case manager
levodopa dose of up to is often critical to help family and care- CORTICOBASAL DEGENERATION
1200 mg/d in divided givers plan for care needs. Palliative CBD is an atypical parkinsonian syn-
doses as tolerated. Partial care also should be considered, and drome with predominant involvement
response is possible in frank discussion of advance directives of the cortex and basal ganglia that
early progressive should be pursued. presents with varied phenotypes.
supranuclear palsy, Although no one medication treats The classic presentation with asym-
particularly in progressive
all the symptoms of PSP, specific treat- metric rigidity, dystonia, and ideomo-
supranuclear
ments may be helpful. For parkinson- tor apraxia is now referred to as CBS,
palsyYparkinsonism.
ism, a levodopa trial up to 1200 mg/d but CBD is increasingly also recognized
h The most common (up to 300 mg per dose if it can be to present with features that may over-
presenting features for
tolerated) for 1 month is recommended lap with FTD, primary progressive
corticobasal degeneration
to determine responsiveness. PSP- aphasia, Alzheimer disease, posterior
are asymmetric hand
clumsiness or apraxia
parkinsonism in particular is often levo- cortical atrophy, and PSP. Typically,
followed by early dopa responsive initially and contrasts marked asymmetry of involvement is
bradykinesia, frontal with that observed in classic Richardson the most striking feature and helps dif-
syndrome, tremor, syndrome and other variants. Dopa- ferentiate CBD from other degenerative
and rigidity. mine agonists, however, often provide disorders. The most common present-
minimal benefit. Amantadine has been ing feature is asymmetric hand clumsi-
reported to have benefit for gait and ness followed by early bradykinesia, a
dysphagia, but studies to support this frontal syndrome, tremor, and rigidity.30
treatment have been limited.27 Anticho- The mean onset of disease occurs in the
linergics should be avoided due to the sixth decade, and prognosis is generally
potential for confusion. Coenzyme Q10 poor with a mean survival of about
is a well-tolerated supplement and has 7 years from diagnosis. Typical features
recently been shown in a small ran- include marked asymmetry, focal ri-
domized clinical trial to provide mod- gidity, coarse rest/action tremor, limb
est benefit in PSP, including slight dystonia (followed by contractures),
improvement in cognitive function.28 alien limb phenomenon, hand, limb,
Painful dystonic posturing of the neck gait, or speech apraxia, myoclonus, cor-
and limbs, blepharospasm, and eye- tical sensory loss, language deficits,
opening apraxia may be treated with frontal/cortical dementia, oculomotor
botulinum toxin. For cognitive decline dysfunction (gaze palsy, impaired con-
and dementia, cholinesterase inhibi- vergence), bulbar impairment, postural
tors such as rivastigmine may provide instability, gait difficulty, hyperreflexia,
modest benefit. Mood disturbance in- and extensor plantar response. Poor
cluding depression, anxiety, and irrita- levodopa response tends to occur, but
bility should be identified and treated high-dose trials are warranted early in
with antidepressants. For apathy, acti- the disease as in PSP (levodopa dose of
vating antidepressants such as bupro- up to 1200 mg/d for 2 to 3 months as
pion, venlafaxine, sertraline, and tolerated) and sometimes provide par-
fluoxetine are preferred over other se- tial benefit. Case 5-2 illustrates a typical
lective serotonin reuptake inhibitors case of CBS.
(SSRIs), which may worsen apathy. If Ideomotor apraxia, myoclonus,
pseudobulbar affect is marked, asymmetric rigid-bradykinetic syndrome,
dextromethorphan-quinidine, a tricyclic and later-onset gait/balance disturbance
1128 www.ContinuumJournal.com August 2016
have been reported as the best pre- certain task (eg, use a screwdriver or
dictors for CBS diagnosis.31 Ideomotor cut with a pair of scissors). This type of
apraxia is defined by an inability to apraxia can be difficult to distinguish
perform a skilled motor task despite from limb-kinetic apraxia, which is
having intact language, motor, and frequently seen in parkinsonisms, but
sensory function. Examples include in- is independent of modality (imitation
ability to imitate gestures or mime a versus miming). Peculiar to CBS, alien
KEY POINT
h Ideomotor apraxia is
defined by an inability to
Case 5-2
An 80-year-old right-handed man with history of hypertension, prostatic
perform a skilled
hypertrophy, and deep venous thrombosis presented with symptoms of
motor task despite having
progressive gait difficulty, falls, increasing fatigue, tremulousness, and left
intact language, motor,
hand dysfunction that he had experienced over the past 2 years. The
and sensory function.
patient’s wife reported that his gait and movement had slowed several
Examples include inability
years prior, but had worsened further in the setting of deep venous
to imitate gestures or
thrombosis and leg edema. Recently, he had begun dragging his left leg
mime a certain task (eg,
more. The patient noted increasing stiffness in his left arm and tended to
use a screwdriver or cut
hold it flexed at his side. He felt that his symptoms were beginning to
with a pair of scissors).
spread to his right side and reported symptoms of micrographia.
This type of apraxia can
Additional symptoms included hoarse, slowed speech, a decrease in facial
be difficult to distinguish
expression, and mild difficulty swallowing. If he ate too quickly he would
from limb-kinetic apraxia,
hiccup, and swallowing pills had become difficult. The patient denied
which is frequently seen
changes in cognition, memory, or mood. He had previously been evaluated
in parkinsonisms, but is
by a local neurologist, diagnosed with parkinsonism, and treated with a
independent of modality
dopamine agonist with some subjective symptomatic benefit. The addition
(imitation versus miming).
of carbidopa/levodopa did not provide additional benefit.
On examination (Supplemental Digital Content 5-2, links.lww.com/
CONT/A204), the patient was fully oriented but displayed mild disorganized
thought processes, and his cognition and language were otherwise intact.
The patient’s speech was characterized by mild hypokinetic dysarthria.
He had slight facial hypomimia, reduced vertical saccades, and slowed
optokinetic nystagmus. His left upper extremity tone was rigid, and he tended
to hold the arm flexed at his side, but without tremor. Ideomotor apraxia
and reduced graphesthesia were noted in his left hand, but no neglect. The
patient’s gait was slow and stiff with the left arm held flexed, and his left leg
dragged. Postural reflex was reduced on pull testing. Review of his brain MRI
suggested possible asymmetric cerebral atrophy, right greater than left, and
‘‘beaking’’ of his midbrain.
After his initial presentation, the patient’s symptoms rapidly progressed
with increasing left-sided rigidity, dystonic posturing, alien limb
phenomenon, limb-kinetic apraxia, and cortical sensory deficits. He had
increasing symptoms of vertical gaze palsy, gait difficulty, falls, and he
required a wheelchair and assistance with activities of daily living. His speech
remained mildly dysarthric, but was characterized by some grandiosity and
nonsensical statements. He remained on a dopamine agonist (due to
subjective benefit over levodopa) and received botulinum toxin injections
for left upper extremity dystonia and mild antecollis.
Comment. This case demonstrates progressive asymmetric limb
dysfunction, rigid bradykinesia, dystonia, apraxia, and cortical sensory
deficits consistent with probable corticobasal syndrome. Later progression
of cognitive deficits, axial rigidity, falls, and supranuclear palsy raise the
possibility of a corticobasalYprogressive supranuclear palsy syndrome.
a
TABLE 5-6 Corticobasal Syndrome Phenotypes
addition to the cortex, includes the basal PSP, rehabilitative services and mul-
ganglia, thalamus, substantia nigra, sub- tidisciplinary approaches are critical to
thalamic nucleus, and red nucleus. Path- maintain function as long as possible
ologic diagnosis is characterized by despite progressive decline. Regular
widespread but topographic deposi- exercise and activity early in the dis-
tion of 4R-predominant, hyperpho- ease are most beneficial and may delay
sphorylated tau in neurons and glia, disability. Despite the limitations in
astrocytic plaques, and corticobasal in- treatment, a levodopa dose trial up to
clusions.35 In subcortical nuclei, such 800 mg/d to 1200 mg/d should be at-
as the substantia nigra, intranuclear in- tempted; however, dopaminergic ther-
clusions are reminiscent of globose apy rarely provides improvement and
neurofibrillary tangles, but those in may induce dyskinesia or intolerance.
cortex are granular, crescent shaped, Clonazepam or levetiracetam may im-
or globular.36 Ballooned neurons with prove myoclonus, and muscle relaxants
diffuse cytoplasmic immunoreactivity (eg, baclofen) and botulinum toxin can
to !"-crystallin and ubiquitin are com- help painful rigidity and dystonic con-
mon, but not specific to CBD. ‘‘Coiled tractures that limit function. Experi-
bodies’’ are frequent in oligodendrog- mental therapeutics have focused on
lia, but, unlike PSP, tufted astrocytes tau pathology (see previous section on
are absent. PSP therapeutics).
Therapeutic Strategies
Treatment in MSA focuses mainly on
supportive therapy and should involve
allied health care and rehabilitation
services because of the multisystem
nature of disease. Some 30% to 60% of
patients with MSA initially respond to
dopaminergic therapy. In the absence
of other treatments, a trial of up to
1000 mg/d to 1200 mg/d of levodopa
(300 mg per dose if tolerated) for a
period of 3 months is supported and
FIGURE 5-5 Glial cytoplasmic inclusions in multiple system
atrophy. Oligodendroglial cytoplasmic inclusions is the mainstay of initial therapy for
here are stained with antibody to human parkinsonism in MSA. Dopamine ago-
!-synuclein.
nists, because of autonomic and other
issues, are generally inferior to levodopa
images in a hot cross bunYlike pattern. for MSA and have not been studied
Additionally, PET scans often show carefully in this setting. The challenge is
decreased striatal and frontal metabo- to balance the benefits of therapy with
lism. DAT (125I-ioflupane) SPECT also the development of motor complica-
typically shows asymmetric reduced tions that may appear earlier in MSA as
striatal binding.46 Autonomic testing also compared to classic PD. These MSA fea-
can be helpful and include tilt-table tures include dyskinesia, frequently in-
testing, 24-hour ambulatory blood volving the jaw and face, and orthostatic
pressure and heart rate monitoring, hypotension. Alternative therapies such
and baroreceptor sensitivity (ie, the as deep brain stimulation are not recom-
baroreflex mechanism or ability to mended due to poor response.
regulate blood pressure by controlling Autonomic symptoms such as ortho-
heart rate, contractility, and peripheral static hypotension are treated first with
resistance) for orthostatic hypotension. conservative measures including oral
In the office, testing should include hydration, increased salt intake, and
supine blood pressure with heart rate, compression stockings or abdominal
then standing blood pressure and binder. If still symptomatic, pharmaco-
heart rate after 3 minutes. A drop in logic therapy with fludrocortisone or
systolic blood pressure of more than desmopressin, which increase blood
20 mm Hg or drop in diastolic blood volume, may be helpful but are con-
pressure of more than 10 mm Hg with traindicated in patients with heart fail-
minimal rise in heart rate is diagnostic. ure. Midodrine, an !1 agonist, can also
Other tests may include sweat testing be used but has the potential to cause
(eg, quantitative sudomotor axon reflex supine hypertension. Recently, the US
test [QSART]) and gastric emptying study Food and Drug Administration (FDA)
(for gastroparesis), and urodyamics for approved the use of droxidopa for
1136 www.ContinuumJournal.com August 2016
FIGURE 5-6 Axial T2-weighted MRI of a patient with multiple system atrophyYparkinsonian type
demonstrating slitlike hyperintensity (A, arrows) at the rim of the right putamen,
fluid-attenuated inversion recovery (FLAIR) hypointensity of posterior putamen (B,
arrows), and typical hot cross bun sign representing atrophy and gliosis of the pons (C).
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Imaging correlates of pathology in archneur.65.8.1074.
corticobasal syndrome. Neurology
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2010;75(21):1879Y1887. doi:10.1212/
Alpha-synuclein cortical Lewy bodies
WNL.0b013e3181feb2e8.
correlate with dementia in Parkinson’s
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of tauopathies in neurodegenerative
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dementias. Alzheimers Res Ther 2014;
Cognitive status correlates with
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neuropathologic stage in Parkinson disease.
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Multiple system atrophy: an update. Lancet doi:10.1212/01.WNL.0000158422.41380.82.
Neurol 2009;8(12):1172Y1178. doi:10.1016/
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40. Köllensperger M, Geser F, Seppi K, et al. Int J Geriatr Psychiatry 2012;27(5):443Y453.
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Disord 2008;23(8):1093Y1099. doi:10.1002/
52. Graff-Radford J, Murray ME, Lowe VJ,
mds.21992.
et al. Dementia with Lewy bodies: basis
41. Jecmenica-Lukic M, Poewe W, Tolosa E, of cingulate island sign. Neurology
Wenning GK. Premotor signs and symptoms 2014;83(9):801Y809. doi: 10.1212/
of multiple system atrophy. Lancet Neurol WNL.0000000000000734.
2012;11(4):361Y368. doi:10.1016/ 53. Gomperts SN, Rentz DM, Moran E,
S1474-4422(12)70022-4. et al. Imaging amyloid deposition in Lewy
42. Köllensperger M, Geser F, Ndayisaba JP, et al. body diseases. Neurology 2008;71(12):
Presentation, diagnosis, and management of 903Y910. doi:10.1212/01.wnl.
multiple system atrophy in Europe: final 0000326146.60732.d6.
analysis of the European multiple system 54. Mollenhauer B, Bibl M, Trenkwalder C, et al.
atrophy registry. Mov Disord 2010;25(15): Follow-up investigations in cerebrospinal
2604Y2612. doi:10.1002/mds.23192. fluid of patients with dementia with Lewy
43. Brown RG, Lacomblez L, Landwehrmeyer BG, bodies and Alzheimer’s disease. J Neural
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multiple system atrophy and progressive doi:10.1007/s00702-004-0235-7.
supranuclear palsy. Brain 2010;133(pt 8): 55. Hack N, Fayad SM, Monari EH, et al.
2382Y2393. doi:10.1093/brain/awq158. An eight-year clinic experience with
44. Ahmed Z, Asi YT, Sailer A, et al. The clozapine use in a Parkinson’s disease
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Neuropathol Appl Neurobiol 2012;38(1):
56. Cummings J, Isaacson S, Mills R, et al.
4Y24. doi:10.1111/j.1365-2990.2011.01234.x.
Pimavanserin for patients with Parkinson’s
45. Wenning GK, Jellinger KA. The role of disease psychosis: a randomised,
alpha-synuclein in the pathogenesis of placebo-controlled phase 3 trial. Lancet
multiple system atrophy. Acta Neuropathol 2014;383(9916):533Y540. doi:10.1016/
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s00401-004-0935-y.
57. Rolinski M, Fox C, Maidment I, McShane R.
46. Perju-Dumbrava LD, Kovacs GG, Pirker S, Cholinesterase inhibitors for dementia with
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14651858.CD006504.pub2.
47. McKeith IG, Dickson DW, Lowe J, et al.
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Diagnosis and
Address correspondence to
Dr Elan D. Louis, Yale School
of Medicine, Department of
Neurology, LCI 710, 15 York St,
KEY POINT
h Tremors are rhythmic a neurologic examination followed by focused neurologic examination. First,
oscillations of a diagnosis and, ultimately, treatment. the examiner should try to elicit postural
body part. tremor in the arms (ie, tremor observed
APPROACH TO THE PATIENT during sustained arm extension). The
WITH TREMOR examiner should assess the following
The approach to the patient with tremor, features about the postural tremor:
as with any neurologic patient, begins & Are the movements regularly
with a history and then includes a neu- recurrent and oscillatory?
rologic examination. & Across which joints are the
movements occurring and in
Medical History what directions?
The first step is to elicit a medical his- & Are the tremors in each arm
tory. This history should include an occurring synchronously (ie,
initial set of questions used to determine in phase)?
whether the patient has an action or a & Does the postural tremor have a
resting tremor. Open-ended questions reemergent quality (ie, is it
such as, ‘‘What type of tremor do you initially absent)?
have?’’ may be followed by a series of & Is the tremor accompanied by
more specific questions about tremor abnormal postures in the same
such as, ‘‘Do you have your tremor when limb (eg, flexed posturing or
you are holding a cup?’’ This is then dystonic postures)?
followed by additional questions that & Is the tremor characterized by
elicit information on the following: distractibility (ie, a decrease or
& The body regions that are involved cessation of tremor when
& The limb and body positions or volitionally performing a task [eg,
the specific maneuvers that elicit finger tapping with opposite
or suppress the tremor hand]), entrainment (ie, the tremor
& The age and time course of onset may be brought into a specific
and evolution of symptoms over time rhythm), or suggestibility (ie, the
& Whether the patient is aware or tremor may be induced with
unaware of the tremor certain stimuli)?
& The presence of any accompanying Next, the examiner should try to eli-
pulling sensations or pain cit kinetic tremor (ie, tremor that oc-
& The presence of associated curs during movement) by asking the
movements or additional patient to perform the finger-nose-
neurologic symptoms finger maneuver, draw spirals or write
& The current use of potential a sentence, pour water between cups,
tremor-inducing medications
or drink from a cup. The examiner
& The current use of tremor- should assess the following features:
exacerbating substances
(eg, caffeine) & Does the tremor have an
& Experiences of diarrhea, weight intentional component (ie, does it
loss, or heat intolerance worsen as the limb approaches
& Family history of tremor in first- or a target)?
second-degree relatives & Are dystonic postures present (eg,
during the finger-nose-finger
Neurologic Examination maneuver)?
After obtaining a patient’s medical his- & What is the relative severity of
tory, the next step is a detailed and kinetic tremor versus postural
KEY POINTS
h Given its progressive which is in excess of that seen in into a more complex, multidirectional
nature and propensity similarly aged controls. In most pa- tremor. Unless it is severe, the neck
to result in functional tients, this is mild, although in some tremor, which is a postural tremor,
disabilities, the term it may be of moderate severity. Some should subside and then resolve when
benign essential tremor evidence indicates that this gait ataxia the patient is lying on his or her back
is no longer favored. is more pronounced in patients who with the head fully at rest. Isolated
h The jaw tremor of have midline cranial tremors (eg, tremors neck tremor, with minimal or no ac-
essential tremor typically of the neck, jaw, and voice).5 companying arm tremor, is extremely
occurs when the Initially in essential tremor, the rare and should raise suspicion that
mouth is open rather tremor may be mild and asymptomatic the diagnosis is dystonia rather than
than closed. and may not worsen for many years. essential tremor. A curious feature of
However, in most individuals, the the neck tremor of essential tremor is
tremor worsens with time. Several pat- that patients are often unaware of its
terns of progression have been de- presence, particularly when it is mild
scribed. The two most common are: (Case 6-1). The presence of dystonic
(1) late-life onset (after the age of 60) posturing in essential tremor cases is
with progression and (2) early-life controversial, although it is likely that
onset (before the age of 40) with mild, the presence of a mild dystonic posture
stable tremor for many years that in the tremulous arm in some cases
then has a late-life progression. The does not preclude a diagnosis of essen-
least common pattern is that of early- tial tremor, especially when the dys-
life onset with marked worsening over tonic posture is a late finding in a
the ensuing years to decade.6 Few case with long-standing and severe
prospective, longitudinal natural his- essential tremor.
tory studies exist, but the best esti- Thirty percent to 50% of ‘‘essential
mates of rate of change indicate that tremor’’ cases are misdiagnosed, with
arm tremor worsens by 2% to 5% per many of these patients having PD or
year.7 With the progression of time, dystonia rather than essential tremor.
the tremor tends to spread beyond Differentiation from PD may be made
the hands and arms so that patients readily, however, by the absence of ri-
develop cranial tremors (neck, voice, gidity, the absence of other signs of
jaw). These are particularly prevalent parkinsonism (eg, hypomimia), the ab-
in women with essential tremor, sence of bradykinesia that is in excess
among whom the risk of neck tremor of age (ie, absence of slowness that is
is several times higher than that of men above and beyond that seen in normal
with essential tremor (Supplemental aging), and the absence of bradykinesia
Digital Content 6-1, links.lww.com/ accompanied by decrement (ie, absence
CONT/A180). The prevalence of neck of a sequential decrement in amplitude
tremor is the highest of these cranial during finger taps).8 The characteristics
tremors, with voice tremor being less of the tremor are also important in dis-
so, and jaw tremor being even less tinguishing a patient with essential
common. The jaw tremor is more often tremor from one with PD. The presence
one that is seen when the mouth is of isolated postural tremor (ie, postural
held open or during speech rather tremor with minimal kinetic tremor),
than at rest; the latter is more a feature a postural tremor predominantly in-
of PD-related jaw tremor. Neck tremor volving the metacarpophalangeal
often begins as a unidirectional tremorV joints rather than the wrist, or a postural
‘‘no no’’ (ie, horizontal) or ‘‘yes yes’’ tremor characterized by greater wrist ro-
(ie, vertical)Vbut with time can evolve tation than wrist flexion and extension,
1146 www.ContinuumJournal.com August 2016
are all indicators that the likely diagno- essential tremor from the spinocere-
sis is emerging PD rather than essential bellar ataxias. Hyperthyroidism can be
tremor. Reemergent tremor is a pos- assessed by clinical history (eg, diar-
tural tremor that commences after a rhea, weight loss, or heat intoler-
brief latency of several seconds, rather ance) as can the use of medications
than immediately, and is a feature of PD. (eg, lithium, valproate) or other sub-
Flexed posturing of the hand during stances (eg, caffeine, tobacco) that
arm extension is an additional marker produce or exacerbate tremor. A dif-
of parkinsonism. Dystonia in the arm is ficult differential is between a mild
characterized by dystonic posturing case of essential tremor and an indi-
(eg, spooning of the fingers, referring vidual with enhanced physiologic
to the tendency during arm extension tremor, although the presence of neck
to flex the wrist and hyperextend the tremor should exclude the latter.
metacarpophalangeal and phalangeal Computerized tremor analysis, with
joints) (Supplemental Digital Content inertial loading (ie, placing a weight
6-1, links.lww.com/CONT/A180) or the on the hand), can assist with this
presence of a tremor that is neither differential. In patients with a tremor
rhythmic nor oscillatory. The possibility of central origin (eg, essential tremor),
of neck dystonia should be assessed and the primary tremor frequency should
is characterized by head tilt or rotation not change with inertial loading. Other
with head tremor, hypertrophy of the features that support the essential
sternocleidomastoid muscle, the pres- tremor diagnosis are the presence of
ence of a tremor null point, or a sensory essential tremor in one or more first-
trick by history (ie, a maneuver such as degree relatives. Reduction in tremor
touching the chin that lessens the with ethanol use is often used as a
tremor). Absence of cerebellar speech diagnostic marker; however, this is not
(ie, either scanning or dysarthric) and very specific and of limited utility.
absence of nystagmus distinguishes Patients with most tremor disorders
Continuum (Minneap Minn) 2016;22(4):1143–1158 www.ContinuumJournal.com 1147
KEY POINT
h With enhanced often experience a reduction in tremor agents that have been used include
physiologic tremor, no following ethanol consumption. topiramate, gabapentin, and benzodi-
intentional component The tremor of essential tremor may azepines (alprazolam or clonazepam)
occurs on the be severe enough to result in embar- (Table 6-1). High-frequency thalamic
finger-nose- rassment and functional disability, and stimulation (ie, deep brain stimulation
finger maneuver. these are the main motivations for [DBS]) markedly reduces the severity
treatment.9 Beta-blockers (especially of the tremor, as does thalamotomy, in
propranolol) and primidone, alone or patients with severe pharmacologically
in combination, are the most effective refractory tremor.
pharmacologic therapies, although many
patients choose to discontinue these Enhanced Physiologic Tremor
medications due to their limited effi- Enhanced physiologic tremor is an ac-
cacy (Table 6-1). Propranolol has been tion tremor of the hands that occurs
used in doses up to 320 mg/d, although to some extent in all people.10 The pos-
doses in excess of 100 mg/d are rarely tural and kinetic components are gen-
tolerated in the elderly, with the main erally several Hz faster and generally
issue being slowed heart rate. Asthma have a lower amplitude than those seen
is a relative contraindication to the use in essential tremor,10 with the caveat
of propranolol but is not an absolute that at disease onset, patients with es-
contraindication and must be assessed sential tremor have a low-amplitude
on a case-by-case basis. Primidone is tremor that may be difficult to dis-
given in doses up to 750 mg/d, although tinguish from enhanced physiologic
lower doses are often effective. An tremor.11 Unlike essential tremor, no
acute nausea and ataxia is observed in intentional component occurs on the
approximately 25% of patients who are finger-nose-finger maneuver. Voice and
prescribed this medication, and pre- limb tremor may be present but not
loading the patient with phenobarbital head (ie, neck) tremor. Cogwheeling
(eg, 30 mg 2 times a day for 3 days) is may be present, but it is not accom-
one method that is used to avoid this panied by rigidity. On quantitative
unwanted side effect. These drugs re- computerized tremor analysis, inertial
sult in a mild to moderate reduction in loading reveals a pattern that is con-
the amplitude of tremor in 30% to 70% sistent with a peripherally generated
of patients, but they do not abolish rather than a centrally generated tremor
it unless the tremor is mild. Other (ie, a reduction in the primary tremor
frequency occurs with inertial loading).
Medications and Treatment should begin with reas-
TABLE 6-1
Dosage Ranges for surance that the patient does not have
Essential Tremor essential tremor or PD. Many of the
individuals who present to a clinician
Medication Dosage Range do so because they are also anxious.
Propranolol 10Y320 mg/d Beta-blockers, at low dose (eg, pro-
Primidone 25Y750 mg/d
pranolol up to 60 mg/d or used in
a 10 mg to 60 mg dose on an as-
Topiramate 25Y300 mg/d needed basis), and benzodiazepines
Gabapentin 100Y1800 mg/d may be effective.
Alprazolam 0.125Y3 mg/d
Drug-Induced Action Tremor
Clonazepam 0.5Y4 mg/d
A variety of medications may produce
or exacerbate action tremor, and the
1148 www.ContinuumJournal.com August 2016
KEY POINT
h Voice tremor in patients furthermore, they should be of mild to 60 mg/d), benzodiazepines, or
with dystonia is often severity relative to the tremor itself. beta-blockers. For dystonic neck
associated with Tremor in the neck or voice is tremor, other options include IM botu-
voice breaks. another issue worth discussing. Patients linum toxin injections, selective dener-
with neck dystonia (ie, torticollis) may vation, or DBS.
also have neck tremor (Case 6-2).17
This tremor is generally neither strictly Primary Writing Tremor
rhythmic nor oscillatory and may be Primary writing tremor is a task-specific,
accompanied by twisting or tilting of kinetic hand tremor that occurs pri-
the neck, jerklike or sustained neck marily or only during writing and does
deviation, hypertrophy of neck mus- not occur or is milder during other
cles, or a symptom of pulling sensations tasks that involve the use of the
or pain in the neck. These features do hands.10,19 The current definition of
not occur in essential tremor. Also, in primary writing tremor excludes pa-
contrast to the head tremor of essential tients who have dystonic postures with
tremor, which generally resolves when hand tremor while writing (ie, dystonic
the patient lies down, dystonic head writing tremor).10 Primary writing tremor
tremor often persists while the patient has a similar frequency to that seen in
is recumbent.18 Voice tremor may also patients with essential tremor (ie, 4 Hz
be present in patients with vocal cord to 8 Hz) and is relieved by ethanol con-
dystonia (ie, spasmodic dysphonia), but sumption in 30% to 50% of cases.19 The
in contrast to the voice tremor of es- mechanisms that underlie primary writ-
sential tremor, is often associated with ing tremor are unclear, and it is debated
voice breaks or strangulated speech. whether the condition represents a
The treatment of dystonic tremor variant of essential tremor or a variant
includes the use of medications used of dystonia, and in some families all
to treat dystonia (ie, trihexyphenidyl three conditions may be present.20
up to 10 mg/d in adults, baclofen up Tremor in patients with essential tremor
Case 6-2
A 43-year-old woman presented for a neurologic consultation because of
neck pain with tremor. She stated that her neck pain had begun about
5 years previously, mainly on the left side. For the past 3 years, she had felt
a pulling sensation and increased pain in the neck region. She also
described that her head had been turning to one side and sometimes it
even felt shaky. She had not noticed any hand tremor. On examination,
there was a mild postural tremor of the left arm with a little bit of spooning
of the hand on that side. No tremor occured during the finger-nose-finger
maneuver. Her left sternocleidomastoid muscle was slightly hypertrophic,
and her head tended to preferentially turn to the right and shake
intermittently. The shakiness was irregular. This head tremor persisted even
when she lay down on the examining table. She was treated with IM
botulinum toxin injections to several neck muscles, which helped diminish all
of her symptoms, although they did not resolve completely.
Comment. This case illustrates a number of key features of dystonic
head (neck) tremor, including the fact that the tremor is often irregular
and that it often persists in the recumbent position. Furthermore, it may
be accompanied by pain or pulling sensations.
KEY POINTS
Psychogenic Tremor The treatment of psychogenic trem-
h The presence of
entrainment, distractibility, This type of tremor occurs in patients or usually begins with a discussion of
and suggestibility all with specific psychiatric conditions, the diagnosis, recognition of the pa-
point to a diagnosis of especially conversion disorder, and tient’s suffering, and a referral to a
psychogenic tremor. malingering.28 By history, the tremor psychiatrist in order to explore the
h Wing-beat tremor is often has a sudden (ie, abrupt) start underlying psychiatric issues.
considered a classic with maximal tremor at onset rather
tremor in Wilson than an insidious onset followed by a Wilson Disease With
disease, but it is not the slowly progressive course. On examina- Associated Tremor
most common type of tion, the tremor often has nonphysiologic Patients with Wilson disease may pres-
tremor in that disease. or unusual features (eg, may exhibit ent with a wide range of involuntary
variable frequency or change direction, movements, including tremor.31,32 In-
and an unusual combination of rest, deed, tremor ranks among the eight
postural, and kinetic tremors may major symptoms reported by patients
be seen) (Case 6-3). On examination, with Wilson disease who have neuro-
the clinician may see signs that are logic features.33 Tremor is usually ac-
suggestive of psychogenic tremor, companied by other neurologic signs,
including entrainment (ability of the although there are rare reports of iso-
examiner to alter the rhythm of the lated tremor and even rarer reports of
patient’s tremor by having it match isolated action tremor.34 Although the
the rhythm of a tremor the examiner classic tremor associated with Wilson
produces), distractibility (ability of disease is the wing-beat tremor (pres-
the examiner to stop the tremor by ent on abduction of the shoulder and
asking the patient to perform certain flexion of the elbow), it is not the most
mental or physical tasks), and sug- commonly observed type of tremor.32,35
gestibility (ability of the examiner to Overall, the tremor phenomenology
bring on the tremor with the power of is quite varied. Indeed, across patients,
suggestion).29 Interestingly, on quan- a wide range of tremors may occur, in-
titative computerized tremor analysis, cluding kinetic tremor as well as resting
inertial loading can result in a para- tremor, postural and intention tremors,
doxical increase in tremor amplitude tremors that can be symmetric or
rather than the expected decrease in asymmetric, those that are low ampli-
amplitude that should be seen with tude and others that are high ampli-
organic tremors.30 tude, and those that are intermittent,
Case 6-3
A 27-year-old woman presented for a neurologic evaluation with a reported
tremor that had begun suddenly 2 years previously after she had fallen down
the stairs. The tremor affected her ‘‘entire body’’ and was not relieved by
anything. She had been unable to work as a waitress since the onset of the
tremor and stated that her life was ‘‘falling apart.’’ On examination, she had
a head tremor, which sometimes involved a horizontal movement and, at
other times, involved a vertical movement. At other times it was complex
and rotatory. The tremor was virtually continuous. The examination was
otherwise normal. The examiner was able to stop the tremor for a few
seconds while distracting the patient.
Comment. A number of important features of psychogenic tremor are
illustrated in this case, including its sudden onset, its often variable quality,
and the fact that it may cease when the patient is distracted.
KEY POINT
h Midbrain (rubral) tremor characterized by sensory deficits, weak- the pontine-midbrain region, affecting
is generally a unilateral ness, wasting (Supplemental Digital Con- cerebellar outflow tracts and dopaminer-
tremor accompanied tent 6-3, links.lww.com/CONT/A182), gic nigrostriatal fibers.53 There are also
by rest, postural, and diminished/absent deep tendon re- reports of lesions occurring elsewhere
and kinetic/intentional flexes is readily apparent in the tremu- (eg, the thalamus),54 which is one of
components. lous limb or limbs,48,49 although the the motivations for referring to the
severity of the weakness does not ne- tremor as Holmes tremor rather than
cessarily correlate with the severity of rubral tremor. As the dopaminergic
the tremor.50 The tremor disappears if system is involved in most cases,
neuropathic weakness progresses to treatment with levodopa (100 mg/d to
the point of paralysis. The underlying 1000 mg/d) may be beneficial.55 In
mechanisms are likely to be diverse and addition, medications that are used
may involve central as well as peripheral for the treatment of essential tremor
components.44 If the tremor occurs may be effective. DBS has proven
in the setting of an immunoglobulin- beneficial in some cases as well.55
mediated disease, then immunosuppres-
sive therapies, such as corticosteroids, RESTING TREMOR
IV immunoglobulin, cyclophosphamide, The differential for resting tremor is
or plasma exchange may be used. There less extensive than that of kinetic
are several reports of the use of pre- tremor. The main items are PD and
gabalin (up to 450 mg/d) for the treat- drug-induced tremor.
ment of neuropathic tremor.46 The
tremor may respond to DBS.51 Parkinson Disease
The tremor in patients with PD is clas-
Midbrain (Rubral) Tremor sically a tremor at rest. The tremor may
Midbrain tremor has also been re- affect any limb but is generally asym-
ferred to as Holmes tremor or rubral metric, affecting one limb or one side
tremor.10,52 The tremor is generally of the body (ie, arm and leg) preferen-
unilateral and has three components: tially. In patients with arm tremor, the
tremor at rest, postural tremor, and tremor often involves distal joints
kinetic/intentional tremor, with the rel- (eg, fingers and wrist) rather than the
ative severity generally being such that elbow or shoulder. In addition, wrist
kinetic tremor is greater than postural pronation-supination rather than
tremor, which is greater than resting flexion-extension is more common
tremor (Supplemental Digital Con- (Supplemental Digital Content 6-5,
tent 6-4, links.lww.com/CONT/A183). links.lww.com/CONT/A184). In addi-
The tremor is often severe and dis- tion, limb postures (flexed posture of
abling and can render the affected the hand while walking or during arm
limb functionally useless. Patients may extension) is quite common, as are other
have other neurologic signs as well, cardinal signs of parkinsonism. A con-
including mild dystonia or ataxia. The fusing feature of the examination can
tremor may occur in a variety of clinical be the presence of reemergent tremor
settings (eg, in the setting of a brain during arm extension or during activi-
tumor, multiple sclerosis, or slowly ties (eg, pouring water). Tremor may
expanding vascular lesion) and, when affect the jaw, although in contrast to
occurring in the setting of a stroke, the essential tremor, is more often there
tremor may arise after a latency of when the mouth is closed and relaxed
months to years. On brain imaging, a rather than while speaking or holding
lesion is often but not always present in the mouth open.
1154 www.ContinuumJournal.com August 2016
16. Defazio G, Conte A, Gigante AF, et al. 30. Schwingenschuh P, Katschnig P, Seiler S, et al.
Is tremor in dystonia a phenotypic feature of Moving toward ‘‘laboratory-supported’’
dystonia? Neurology 2015;84(10):1053Y1059. criteria for psychogenic tremor. Mov Disord
doi:10.1212/WNL.0000000000001341. 2011;26(14):2509Y2515. doi:10.1002/
mds.23922.
17. Jankovic J, Leder S, Warner D, Schwartz K.
Cervical dystonia: clinical findings and 31. Soltanzadeh A, Soltanzadeh P, Nafissi S, et al.
associated movement disorders. Neurology Wilson’s disease: a great masquerader. Eur
1991;41(7):1088Y1091. Neurol 2007;57(2):80Y85.
18. Agnew A, Frucht SJ, Louis ED. Supine head 32. Lorincz MT. Neurologic Wilson’s disease.
tremor: a clinical comparison of essential Ann N Y Acad Sci 2010;1184:173Y187.
tremor and spasmodic torticollis patients. doi:10.1111/j.1749-6632.2009.05109.x.
J Neurol Neurosurg Psychiatry 2012;83(2):
33. Walshe JM, Yealland M. Wilson’s disease:
179Y181. doi:10.1136/jnnp-2011-300823.
the problem of delayed diagnosis. J Neurol
19. Bain PG, Findley LJ, Britton TC, et al. Primary Neurosurg Psychiatry 1992;55(8):692Y696.
writing tremor. Brain 1995;118(pt 6):1461Y1472.
34. Frucht S, Sun D, Schiff N, et al. Arm tremor
20. Cohen LG, Hallett M, Sudarsky L. A single secondary to Wilson’s disease. Mov Disord
family with writer’s cramp, essential tremor, 1998;13(2):351Y353.
and primary writing tremor. Mov Disord
1987;2(2):109Y116. 35. Starosta-Rubinstein S, Young AB, Kluin K,
et al. Clinical assessment of 31 patients
21. Louis ED, Ford B, Wendt KJ, et al. A comparison with Wilson’s disease. Correlations with
of different bedside tests for essential tremor. structural changes on magnetic resonance
Mov Disord 1999;14(3):462Y467. imaging. Arch Neurol 1987;44(4):
22. Rana AQ, Vaid HM. A review of primary 365Y370.
writing tremor. Int J Neurosci 2012;122(3): 36. Machado A, Chien HF, Deguti MM, et al.
114Y118. doi:10.3109/00207454. Neurological manifestations in Wilson’s
2011.635827. disease: report of 119 cases. Mov Disord
2006;21(12):2192Y2196.
23. Yaltho TC, Ondo WG. Orthostatic tremor: a
review of 45 cases. Parkinsonism Relat Disord 37. Saito T. Presenting symptoms and natural
2014;20(7):723Y725. doi:10.1016/j.parkreldis. history of Wilson disease. Eur J Pediatr
2014.03.013. 1987;146(3):261Y265.
Movement Disorders
Address correspondence to
Dr Manju A. Kurian, Room
111, Level 1 Clinical and
Molecular Genetics Unit,
KEY POINTS
h Movement disorders genes and movement disorder syn- movements. The most common vocal
in childhood are dromes in childhood. tics are throat clearing and grunts.
heterogeneous and Accurate diagnosis of childhood- However, a remarkable breadth of
range from mild onset movement disorders requires motor and vocal tics may be observed
self-limiting phenotypes careful ascertainment of clinical history, from any body part. Tics are stereo-
to more severe detailed neurologic examination (for typical and repetitive for periods of
progressive recognition of phenomenology and time, but tend to change over time
neurodegenerative associated features), and a broad (months and years). The characteris-
disorders. tic features of tics are their repeti-
knowledge of potential differential di-
h A number of benign agnoses. This article provides an up- tive stereotypical nature, fluctuation
movement disorders of dated overview of movement disorders (waxing and waning), suppressibility,
childhood have been in childhood, with particular focus on and suggestibility.
identified, which are Tic duration is used to separate tics
newly recognized conditions.
transient in nature and into transient tic disorder, which occurs
usually have a good BENIGN MOVEMENT for less than 12 months, and chronic
long-term prognosis.
DISORDERS OF CHILDHOOD disorders, which occur for longer than
A number of relatively benign move- 12 months, and include: chronic motor
ment disorders of childhood have been tic disorder, chronic vocal tic disorder,
identified, relating to specific stages and when both motor and vocal tics
of normal development (Table 7-1).3 are present, Tourette syndrome. The
The underlying basis of such move- time of 12 months is used in the de-
ment disorders is not fully under- finition, as when tics last for longer
stood, but some are thought to be a than 12 months they are more likely to
manifestation of the developing brain, continue for much of childhood and
reflecting central nervous system im- adolescence. Despite being common
maturity. The majority of these con- (transient tics affect approximately 5%
ditions occur early in life, during the to 10% of children at some time, and
neonatal period, infancy, and early Tourette syndrome affects 0.5% of chil-
childhood, with resolution of symp- dren), these disorders remain poorly
toms over time. Furthermore, other understood and underrecognized by
neurologic symptoms are rarely pres- both clinicians and laypeople. Patients
ent, and most children are found to are often referred to opticians (for
have a normal neurologic examina- blinking and eye movements), otolar-
tion. Accurate recognition is crucial yngologists (for throat clearing), or re-
to avoid unnecessary investigations spiratory physicians (for repetitive
and provide families with reassur- cough) before a diagnosis is made. Tics
ance regarding long-term prognosis, are often mislabeled as habits.
where appropriate. Neurodevelopmental disorders are
also overrepresented in patients with
TICS, TOURETTE SYNDROME, Tourette syndrome, and a significant
AND STEREOTYPIES minority of patients may have autism
Tics are the most common movement spectrum disorder, sensory processing
disorder in childhood and can be disorder, or other dysexecutive prob-
separated into motor tics or vocal tics. lems, which can affect school and
Motor tics typically involve the face, general functioning. Tourette syn-
head, and shoulders, although they drome is not a disease but a symptom
can affect any body part. The most syndrome, and the etiology is likely
common motor tics are blinking, eye multifactorial with genetic vulnerabil-
movements, grimacing, and head ity factors plus environmental factors.4
1160 www.ContinuumJournal.com August 2016
Average Age
at Symptom Associated
Condition Symptom Onset Resolution Clinical Features Etiology
Jitteriness Neonatal period Midinfancy Generalized Hypoxic ischemic
rhythmic oscillation encephalopathy,
hypoglycemia,
hypocalcemia,
drug withdrawal
Benign neonatal Neonatal period Midinfancy Repeated myoclonic None known
sleep myoclonus jerks in sleep
Benign myoclonus Infancy Usually by 2 years Myoclonic spasms None known
of early infancy of the neck, trunk,
and limbs, similar
to infantile spasms
Spasmus nutans Infancy Within few months, Horizontal/vertical Rarely, cerebellar
nystagmus can head tremor with abnormalities on
persist pendular nystagmus neuroimaging
Infantile Infancy Early childhood Limb posturing, None known
masturbation but may persist rocking, thigh
adduction with
genital manipulation/
pressure over
pubic area
Shuddering Infancy to end of Usually gets Shivering None known
the first decade better with age movements of
head, shoulders,
and upper limbs,
often with facial
grimace
Benign idiopathic Infancy Usually by 1 year Segmental dystonia, None known
dystonia of infancy usually upper limb
Benign paroxysmal Infancy Midchildhood Paroxysmal head Mutation in
torticollis of infancy tilt, often with CACNA1A;
vomiting, irritability, mutation in PRRT2
pallor
Paroxysmal tonic Infancy Midchildhood Paroxysmal Mutation in
upgaze of infancy deviation of eyes CACNA1A;
upward/downward hypomyelination,
periventricular
leukomalacia,
vein of Galen
malformation,
pinealoma
Head nodding Usually by early Normally resolves Horizontal, vertical, Onchocerca
childhood in a few months, and oblique head volvulus infection
but may last movements (sub-Saharan
through childhood Africa)
KEY POINT
h Tics and stereotypy are The most important management include rocking, flapping, and body-
the most common aspect of Tourette syndrome is to tensing. However, some stereotypies
movement disorders of make a confident diagnosis and edu- are extremely complex, including
childhood. Diagnosis is cate the child, family, and school that twisting, grimacing, and posturing.
dependent on careful Tourette syndrome is a neurologic The most important characteristics
history, observation, disorder and is not the child’s fault of stereotypy are: (1) the movements
and parental videos. so that the family understands and have a stereotypical nature (ie, the
Education of the family accepts the diagnosis. In addition, in- episodes are similar); (2) the patient is
and searching for forming the family that the tics typi- partially distractible (although the
neurodevelopmental cally improve between 11 and 20 years child may subsequently need to com-
and neuropsychiatric
of age can be reassuring. In ap- plete the movement after being dis-
comorbidity are
proximately 80% of patients, psy- tracted); and (3) the episodes are often
paramount, as
associated comorbidities
choeducation is all that is required. more likely to occur with certain stim-
such as anxiety and The need for more intervention is uli, such as excitement or anticipation
obsessive-compulsive dictated by impairment in social or (eg, waiting in a line), participation in a
disorder can exacerbate global functioning. When impair- favorite activity (eg, watching televi-
the movements and are ment occurs, treatment can include sion), or sometimes boredom (eg,
arguably more amenable psychological approaches including riding in the back of a car). Parental
to psychological or tic reversal therapy. When medical videos are highly informative and es-
medical treatments. treatments are required, the family sential for diagnosis. Stereotypy is
needs to understand that medication more common in children with devel-
will only reduce tics by 30% to 50% at opmental disorders, such as language
best, although this can be useful. In delay and autism spectrum disorder, but
general, clonidine or guanfacine is the complex motor stereotypy can also
first-line therapy, and antipsychotics occur in normally developed children.5
such as risperidone, are restricted to Detailed assessment for subtle neuro-
more severe cases. Other agents includ- developmental disorders is important
ing tetrabenazine, baclofen, topiramate, as this may present therapeutic op-
and benzodiazepine can be considered, tions, although the treatment of ste-
and deep brain stimulation (DBS) can reotypy itself is challenging and
be used for the most severely affected drugs are ineffective. Psychological
patients who have failed medical ther- approaches may be useful in well-
apy and who have failed to improve motivated cognitively able individuals.
in adolescence. Screening for comor- Many normally developed older chil-
bid diagnoses of attention deficit disor- dren with stereotypy have associated
der, obsessive-compulsive disorder, or neuropsychiatric conditions, such as
associated problems, is essential as attention deficit hyperactivity disorder,
these are frequently more important anxiety, or tics.5 Some children with
to treat than the tics. complex stereotypy describe complex,
Stereotypy is a common movement sometimes imaginary, thoughts during
phenotype and a normal feature of the movements.6
infant development, but when stereo-
typy continues beyond this period, ACQUIRED MOVEMENT
the episodes can become concerning DISORDERS
to parents (less so for the child) Acquired brain disorders such as trau-
because of the unusual nature of the matic brain injury, hypoxic ischemic
episodes and the potential for social injury, and infectious and autoim-
stigmatization. Stereotypies are re- mune processes can result in transient
petitive movements; classic examples or persistent movement disorders.
1162 www.ContinuumJournal.com August 2016
tremor all observed. Arguably the most tures such as seizures and confusion
characteristic movement disorder of (Case 7-1). The syndrome is now very
antiYNMDA receptor encephalitis is recognizable, and, if suspected, immu-
the repetitive stereotypical clonic or nosuppressive therapy should be
tonic posturing that results in purpose- started while awaiting results of CSF
less, repetitive, and sometimes violent and serum NMDA receptor antibody
agitated movements.12 Some of the tests. Early treatment and the willing-
postures can be reminiscent of the syn- ness to use second-line immunother-
drome catatonia. The movements apy (rituximab or cyclophosphamide)
rarely occur in isolation but instead improve outcomes and reduce relapses.13
are part of a complex evolving enceph- Other autoimmune encephalopa-
alopathy syndrome with aphasia, psy- thies include basal ganglia encephalitis,
chosis, agitation, and dysautonomia which is a rare pure basal ganglia in-
as well as nonspecific encephalitis fea- flammatory encephalitis with restricted
Case 7-1
A previously healthy 7-year-old girl presented with a change in behavior and
restlessness. Over the following week, the illness progressed, with increasing
agitation and apparent delusional thoughts with repeated statements of
‘‘I’m going to die.’’ Examination revealed a generalized movement disorder
with repetitive restless movements, including scratching her face and cycling
movements of her legs. In the second week, she had three focal seizures
and became mute. MRI brain was normal, CSF showed 20 monocytes/mm3,
although infectious screening of CSF and blood was negative including
herpes simplex virus, and EEG showed nonspecific slowing. A clinical diagnosis
of antiYN-methyl-D-aspartate (NMDA) receptor encephalitis was made, and
a 5-day course of IV methylprednisolone was started in addition to IV
immunoglobulin (IVIg). Ten days later, she showed no apparent improvement
and remained mute and unresponsive to her parents and environment
despite apparently being awake. She only slept for 2 hours a night and had
ongoing purposeless stereotypical repetitive movements of her limbs and
face. Fourteen days after commencing immunotherapy, the CSF NMDA
receptor antibodies returned positive, and, given the lack of improvement,
rituximab 375 mg/m2 weekly for 4 weeks was started. Ten days after starting
rituximab, she started to make improvements. Her movement disorder
evolved to dystonic posturing, but she became more interactive and less
agitated. After a 2-month admission, she was discharged on a 6-month total
oral prednisolone taper. She remained B-cell depleted for 6 months and
continued to improve. At 12 months, all of her symptoms had resolved,
although her school performance lagged slightly behind.
Comment. This case exemplifies the movement phenomenology in
antiYNMDA receptor encephalitis, with restless stereotypical movements
later followed by dystonia. The case also exemplifies the fact that the
movement disorder rarely occurs in isolation and is almost always accompanied
by other changes in neurologic function, in this case, cognitive changes, loss
of speech, seizures, and agitated psychosis. The case also demonstrates that it
is possible to make a clinical diagnosis and start treatment before getting
confirmatory diagnostic results. A positive antibody result empowers the
clinician to use rituximab or other immunosuppression if the patient does
not adequately respond to first-line therapy.
KEY POINTS
h Acute presentation of a Although rare, the emergence of dyskinesia in (often genetic) epilep-
new movement disorder such autoimmune encephalopathies sies, amphetamine or other stimulant
with rapid evolution has radically changed the clinical ap- use or misuse, withdrawal movement
should prompt proach to the child with acute autoim- disorders such as with midazolam
neuroimaging to mune movement disorders. Rather infusion withdrawal, and cancer drug
exclude a structural or than observation and symptomatic use resulting in movement disorders,
vascular cause. therapy, increasing willingness exists often with leukoencephalopathies.23
h Iatrogenic etiologies to use immunotherapies, as early rec-
should be considered as ognition and intervention appear to Treatment Strategies for
a differential diagnosis improve outcomes. Acquired Movement Disorders
for movement disorders, The primary approach to the child with
and a detailed drug Stroke and Other an acquired movement disorder is
history and toxicology Space-Occupying Lesions defining the etiology and then treating
screen may aid in Any patient presenting with an acute the underlying cause. Defining and
the diagnosis of
movement disorder requires neuroim- treating the cause of disease in a timely
such disorders.
aging, and MRI is the optimal modal- fashion provides the best chance of
h Acquired movement ity. Movement disorders that affect a good outcome and reduces the
disorders have multiple one side of the body, referred to as potential destructive nature of disease.
potential causes.
hemidystonia or hemichorea, can be Symptomatic treatment of acquired
Although investigations
caused by acute vascular events, such as movement disorders is generally unsat-
such as MRI, CSF
analysis, and
stroke or vasculitis, and MRI with isfactory, and patients with autoim-
autoantibody testing are diffusion-weighted imaging is part of mune movement disorders appear to
important, it cannot be the diagnostic pathway. Moyamoya dis- be vulnerable to drug adverse events;
overemphasized that a ease and other vasculopathies may for example, neuroleptic drugs can
careful clinical history present with chorea, and surgical inter- induce akinesia and neuroleptic malig-
and examination for vention can improve the movement nant syndrome in Sydenham chorea
specific movement disorder and reduce the risk of ongoing and antiYNMDA receptor encephalitis,
disorder phenomenology stroke.22 Likewise, tumors or other respectively.24 Agents such as benzo-
is essential. The focus space-occupying lesions involving the diazepines or "2 -agonists may be
should be on defining subcortical structures may present with safer treatments for acquired move-
the etiology and
acute or subacute onset of movement ment disorders, but the evidence base
providing specific
disorders, and imaging is diagnostic. is limited.
targeted intervention.
Early recognition and
Toxic/Iatrogenic Causes GENETIC MOVEMENT DISORDERS
intervention are
increasingly emphasized. Iatrogenic or toxic mechanisms are Advances in molecular genetic tech-
important causes of movement disor- niques, such as chromosomal micro-
ders, but they are usually moderately array studies, targeted next-generation
straightforward to diagnose as a clear multiple gene panels, and whole
temporal association of drug usage exome/genome sequencing strategies,
and onset of movement disorder usu- have led to a significant increase in the
ally exists. Direct questioning regard- diagnosis of genetic movement disor-
ing potential drug ingestion is ders of childhood. Furthermore, a
therefore an important part of the large number of new genetic disor-
clinical history in children who acutely ders have been identified and clini-
present with involuntary movements cally characterized.
or postures. More common asso-
ciations include neuroleptic-induced Primary Genetic Dystonia
dystonia/neuroleptic malignant syn- Traditionally, genetic dystonias have
drome, antiepileptic drugYinduced been classified according to a DYT
1166 www.ContinuumJournal.com August 2016
Paroxysmal/ Pattern of
DYT Number Nonparoxysmal Clinical Presentation Inheritance Causative Gene
DYT1 Nonparoxysmal Early-onset primary Autosomal dominant TOR1A
generalized idiopathic
torsion dystonia
DYT5a Nonparoxysmal Dopa-responsive Autosomal dominant GCH1
dystonia
DYT5b Nonparoxysmal Tyrosine hydroxylase Autosomal recessive TH
deficiency
DYT8 Paroxysmal Paroxysmal Autosomal dominant MR1
nonkinesogenic
dyskinesia
DYT10 Paroxysmal Paroxysmal kinesogenic Autosomal dominant PRRT2
dyskinesia
DYT11 Nonparoxysmal Myoclonus dystonia Autosomal dominant SGCE
DYT12 Nonparoxysmal Rapid-onset Autosomal dominant ATP1A3
dystonia-parkinsonism
DYT18 Paroxysmal Paroxysmal Autosomal dominant SLC2A1
exercise-induced
dyskinesia
DYT23 Nonparoxysmal Myoclonus dystonia Autosomal dominant CACNA1B
DYT26 Nonparoxysmal Myoclonus dystonia Autosomal dominant KCTD17
disease presentations, including writer’s encoding the "3 subunit of the Na+/
cramp, dystonic tremor, and exercise- K+Yadenosine triphosphatase (ATPase)
induced dystonia, have all been de- pump. Affected patients usually present
scribed.27 Associations of GCH1 carriers acutely or subacutely (from over a few
manifesting early-onset Parkinson dis- minutes to months) with rostrocaudal
ease have been reported.28 DYT5b progression of dystonia-parkinsonism
tyrosine hydroxylase deficiency repre- and significant bulbar dysfunction.
sents another form of dopa-responsive It has become clear that the clinical
dystonia but is more complex, often spectrum of ATP1A3-related disease is
with concurrent features of parkinson- broad, encompassing a number of other
ism, other motor features, and neu- overlapping phenotypes, including al-
rodevelopmental delay.29 Although ternating hemiplegia of childhood as
response to levodopa can lead to sig- well as cerebellar ataxia, areflexia, pes
nificant clinical benefit in type B cavus, optic atrophy, and sensorineural
(hypokinetic rigid phenotype), the hearing loss (CAPOS) syndrome.31 The
earlier-onset type A subtype, associated reasons for this phenotypic pleiotropy
with neonatal encephalopathy, is more may be mutation dependent but are
drug resistant. Tyrosine hydroxylase yet to be fully elucidated.
deficiency is likely a phenotypic spec- Heterozygous mutations of CACNA1B
trum with a number of intermediate and KCTD17 have been described in
forms. Patients with tyrosine hydroxy- extended families with childhood-
lase deficiency often require much onset myoclonus dystonia.32,33 Car-
higher doses of levodopa to produce diac arrhythmias are additionally
a therapeutic response than in auto- reported in those with CACNA1B vari-
somal dominant GCH1 deficiency. ant p.R1389H. CaV2.2 channels car-
DYT11, or myoclonus dystonia syn- ried less current when compared with
drome, has clinical onset in childhood wild-type channels; it is postulated
(median age 5 years) and frequently that such altered channel properties
presents with early myoclonus affect- could affect neurotransmitter release at
ing the upper limbs and neck with excitatory and inhibitory channels.
predominantly upper (but also lower) Screening of another patient cohort
limb dystonia.30 More pronounced with myoclonus dystonia for this mis-
truncal involvement is evident later sense change has not identified fur-
in childhood and adolescence. Al- ther cases, with observation of this
cohol responsiveness is sometimes rare variant in control populations.
reported in older patients. Comorbid The significance of this mutation re-
neuropsychiatric features are com- mains yet to be fully determined.34
monly reported. Affected patients KCTD17Yassociated protein is pos-
have heterozygous mutations in SGCE, tulated to show significant putami-
encoding the *-sarcoglycan protein. nal expression, and KCTD17 gene
Disease mechanisms are not yet fully mutations result in impairment of en-
elucidated, but mutations are postulated doplasmic reticulumYdependent cal-
to impair targeting of *-sarcoglycan to cium signaling.
the plasma membrane, affecting pro-
teasomal degradation, protein glycosyl- Genetic Chorea
ation, and ectodomain shedding. A number of genes causing primarily
DYT12 is a rarer cause of genetic choreiform dyskinesia have been re-
dystonia-parkinsonism due to autoso- ported. Often children with such con-
mal dominant mutations in ATP1A3, ditions manifest chorea as part of a
1168 www.ContinuumJournal.com August 2016
KEY POINTS
h Genetic paroxysmal
movement disorders
Case 7-2
Following an unremarkable pregnancy, a male infant was born by emergency
of childhood have been
cesarean delivery for fetal bradycardia/decelerations. His parents were fit and
increasingly
healthy, with no significant family history of note. He was born in good
recognized, and some
condition, with excellent Apgar scores (9/10 at 1 and 5 minutes), and had an
have important
uneventful early neonatal course. Abnormal involuntary movements were
treatment implications.
noted from midinfancy, which were initially paroxysmal in nature, often
Paroxysmal movement
occurring in clusters several times a day, with periods of relapse and remission.
disorders may often
Choreiform limb movements were reported, with orolingual dyskinesia
coexist with other
and mild truncal athetosis. The movement disorder progressed through early
episodic conditions,
childhood, eventually becoming nonparoxysmal and continuous in nature.
including epilepsy
Involuntary movements began to disrupt his sleeping pattern. He did not
and migraine.
show clinical response to a number of medications, including carbamazepine,
h Nonepileptic myoclonus levetiracetam, and tetrabenazine. Detailed neurologic investigation revealed
should prompt testing for normal brain and spine MRI, as well as normal blood, urine, and CSF screening
genetic and for metabolic disorders. Routine diagnostic testing for NKX2-1-AS1, SLC2A1,
neurometabolic and SGCE were negative. Whole exome sequencing undertaken on a
syndromes. research basis identified a previously reported mutation in ADCY5, which
was confirmed to be de novo.
Comment. This case clearly exemplifies the typical disease pattern of
ADCY5-related disease. Although dyskinetic cerebral palsy may be in the
differential diagnosis here, a number of features in this child’s history should
prompt investigation of an alternative cause, including the relatively uneventful
antenatal/postnatal course, evidence of normal neuroimaging, and clear
disease progression with worsening of symptoms. Testing for benign hereditary
chorea is reasonable, but negative sequencing for NKX2-1-AS1 should alert
the clinician to look for other causes of benign hereditary chorea mimics
and initiate ADCY5 testing. Further clinical clues toward this diagnosis
include the disruption of sleep and progressive nature of disease.
KEY POINT
h A number of recessive described in childhood (Table 7-4), other cerebellar features of tremor,
genetic ataxias have and many are complex progressive head titubation, and nystagmus, as
been identified, neurologic disorders. well as myoclonus, dystonia, hypo-
including Friedreich Friedreich ataxia is the most com- reflexia, and retinitis pigmentosa.43
ataxia and ataxia monly reported, with clinical features Disease is caused by mutations in
telangiectasia. of a progressive, mainly sensory, cer- the "-tocopherol transfer protein, with
ebellar ataxia with speech difficulties, impaired incorporation of vitamin E
absent reflexes, pyramidal tract signs into very low density lipoproteins and
with weakness, hypertrophic cardio- subsequent excess loss of vitamin E.
myopathy, diabetes mellitus, and sen- Low vitamin E levels are detectable on
sorineural deafness. 42 Expanded blood testing.
guanine-adenine-adenine (GAA) re- Ataxia telangiectasia presents with
peats within intron 1 of frataxin (FXN) gait disturbance and truncal instability
are thought to impair exon splicing in early childhood, but choreiform
with reduced protein expression. movements and dystonia are also
Frataxin is postulated to have a role in described.44 Often, subtle abnormali-
mitochondrial iron metabolism, and ties in ambulation precede the onset
dyshomeostasis is thought to lead to of ocular and cutaneous telangiectasia.
increased free radical damage and oxi- Patients are at risk of immunodefi-
dative stress. Ataxia with vitamin E de- ciency (secondary to low immunoglob-
ficiency can mimic many of the features ulins) and lymphoreticular neoplasia.
seen in Friedreich ataxia and is charac- A raised "-fetoprotein can be a useful
terized by a progressive ataxia with disease marker. The disease is due to
Movement
Condition Inheritance Gene(s) Age of Presentation Symptomatology
Friedreich ataxia Autosomal FXN Childhood: 2Y15 years Ataxia
recessive
Ataxia with isolated Autosomal TTPA Childhood Ataxia, other cerebellar
vitamin E deficiency recessive features such as
tremor, nystagmus
Ataxia telangiectasia Autosomal ATM Early childhood: Ataxia, chorea,
recessive G5 years athetosis, dystonia,
eye movement
abnormalities
Ataxia with oculomotor Autosomal APTX (ataxia Mid childhood and later Ataxia, oculomotor
apraxia recessive with oculomotor childhood apraxia, chorea,
apraxia type 1) athetosis
SETX (AOA2)
Ataxia of Autosomal SACS Childhood to adulthood Ataxia
Charlevoix-Saguenay recessive
Spinocerebellar ataxia Autosomal Many genes, Childhood to adulthood Ataxia, dystonia, and
dominant or including ATXN1, chorea also sometimes
autosomal ATXN2, ATXN3, present, parkinsonism
recessive ATXN7
Organic acidurias
Glutaric aciduria Infancy Hyperkinesia, Organic acids: GCDH
type 1 dystonia, Glutaric acid,
choreoathetosis 3-hydroxyglutaric acid
Fibroblast assay:
Reduced glutaryl-
coenzyme A
dehydrogenase
activity
Acylcarnitines:
Glutarylcarnitine
MRI: Enlarged
subdural spaces,
frontotemporal
atrophy, bat wing
dilatation of
sylvian fissures
Methylmalonic Infancy Dystonia, hypotonia Organic acids: MUT
aciduria Elevated
methylmalonic acid
Propionic acidemia Infancy Dystonia, Organic acids: PCCB, PCCA
choreoathetosis, Elevated
spasticity propionic acid
Aminoacidopathies
Homocystinuria Infancy Dystonia Abnormal plasma CBS, MTRR,
and urine MTR, MMACHC,
homocysteine MTHFR
Hartnup disease Infancy Ataxia, spasticity, SLC6A19
dystonia
TABLE 7-5 Pediatric Parkinsonism and Complex Neurometabolic Syndromes Continued from page 1175
TABLE 7-5 Pediatric Parkinsonism and Complex Neurometabolic Syndromes Continued from page 1177
Case 7-3
A female infant was born to fit and healthy consanguineous parents. She
was born in good condition and did not require any resuscitation, nor was
she admitted to the neonatal intensive care unit. She was discharged on
day 2 of life. From the early neonatal period, she was irritable, with
difficulty in feeding and a disrupted sleep pattern. The parents reported
that often she would look as if she were half asleep, with her eyes half
closed. She was profoundly hypotonic and had delay in her motor milestones.
By 2 to 3 months of age, abnormal eye movements were noted, and the
family described periods when her eyes would deviate to the right and fixate
in an upward gaze lasting from seconds to several hours. Often during
these periods her body would be arched and hands fisted. The parents also
noted that she always seems to have a cold with nasal congestion, and even
during the winter, her hands and the back of her head were sweaty. During
infancy, she developed a complex movement disorder, with dystonic
posturing of her limbs, truncal athetosis, tremulous hand movements, and
occasional myoclonic jerks. A diagnostic lumbar puncture was undertaken,
and CSF neurotransmitter analysis revealed a low homovanillic acid, low
5-hydroxyindoleacetic acid, and normal pterin profile. CSF 3-O-methyldopa
and 5-hydroxytryptophan were markedly elevated. Further testing
revealed low aromatic L-amino acid decarboxylase plasma enzyme activity.
Molecular testing revealed that she was a compound heterozygote for two
mutations in the DDC gene, one reported in association with aromatic L-amino
acid decarboxylase deficiency and the other a novel 2-base pair deletion.
Comment. This case illustrates a child with a very-early-onset neurologic
disorder, characterized by severe motor delay, hypotonia, and mixed
movement symptomatology. The ptosis and severe hypotonia could indeed
be presenting features of neuromuscular disease, although the complex
movement disorder and presence of autonomic features (sweating, nasal
congestion, ptosis) should prompt CSF neurotransmitter analysis to look for
disorders of monoamine metabolism. This patient’s CSF findings are indeed
classic for aromatic L-amino acid decarboxylase deficiency, later confirmed
by enzyme assay and molecular genetic testing. This patient’s first mutation
has already been reported in the literature associated with aromatic L-amino
acid decarboxylase deficiency. The second mutation, although novel as a
2-base pair deletion, will lead to a frameshift with significant alteration to
the protein and likely premature stop.
undetermined cause will often have an with primary dystonia due to DYT158
early trial of levodopa to rule out a but has also been used as palliation in a
treatable dopa-responsive dystonia.27 number of other genetic disorders, such
Symptomatic treatment of dystonia as pantothenate kinaseYassociated
is managed with a number of differ- neurodegeneration. Chorea can often
ent agents, including baclofen, trihe- be difficult to manage from a therapeu-
xyphenidyl, the benzodiazepines,57 and, tic perspective, but tetrabenazine, ben-
more recently, clonidine and gabapentin. zodiazepines, and antiepileptic drugs (eg,
More invasive therapies, such as intra- levetiracetam, sodium valproate, carba-
thecal baclofen and DBS, are also used. mazepine) can be used.59 The paroxys-
DBS is particularly effective for children mal disorders have specific treatments,
Case 7-4
A 12-year-old girl with no significant medical problems presented with
shaking movements of the arms. She had attended school as usual the day
before but had onset of shaking movements the preceding evening, and
her condition had deteriorated dramatically over the course of the next
day. She had no other change in function. Examination revealed dramatic
coarse shaking of the upper limbs but no abnormal movements of the legs,
head, or trunk. Her walking revealed unsteadiness with significant wobbling
but without falls. During observation, it was noted that her symptoms
fluctuated significantly; she was observed to use her mobile phone normally
without shaking, and her shaking varied according to the people around
her. Her behavior, thinking, and memory were normal, and formal neurologic
examination was also unrevealing. On subsequent history, it became
apparent that she had been the victim of significant bullying at school.
The school described her as a kind, diligent, and sensitive girl who was
training 5 nights a week in state-level athletic competition. MRI brain and
EEG were normal.
Comment. The incongruous and inconsistent nature of this patient’s
movement disorder led to a diagnosis of a psychogenic movement disorder,
presumably secondary to the significant stressors. Psychological input
uncovered some baseline anxiety and fears of failure with perfectionism
and some obsessive-compulsive behavior. A confident diagnosis and
acceptance of the diagnosis by the family, followed by a multidisciplinary
rehabilitation with physical therapy and psychological input resulted in a
rapid improvement and return to normal function.
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Chorea
Address correspondence to
Dr Tiago A. Mestre,
Parkinson’s Disease and
Movement Disorders Centre,
Civic Campus, The Ottawa Tiago A. Mestre, MSc, MD
Hospital, 1053 Carling Ave,
Rm 2174, Ottawa,
ON K1Y 4E9, Canada,
tmestre@toh.on.ca. ABSTRACT
Relationship Disclosure: Purpose of Review: This article reviews the clinical approach to the diagnosis of
Dr Mestre receives personal
compensation for serving on adult patients presenting with chorea, using Huntington disease (HD) as a point of
the scientific advisory board reference, and presents the clinical elements that help in the diagnostic workup.
of AbbVie, for speaking Principles of management for chorea and some of the associated features of other
engagements for Teva
Pharmaceutical Industries Ltd, choreic syndromes are also described.
and for educational events Recent Findings: Mutations in the C9orf72 gene, previously identified in families
for WebMD. Dr Mestre with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both,
receives grant support from
the Parkinson Study have been recognized as one of the most prevalent causes of HD phenocopies in
Group/Parkinson Disease the white population.
Foundation. Summary: The diagnosis of chorea in adult patients is challenging. A varied
Unlabeled Use
of Products/Investigational
number of associated causes require a physician to prioritize the investigations, and
Use Disclosure: a detailed history of chorea and associated findings will help. For chorea presenting
Dr Mestre reports as part of a neurodegenerative syndrome, the consideration of a mutation in the
no disclosure.
C9orf72 gene is a new recommendation after excluding HD. There are no new
* 2016 American Academy
of Neurology. treatment options for chorea, aside from dopamine blockers and tetrabenazine.
There are no disease-modifying treatments for HD or other neurodegenerative
choreic syndromes.
Neurodegenerative Relevant
Conditions Demographics Core Features Useful Investigations
Most common neurodegenerative choreic syndromes
Huntington Estimated prevalence Chorea (onset); Caudate atrophy (MRI),
disease (HD) is 5/100,000 (with depression, apathy, genetic test (HTT gene,
geographic variation); irritability, cognitive CAG repeat expansion
modal age group for impairment, parkinsonism, 935)
onset is 30Y50 years of age and dystonia (later
stages)
Huntington Common cause Ataxia in an Caudate and cerebellar
diseaseYlike (HDL) for HD-negative HD phenocopy atrophy, putaminal rim
syndrome neurodegenerative enhancement (MRI),
type 4 (HDL4)/ chorea genetic test (TBP gene,
Spinocerebellar (white populations) CAA/CAG repeat
ataxia (SCA) type expansion 942)
17 (SCA17)
C9orf72-related Common cause HD phenocopy, ataxia, Genetic test (C9orf72
HD phenocopy for HD-negative parkinsonism, and upper gene, GGGGCC/G4C2
neurodegenerative motor neuron signs, hexanucleotide repeat
chorea (white phenotypic heterogeneity expansion 960 are
populations) in families definitely pathogenic)
HDL2 Exclusive to HD phenocopy Caudate atrophy (MRI),
sub-Saharan acanthocytosis (fresh
African descendants blood film) in about
10% of patients, genetic
test (JPH3 gene, CTG
repeat expansion 940,
fully penetrant)
Rare neurodegenerative syndromes, chorea as a classic prominent feature
Chorea-acanthocytosis Estimated prevalence of Chorea, dystonia Acanthocytosis (fresh
(Levine-Critchley 1000 cases worldwide; (orofacial involvement, blood film), elevated
syndrome) young adult onset tongue protrusion), creatine kinase, chorein
tics, self-mutilation, absent in red blood cells,
seizures, sensorimotor predominant atrophy of
axonal polyneuropathy, the head of caudate (MRI),
hepatomegaly, splenomegaly genetic test (VPS13A gene)
McLeod syndrome Rarer than Chorea, dystonia, Acanthocytosis (fresh blood
chorea-acanthocytosis; parkinsonism, psychiatric film), antigen Kell absent/
exclusive to males and features, seizures, reduced in red blood cells,
with a later onset (after sensorimotor axonal elevated creatine kinase
fourth decade) neuropathy, cardiomyopathy, and liver function test,
hepatosplenomegaly, genetic test (XK gene)
hemolytic anemia
Continued on page 1188
Neurodegenerative Relevant
Conditions Demographics Core Features Useful Investigations
HDL1 Very rare (four Chorea, ataxia, prominent Atrophy of basal ganglia,
families reported5) psychiatric features, cerebellum, frontal and
myoclonus, seizures temporal lobes (MRI),
genetic test (PRNP gene,
eight octapeptide
repeat insertions)
Dentatorubral- Most common in Ataxia, chorea, myoclonus, Atrophy of cerebellum,
pallidoluysian atrophy Japan (1/208,000), rare dementia, seizures brainstem, cerebrum;
in non-Japanese hyperintensity in
populations periventricular white
matter (MRI), genetic test
(ATN1 gene, CAG
repeat expansion 947,
fully penetrant)
Neuroferritinopathy Reported in Cumbria, Chorea/dystonia with Hypointensity in dentate
United Kingdom, and orofacial involvement, nuclei, red nuclei, basal
France; estimated nontremulous parkinsonism ganglia, thalami, rolandic
prevalence of (less frequent), maintained cortex (T2*), bilateral
G1/1 million (very rare) asymmetrical features, pallidal necrosis with cystic
ataxia (rarer), late degeneration (MRI), low
neuropsychiatric and serum ferritin, genetic test
cognitive symptoms (FTL gene)
(later feature)
Aceruloplasminemia Estimated prevalence Dystonia (craniocervical), Low serum ceruloplasmin
of 1/1 million to parkinsonism, chorea and and high ferritin,
1/1.2 million (very rare); ataxia, depression, cognitive hypointensity in the
onset at middle age dysfunction, anemia, striatum, thalamus, and
diabetes mellitus, retinal dentate nucleus (T2* MRI),
degeneration preceding genetic test (CP gene)
neurologic manifestations
Neurodegenerative syndromes, chorea as a rare manifestation
SCA1 Rare chorea-athetosis, Cerebellar atrophy (MRI),
ataxia, dystonia, dementia, genetic test (ATXN1 gene,
early hyperreflexia, triplet repeat expansion
late neuropathy 939, fully penetrant)
SCA2 Rare chorea-athetosis, Cerebellar atrophy (MRI),
ataxia, hyperreflexia, genetic test (ATXN2 gene,
earlier slow saccades, CAG/CAA repeat expansion
levodopa-responsive, 932, fully penetrant)
parkinsonism, dystonia,
dementia, early neuropathy
Neurodegenerative Relevant
Conditions Demographics Core Features Useful Investigations
SCA3 Rare chorea-athetosis, Cerebellar atrophy (MRI),
ataxia, levodopa-responsive, genetic test (ATXN3 gene,
parkinsonism, dystonia, triplet repeat expansion
hyperreflexia/spasticity, 951, fully penetrant)
late neuropathy
Wilson disease Chorea is relatively rare, Kayser-Fleischer rings
predominantly parkinsonism (slit-lamp examination),
and dystonia (with risus eye-of-the-panda sign,
sardonicus), ataxia, variable white matter
psychiatric symptoms, lesions in brainstem,
seizures can occur (G10%), cerebellum (MRI), low
KayserYFleischer rings, serum ceruloplasmin, high
arthropathy, hemolytic anemia urine copper (24-hour
urine), high liver copper
content on biopsy,
genetic test (CP gene)
Pantothenate Single case with Head and upper limb Bilateral hypointensity in
kinaseYassociated chorea reported, onset chorea with later the putamen, caudate,
neurodegeneration at age 766 generalization, imbalance substantia nigra, and
dentate nuclei,
eye-of-the-tiger signa (MRI),
acanthocytosis (fresh blood
film) in about 10% of
patients,a genetic test
(PANK2 gene)a
Friedreich ataxia Single case with Ataxia, chorea, cognitive Genetic test (FXN gene,
chorea reported3 impairment (at GAA repeat expansion 965,
presentation), dysphagia and fully penetrant)
dysarthria (later stages)
Pallidonigroluysian Very rare7 Chorea (20% of cases), gait Postmortem diagnosis
atrophy or balance disturbance
Lubag disease (TAF1) Filipino origin Dystonia-parkinsonism, Genetic test (TAF1 gene)
chorea is a very rare feature
(also reported in female
carriers)
MRI = magnetic resonance imaging.
a
Diagnostic features of pantothenate kinaseYassociated neurodegeneration, but not documented in the case report.
Acquired causes of chorea are im- chorea that a clinician should consider
portant to take into consideration since in the appropriate setting.8 Other spo-
a few can be treated. Certain elements radic forms of chorea are broadly
in the clinical presentation of acquired divided into immune-mediated, infec-
causes of chorea help in the differential tious, metabolic/endocrine, vascular, and
diagnosis. Chorea secondary to stroke others causes (Table 8-2). This article
and drug-induced chorea are among covers the approach to adult-onset cho-
the most prevalent causes of sporadic rea. As such, conditions with a classic
b Drugs
Antiemetics (dopamine antagonists)
Antiepileptic drugs (eg, phenytoin, carbamazepine, valproic acid)
Antihistamines
Baclofen
Calcium channel blockers
Digoxin
Fluoroquinolones
Levodopa, dopamine agonists (levodopa-induced dyskinesia)
Lithium
Methotrexate, cyclosporine
Neuroleptics (tardive dyskinesia)
Oral contraceptives, estrogen replacement therapy (often with a history of
previous Sydenham chorea)
Psychostimulants (eg, cocaine, amphetamines)
Steroids
Theophylline
Tricyclic antidepressants
b Immune Mediated
Antibody associated (paraneoplastic or idiopathic)9
Associated with neoplasia: collapsin response mediator protein-5 (CRMP5)
(small cell lung carcinoma and thymoma), Hu (small cell lung carcinoma), Yo,
antineuronal nuclear antibody (ANNA) type 1 and type 2, N-methyl-D-
aspartate (NMDA) subunit NR1 (ovarian tumor)
Idiopathic: NMDA subunit NR1 (45% of cases), leucine-rich, glioma
inactivated 1 (LgI1), contactin-associated proteinlike 2 (CASPR2),
glutamic acid decarboxylase 65 (GAD65), IgLON family member 5 (IgLON5),
pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections (PANDAS)
Behçet disease
Celiac disease
Demyelinating disease (rare, hemiballismus reported)10
Sjögren syndrome
Systemic lupus erythematosus/antiphospholipid syndrome
b Infectious
Encephalitis (West Nile virus, mumps, measles, varicella zoster)
Human immunodeficiency virus (HIV) (eg, secondary focal lesion due to
toxoplasmosis, primary central nervous system lymphoma, HIV encephalitis)
Tuberculosis, cysticercosis, borreliosis, neurosyphilis, diphtheria
Variant Creutzfeldt-Jakob disease
b Metabolic/Endocrine
Acquired hepatolenticular degeneration (advanced liver disease)
Electrolyte imbalance (hypoglycemia/hypercalcemia, hypomagnesemia,
hyponatremia)
Hyperthyroidism
Hypoglycemia/hyperglycemia (nonketotic)
Vitamin B12 deficiency (more frequently found as a cause of chorea
in children)
b Vascular
Essential thrombocythemia (one case reported)11
Ischemic/hemorrhagic stroke
Polycythemia rubra vera (elderly, primarily females)
Posterior reversible encephalopathy syndrome
Postpump chorea (more frequent in children)
b Other Causes
Carbon monoxide intoxication
Hydrocephalus
Postanoxic/cerebral palsy
Psychogenic chorea
KEY POINTS
h Chorea may present as Chorea as Symptom (Supplemental Digital Content 8-1,
an isolated symptom or Chorea can present as an isolated links.lww.com/CONT/A188).12 The ad-
as a syndrome with a symptom or a mixed movement dis- vent of a genetic diagnosis for HD
variable combination of order and can be associated with has shown that most of these cases
a mixed movement behavioral and cognitive symptoms, are, in fact, late-onset HD (Case 8-1).13
disorder, behavioral seizures, or symptoms suggestive of In terms of mode of onset, a rela-
and cognitive polyneuropathy. The different symp- tively acute onset of chorea can be
symptoms, seizures, tom complexes identified with a clin- the manifestation of stroke, and also
or polyneuropathy. other causes such as nonketotic hy-
ical interview can give the first clues
h Most of the cases of for a diagnosis and prioritization of perglycemia, chorea gravidarum, or
senile chorea investigations. Chorea is frequently drug-induced chorea (Table 8-2). A
correspond to cases noticed first by a third person and subacute course over a few days or
of late-onset weeks may be the manifestation of
not by the patient; consequently, the
Huntington disease.
information provided by a caregiver infectious process or autoimmune
or family member is particularly im- chorea, including a paraneoplastic
portant for a more rigorous history of syndrome, but does not exclude a
chorea. As with other neurologic symp- metabolic cause.14 In some cases of
toms, the age of onset (adult versus drug-induced chorea, a gradual onset
elderly), the acute versus progressive may occur, such as in levodopa-
mode of onset, and the type of dis- induced dyskinesia in Parkinson dis-
ease course (remitting, paroxysmal, or ease (Supplemental Digital Content
continuous) can favor a specific syn- 8-2, links.lww.com/CONT/A189) or
drome. In terms of age of onset, neuroleptic-induced dyskinesia.15 A
there is the particular case of senile more protracted course of months to
chorea defined as an idiopathic spo- years is usually associated with a neu-
radic form of chorea with onset in the rodegenerative condition. In terms of
elderly in the absence of dementia the time course of chorea, a slowly
Case 8-1
An 88-year-old woman presented with a 6- to 8-year history of progressive
involuntary movements and imbalance, for which she had to use a walker.
The involuntary movements were described as ‘‘shaking’’ and were
increasingly embarrassing to the patient. She had also noticed swallowing
air when eating. The patient did not endorse cognitive or mood symptoms,
and she lived independently at a retirement home. The patient did not have a
family history of chorea. Her examination was remarkable for pronounced
generalized chorea involving the limbs, trunk, and face, as well as an inability
to walk unaided. A diagnosis of senile chorea was made. The investigations at
that time included a head CT, renal and liver function tests, serum glucose,
thyroid-stimulating hormone (TSH), as well as anticardiolipin,
antiphospholipid, and antinuclear antibodies. All investigations were normal.
Genetic testing for Huntington disease (HD) showed a CAG repeat of 39,
confirmatory of a diagnosis of late-onset HD. Two years later, the patient
died at age 90 with complications from dysphagia and dehydration.
Comment. This case is demonstrative of how to approach a case of senile
chorea and how late in life a diagnosis of HD can be made. In a case of
senile chorea, a diagnosis of HD has implications for a patient’s children, who
are at risk of developing HD and may consider predictive genetic testing.
a
TABLE 8-3 Clinical Features of Paroxysmal Dyskinesia
Paroxysmal
Paroxysmal Paroxysmal Exertion-Induced
Kinesigenic Dyskinesia Nonkinesigenic Dyskinesia Dyskinesia
Age of onset Childhood/adolescence Childhood/adolescence Variable (depending
(majority of cases) (majority of cases) on cause)
Episodes
Triggers Sudden movements or Coffee, tea, alcohol Prolonged exertion
intention to move (more consistent), anxiety, (more frequently),
excitement, fatigue fasting, stress, anxiety
Duration Brief, majority of episodes Typically more prolonged, Episode ends with rest
G1 minute 10 minutes to 4 hours
Frequency Up to hundreds of episodes Weekly episodes more Dependent on triggers
a dayb commonb
Treatment Good response to Avoid triggering factors; Avoid triggering factors,
antiepileptics; carbamazepine poor response to treat underlying cause
is drug of choice benzodiazepines, phenytoin, when applicable
acetazolamide, levodopa
Etiology
Gene associated Proline-rich transmembrane Myofibrillogenesis Glucose transporter 1
with primary protein 2 (PRRT2) regulator 1 (MR-1)d (SLC2A1)e (in 20Y25%
formc of cases)
Secondary causes Secondary to brain Secondary to brain injury, Parkinson disease,
injury (vascular, trauma, symptomatic cases are rare dopa-responsive dystonia
multiple sclerosis)
a
Data from Erro R, et al, Mov Disord.16 onlinelibrary.wiley.com/doi/10.1002/mds.25933/abstract.
b
Frequency has a tendency to decrease with age.
c
Genotype-phenotype correlation is incomplete, and overlap of forms of paroxysmal dyskinesia may exist.
d
Potassium calcium-activated channel, subfamily M alpha member 1 (KCNMA1) has been described in one family with cases of
paroxysmal nonkinesigenic dyskinesia and epilepsy.
e
Mutations in the gene SLC2A1 can also cause benign familial infantile seizures, familial infantile convulsions with paroxysmal
choreoathetosis, and hemiplegic migraine.
Case 8-2
A 28-year-old man presented with a 1-year history of difficulty chewing and
abnormal gait. In order to eat, the patient swallowed food in big chunks
without chewing it. There was no history of seizures, and he was otherwise
healthy. There was a known family history of chorea-acanthocytosis in his
brother and two paternal cousins. Examination was remarkable for a left
gum ulcer, dystonic protrusion of the tongue when ingesting food or
speaking, as well as jaw-opening dystonia and recurrent sniffing. He had mild
generalized chorea and slight weakness in his hands and feet. Ankle reflexes
were absent. Gait was abnormal with hesitations, namely with turns. The
investigations identified elevated creatine kinase (422 units/L) and
acanthocytes (more than 10%) in the blood. He was started on
Continued on page 1195
time of a diagnosis based on motor in which the majority of the cases have
features, deficits in cognitive function seizures.5,19,30,32 In DRPLA, it is useful
can be elicited in formal testing.26 to recognize that when the age of
Suicidal ideation is relatively frequent onset overlaps the mean age of onset
(8% to 10%) and should be actively of the adult form of HD, seizures rarely
looked for, especially in patients with occur, and more common presenting
active depression and a previous features are chorea, in addition to dys-
suicidal attempt.27 tonia, parkinsonism, and psychosis.
HD phenocopies in which behav- When the clinician is considering
ioral or cognitive symptoms are part a genetic choreic syndrome, it is
of the clinical presentation include helpful to recognize that certain causes
HDL2, chorea-acanthocytosis, and have a higher incidence, in particular,
dentatorubral-pallidoluysian atrophy geographic areas or ethnic origins
(DRPLA).28Y30 In McLeod syndrome, and, thus, should be prioritized when-
behavioral problems are more com- ever applicable. For example, HDL2
mon and cognitive difficulties are has been reported almost exclusively
milder.29 Self-mutilation of the lip and in subjects with a sub-Saharan African
tongue is a clinical manifestation of ancestry, namely African Americans
chorea-acanthocytosis, but is uncom- and black South Africans, and in the
mon in McLeod syndrome.31 Lesch- rare cases of a presumed non-African
Nyhan syndrome is an X-linked genetic origin, an African ancestor could not
condition in which patients can have be ruled out.33 Neuroferritinopathy
self-mutilating behaviors but the onset has been mostly described in families
occurs in childhood. from the United Kingdom (Cumbria
Chorea gravidarum, antiphospho- region), with a few cases reported in
lipid syndrome, or systemic lupus France and one single case in North
erythematosus are among nondegen- America.34 DRPLA is most frequent in
erative causes of chorea that can Japan, although it is not exclusive to
present with concomitant behavioral that country, with rare cases reported
symptoms, including personality in European and North American pop-
changes, depression, psychotic symp- ulations of non-Japanese ancestry.35
toms, and cognitive impairment.18 The Haw River syndrome corresponds
The occurrence of seizures is a dif- to a family of African Americans orig-
ferentiating feature of some HD inally from North Carolina, and has
phenocopies, occurring in about 50% been reported as a form of DRPLA.36
of the cases in chorea-acanthocytosis
(30% as presenting feature) and Past Medical History
McLeod syndrome, as well as in DRPLA The presence of acute hemichorea
and HDL1, an exceedingly rare entity or hemiballismus in a patient with
KEY POINTS
h In the Western world, significant vascular risk factors sug- SCA17, C9orf72-related HD pheno-
chorea gravidarum has gests stroke as a cause, while in a pa- copy, HDL2, as well as DRPLA, neuro-
become a rare cause tient with diabetes mellitus, a primary ferritinopathy, SCA1, SCA2, SCA3, SCA7,
of chorea. diagnosis of nonketotic hyperglycemia and HDL1.37 In SCA17, most of the
h In C9orf72-related has to be considered in addition. Re- cases reported are sporadic or isolated
Huntington disease, current miscarriages, migraine, and subjects in a family with an ataxic syn-
phenocopies present thrombotic events are a clue for the drome. Although a family with a SCA17
with significant presence of an antiphospholipid syn- mutation and multiple members pres-
phenotypic heterogeneity drome or systemic lupus erythema- enting an HD-like phenotype show
and have, in most of tosus. Hemodialysis, alcoholism, and that phenotypic homogeneity may
the cases, a positive malnutrition can point to extrapontine exist, this is exceedingly rare.38 For
family history. myelinolysis, and the presence of C9orf72-related HD phenocopies,
human immunodeficiency virus (HIV) available data suggest a higher preva-
risk factors provide clues to the clini- lence of a positive family history,
cian for HIV-associated causes of cho- although with phenotypic heteroge-
rea (eg, opportunistic infections neity within the known spectrum of
including toxoplasmosis, progressive C9orf72-related clinical presentations.4
multifocal leukoencephalopathy, and The prevalence of C9orf72-related
HIV encephalitis). HD phenocopies should be further
The occurrence of chorea in a preg- assessed as in the initial case series,
nant woman should raise the possibility only three of the 10 cases reported
of chorea gravidarum. In the Western had chorea in their presentation.4
world, chorea gravidarum is increas- An autosomal recessive inheritance
ingly rare; currently, its most common pattern is compatible with chorea-
causes are antiphospholipid syndrome acanthocytosis and aceruloplasminemia.
and systemic lupus erythematosus.18 In HDL3 also has an autosomal recessive
the past, rheumatic fever was the most inheritance pattern but has only been
prevalent cause for chorea gravidarum, described in a Saudi Arabian family.
but it decreased sharply with the wide- The onset of symptoms is in early
spread use of penicillin.18 childhood, and its presentation re-
sembles the HD Westphal variant.39
Family History An X-linked recessive inheritance pat-
A clear pattern of inheritance will help tern is compatible with McLeod syn-
the clinician prioritize genetic causes drome, although rare female cases
of chorea in the differential diagnosis. have been reported.40
However, it is important to recognize
that the absence of a family history EXAMINATION
does not exclude a genetic disorder The observation of chorea, other
for many possible reasons, including movement disorders, and additional
nonpaternity, de novo mutations (in- neurologic or systemic signs provides
cluding unstable trinucleotide repeats), clues for the differential diagnosis.
premature death of asymptomatic
carriers, as well as partial penetrance Phenomenology of Chorea and
and phenotypic variability. In fact, ge- Related Movement Disorders
netic causes for chorea are frequently Chorea is one of the hyperkinetic
found in sporadic cases (Case 8-1). movement disorders. Chorea (derived
In the presence of a family his- from the Greek word horos, meaning
tory, an autosomal dominant inheri- dance) is characterized by involuntary,
tance pattern is compatible with HD, brief, irregular, random movements
1196 www.ContinuumJournal.com August 2016
Case 8-3
A 73-year-old woman presented to the
emergency department with an 8-day history
of generalized chorea with an acute onset.
There was no relevant past medical history, no
family history of chorea, and no known use
of neuroleptic drugs. Her examination was
remarkable for orofacial dyskinesias and
generalized chorea. The investigations for
vascular and metabolic cases of chorea were
remarkable for severe hyperglycemia on
admission (more than 500 mg/L). The brain
MRI showed bilateral putaminal hyperintensity
in T1-weighted imaging (Figure 8-143).
Chorea persisted beyond the normalization
of the patient’s hyperglycemia. She died
32 days after admission as a result of
unresolved sepsis.
Comment. This case shows that nonketotic
hyperglycemia may be a cause of acute-onset
chorea presenting in a generalized form. FIGURE 8-1 Brain MRI of the patient in Case 8-3 with
bilateral chorea-related nonketotic
The MRI findings highlighted in this case are hyperglycemia exhibiting putaminal
typical of the syndrome of chorea in the hyperintensity in T1-weighted imaging.
setting of nonketotic hyperglycemia. The Reprinted with permission from Mestre TA, et al. J Neurol Neurosurg
MRI findings can be unilateral or bilateral Psychiatry.43 B 2007 BMJ Publishing Group Ltd. jnnp.bmj.com/content/
78/5/549.extract.
consistent with the side(s) of the body
presenting with chorea.
Case modified with permission from Mestre TA, et al, J Neurol Neurosurg Psychiatry.43
B 2007 BMJ Publishing Group Ltd. jnnp.bmj.com/content/78/5/549.extract.
1. Test for thyroid function, renal and liver function, electrolytes, erythrocyte
sedimentation rate, antinuclear antibodies, antiYdouble-stranded DNA
antibodies, anticardiolipin antibodies, and lupus anticoagulant.
2. Perform brain MRI.
3. If inconclusive or known family history of chorea, perform genetic test
for Huntington disease. If the latter genetic test is negative, consider
spinocerebellar ataxia type 17 and C9orf72 in white individuals, and
Huntington diseaseYlike syndrome type 2 in subjects with black
African ancestry.
4. Test for acanthocytes in peripheral fresh blood film. A single negative test is
not sufficient to rule out the presence of acanthocytes and should be done in
a laboratory with appropriate expertise; perform three assays.
DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.
KEY POINTS
h The vast majority of HD are associated with significant phenocopies, and there was no diag-
Huntington disease behavioral abnormalities, with impli- nosis of SCA17. 53
phenocopies remain cations for genetic counseling.50,51 Among rare genetic entities that have
undiagnosed. Genetic testing in HD and other been reported to present as an HD phe-
h Spinocerebellar ataxia neurodegenerative conditions with an nocopy and have an available diagnostic
type 17 and adult onset not only impacts the life of test, Friedreich ataxia was reported as an
C9orf7-related the individual being tested, but also adult-onset choreic syndrome in the
Huntington disease his or her family, especially children. sixth decade of life, in association with
phenocopy are the most For family members at risk, the consid- cerebellar ataxia, and a single case of
frequent causes for a eration of predictive testing is usually adult-onset chorea was found to have
Huntington disease prompted by wishing to know the typical pathology of pantothenate
phenocopy. carrier status but also for a need to in- kinaseYassociated neurodegeneration.3,6
h Caudate atrophy can form life decisions including marriage, In more recent years, there has been
be found in Huntington parenthood, or a professional career. a significant breakthrough in the ge-
disease phenocopies, Genetic counseling is fundamental in netic basis of paroxysmal dyskinesia:
namely in Huntington order for patients to make a decision the myofibrillogenesis regulator 1 (MR-1)
diseaseYlike about predictive testing in a fully gene and the much less frequent
syndrome type 2, informed and free manner. Risks that potassium calcium-activated channel
chorea-acanthocytosis,
are associated with positive predictive subfamily M alpha 1 (KCNMA1) gene
and McLeod syndrome.
testing need to be discussed, includ- were identified in paroxysmal non-
ing the potential issues of discrimina- kinesigenic dyskinesia, the proline-
tion at work or for insurance purposes, rich transmembrane protein 2 (PRRT2)
tension in family and personal relations, gene was identified in paroxysmal
as well as stress on the patient. Legisla- kinesigenic dyskinesia, and the glucose
tion on protection against genetic dis- 1 transporter (SLC2A1 gene) was identi-
crimination exists but varies from fied in paroxysmal exertion-induced
country to country and, in the United (exercise-induced) dyskinesia.
States, can change from state to state. MRI can be helpful in the differential
A significant proportion of patients diagnosis of a suspected neurodegen-
presenting as an HD phenocopy cur- erative choreic syndrome, with atten-
rently remain undiagnosed. An alterna- tion to patterns of atrophy, presence
tive diagnosis is found in as low as of signal changes in T1, T2, and fluid-
2.8% of the cases in tertiary movement attenuated inversion recovery (FLAIR)
disorders centers.3 In an attempt to weighted images, and iron susceptibil-
prioritize investigations, elements related ity imaging. The hallmark feature in
with differentiating clinical features, clinical MRIs found in adult-onset HD
ethnic/geographic origin, and family is caudate atrophy (Figure 8-2). It is
history should be considered as de- important to emphasize that a few
scribed previously. Available clinical adult-onset neurodegenerative HD
data from case series in tertiary HD phenocopies may not be differentiated
centers from Western Europe suggest from HD based on MRI findings, exam-
that SCA17 and C9orf72 gene muta- ples of which include HDL2, chorea-
tions should be prioritized, particularly acanthocytosis, and McLeod syndrome.
in white individuals.4 HDL2 should be Nevertheless, in chorea-acanthocytosis
strongly considered in African Ameri- and McLeod syndrome, T2-weighted
cans. Of note, HDL2 may resemble HD hyperintensity in the striatum, mild gen-
more than any other known disease.52 eralized cortical atrophy (less in McLeod
In a Brazilian cohort, HDL2 and SCA2 syndrome), and hippocampal sclerosis
were the diagnoses found for HD and atrophy (in chorea-acanthocytosis)
1200 www.ContinuumJournal.com August 2016
KEY POINT
h The treatment of
chorea should aim at
reducing related
disability and improving
overall function.
25. van Duijn E, Craufurd D, Hubers AA, et al. 37. Pedroso JL, de Freitas ME, Albuquerque MV,
Neuropsychiatric symptoms in a European et al. Should spinocerebellar ataxias be
Huntington’s disease cohort (REGISTRY). included in the differential diagnosis for
J Neurol Neurosurg Psychiatry 2014;85(12): Huntington’s diseases-like syndromes? J
1411Y1418. doi:10.1136/jnnp-2013-307343. Neurol Sci 2014;347(1Y2):356Y358.
doi:10.1016/j.jns.2014.09.050.
26. Tabrizi SJ, Langbehn DR, Leavitt BR, et al.
38. Schneider SA, van de Warrenburg BP,
Biological and clinical manifestations of
Hughes TD, et al. Phenotypic homogeneity
Huntington’s disease in the longitudinal
of the Huntington disease-like presentation
TRACK-HD study: cross-sectional analysis of
in a SCA17 family. Neurology
baseline data. Lancet Neurol 2009;8(9):
2006;67(9):1701Y1703. doi:10.1212/
791Y801. doi:10.1016/S1474-4422(09)70170-X.
01.wnl.0000242740.01273.00.
27. Hubers AA, van Duijn E, Roos RA, et al. Suicidal
ideation in a European Huntington’s disease 39. Al-Tahan AY, Divakaran MP, Kambouris M,
population. J Affect Disord 2013;151(1): et al. A novel autosomal recessive ‘‘Huntington’s
248Y258. doi:10.1016/j.jad.2013.06.001. disease-like’’ neurodegenerative disorder in a
Saudi family. Saudi Med J 1999;20(1):85Y89.
28. Fischer CA, Licht EA, Mendez MF.
The neuropsychiatric manifestations of 40. Hardie RJ, Pullon HW, Harding AE, et al.
Huntington’s disease-like 2. J Neuropsychiatry Neuroacanthocytosis. A clinical, haematological
Clin Neurosci 2012;24(4):489Y492. and pathological study of 19 cases. Brain
doi:10.1176/appi.neuropsych.11120358. 1991;114(pt 1A):13Y49. doi:13-49.
29. Walterfang M, Evans A, Looi JC, et al. 41. Bowen J, Mitchell T, Pearce R, Quinn N.
The neuropsychiatry of neuroacanthocytosis Chorea in new variant Creutzfeldt-Jacob
syndromes. Neurosci Biobehav Rev disease. Mov Disord 2000;15(6):1284Y1285.
2011;35(5):1275Y1283. doi:10.1016/ doi:10.1002/1531-8257(200011)
j.neubiorev.2011.01.001. 15:6G1284::AID-MDS104393.0.CO;2-Y.
30. Rajput A. Dentatorubral pallidoluysian 42. Mestre T, Ferreira J, Pimentel J. Putaminal
atrophy. Handb Clin Neurol 2011;100:153Y159. petechial haemorrhage as the cause of
doi:10.1016/B978-0-444-52014-2.00008-2. non-ketotic hyperglycaemic chorea: a
31. Hewer E, Danek A, Schoser BG, et al. McLeod neuropathological case correlated with
myopathy revisited: more neurogenic and MRI findings. BMJ Case Reports 2009;2009.
less benign. Brain 2007;130(pt 12):3285Y3296. pii: bcr08.2008.0785. doi:10.1136/
doi:10.1093/brain/awm269 3285-3296. bcr.08.2008.0785.
32. Jung HH, Danek A, Walker RH. 43. Mestre TA, Ferreira JJ, Pimentel J. Putaminal
Neuroacanthocytosis syndromes. Orphanet J petechial haemorrhage as the cause of
Rare Dis 2011;6:68. doi:10.1186/1750-1172-6-68. non-ketotic hyperglycaemic chorea: a
33. Rodrigues GG, Teive HA, Tumas V. Huntington’s neuropathological case correlated with
disease-like 2 and apparent ancestry. Clin Genet MRI findings. J Neurol Neurosurg Psychiatry
2009;75(2):207; author reply 8. doi:10.1111/ 2007;78(5):549Y550. doi:10.1136/jnnp.
j.1399-0004.2008.01055.x. 2006.105387.
34. Ondo WG, Adam OR, Jankovic J, Chinnery PF. 44. Namekawa M, Takiyama Y, Ando Y, et al.
Dramatic response of facial stereotype/tic to Choreiform movements in spinocerebellar
tetrabenazine in the first reported cases of ataxia type 1. J Neurol Sci 2001;187(1Y2):
neuroferritinopathy in the United States. 103Y106. doi:10.1016/S0022-510X(01)00527-5.
Mov Disord 2010;25(14):2470Y2472. 45. Stevanin G, Hahn V, Lohmann E, et al.
doi:10.1002/mds.23299. Mutation in the catalytic domain of protein
35. Becher MW, Rubinsztein DC, Leggo J, et al. kinase C gamma and extension of the
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findings in genetically confirmed 1242Y1248. doi:10.1001/archneur.61.8.1242.
Ataxia
Address correspondence to
Dr Tetsuo Ashizawa, 6670
Bertner Ave, Houston
Methodist Research Institute,
R11-117, Houston, TX 77030, Tetsuo Ashizawa, MD, FAAN; Guangbin Xia, MD, PhD
tashizawa@houston
methodist.org.
Relationship Disclosure:
Dr Ashizawa receives ABSTRACT
research/grant support as Purpose of Review: This article introduces the background and common etiologies of
principal investigator of studies
for Ionis Pharmaceuticals, Inc ataxia and provides a general approach to assessing and managing the patient with ataxia.
(1515598769-CS2); the Recent Findings: Ataxia is a manifestation of a variety of disease processes, and an
Myotonic Dystrophy Foundation; underlying etiology needs to be investigated. Pure ataxia is rare in acquired ataxia
and the National Institutes of
Health (NS083564). Dr Xia disorders, and associated symptoms and signs almost always exist to suggest an
receives research/grant support underlying cause. While the spectrum of hereditary degenerative ataxias is expanding,
as principal investigator of special attention should be addressed to those treatable and reversible etiologies,
studies for Acorda Therapeutics,
Grand Aerie Fraternal Order of especially potentially life-threatening causes. This article summarizes the diseases that
Eagles, the National Institutes of can present with ataxia, with special attention given to diagnostically useful features.
Health (AR065836-01), While emerging genetic tests are becoming increasingly available for hereditary ataxia,
ReproCell Inc, and
ThermoFisher Scientific. they cannot replace conventional diagnostic procedures in most patients with ataxia.
Unlabeled Use of Special consideration should be focused on clinical features when selecting a cost-
Products/Investigational effective diagnostic test.
Use Disclosure:
Drs Ashizawa and Xia report
Summary: Clinicians who evaluate patients with ataxia should be familiar with the
no disclosures. disease spectrum that can present with ataxia. Following a detailed history and neu-
* 2016 American Academy rologic examination, proper diagnostic tests can be designed to confirm the clinical
of Neurology. working diagnosis.
FIGURE 9-1 Afferent and efferent connections of the cerebellum. Main cerebellar afferent
connections are by climbing fibers from the inferior olives through the inferior
cerebellar peduncles, and pontine mossy fibers through the middle cerebellar
peduncles. Cerebellar outputs are from the dentate nucleus and other deep cerebellar nuclei
through the superior cerebellar peduncles.
CLASSIFICATION AND ETIOLOGIES and the features indicated may not occur
OF ATAXIA in all individuals with a particular disease.
There are different ways to classify For many of the rarer ataxic disorders,
ataxias: by age of onset, tempo of the clinical features have been defined on
onset, and clinical course; anatomic the basis of limited clinical experience.
involvement; focal or generalized; or
acquired or inherited. Common etiol- Hereditary Ataxias
ogies (mainly acquired ataxias) are Hereditary ataxias are rare disorders, but
listed in Table 9-2, although signifi- are more frequently diagnosed than they
cant clinical overlap exists among were previously as diagnostic technolo-
them. Hereditary ataxias are listed gies are advancing. Hereditary ataxias
separately in Table 9-3 and Table 9-4. are classified as autosomal dominant, au-
Sporadic ataxia remains a temporary tosomal recessive, X-linked, or mitochon-
diagnosis for adults before a definitive drial ataxias (Table 9-3 and Table 9-4).
etiology is found. Cases in which all The characteristic features may help
specific diagnoses listed in Table 9-3 with recognizing a specific diagnosis.9Y11
and Table 9-4 have been ruled out are Inherited ataxias, especially autoso-
classified as sporadic adult-onset ataxia mal dominant cerebellar ataxias, should
of unknown etiology, which still re- be considered when the disease is
mains a diagnostic challenge.8 transmitted vertically from one genera-
The list of clinical features is only a tion to the next within a family. A
rough guide, and a precise diagnosis documentation of a father-to-son trans-
cannot be based on such features alone. mission ascertains the autosomal dom-
Clinical manifestations can be variable, inant inheritance (Case 9-1).
Second, it provides a basis for genetic gists should consider the diagnosis of
counseling for patients and their families. multiple system atrophyYcerebellar type
Finally, it allows patients to engage in (MSA-C). Documentation of other ner-
support group and research activities vous system involvement, particularly
specific for the genetically defined disease basal ganglia and autonomic dysfunc-
entity. For example, the genotype de- tion, is critical for the diagnosis of
fined by DNA testing will be in inclusion MSA-C in patients with sporadic ataxia
criteria of most, if not all, future clinical (Case 9-2). MRI of the brain may
trials of disease-modifying treatments, provide a clue to the diagnosis of MSA
and once a therapy is developed and with brainstem atrophy causing the hot
approved, patients need to know the cross bun sign and posterior putaminal
genotype of their disease to determine hypointensity and a putaminal hyper-
whether the drug is suitable for them. intense rim on T2*-weighted imaging.
The remaining late-onset degenera-
Sporadic and Idiopathic Adult tive ataxias are often referred to as spo-
Ataxias radic adult-onset ataxia in the category
For older patients presenting with known as idiopathic late-onset cerebel-
sporadic degenerative ataxia, neurolo- lar ataxia. While these two terms have
Continuum (Minneap Minn) 2016;22(4):1208–1226 www.ContinuumJournal.com 1213
been used interchangeably, some ex- and foot deformities, scoliosis, hyper-
perts include MSA-C in the category of trophic cardiomyopathy, and glucose
idiopathic late-onset cerebellar ataxia. intolerance.15 With genetic diagnosis,
the phenotype has expanded to in-
Friedreich Ataxia clude a later presentation (older than
Friedreich ataxia is one of the most 25 years of age up to 60 years of age)
common genetic autosomal recessive and slower progression, which is
ataxia syndromes. Onset is typically in termed late-onset Friedreich ataxia.
childhood and young adulthood with Such individuals have retained re-
progressive ataxia leading to loss of flexes, often referred to as Friedreich
ambulation after 10 to 15 years. Other ataxia with retained reflexes, which
clinical clues include sensory loss due may show spasticity with no cardiac
to dorsal root ganglion and dorsal or skeletal signs.16 The disease arises
column degeneration with areflexia from an abnormal expansion of GAA
Case 9-1
A 44-year-old woman presented with a 6-year history of deteriorating
balance. She had begun to use a cane 1 year prior to presentation. She also
noted neck spasms. Her father and brother had a similar progressive
neurologic disorder. She was of Cuban descent. On examination, she had very
slow saccades, normal pursuit eye movements, and no nystagmus. She had
pancerebellar ataxia with moderate dysmetria, intention tremor and
dysdiadochokinesia in her upper limbs, inability to maintain heel contact to
shin, a wide-based gait, inability to perform tandem standing and walking,
and scanning speech. Reflexes were absent in her arms and trace in her legs.
Cervical dystonia was observed. MRI of the brain showed cerebellar and
brainstem atrophy (Figure 9-212). DNA testing showed a heterozygous CAG
repeat expansion in the ATXN2 gene.
repeats in the frataxin gene (FXN), of GAA repeats on the smaller allele.
although point mutations may be Loss of frataxin function in mitochondria
present on one of the chromosomes leads to iron-sulfur cluster deficits, im-
in lieu of the GAA expansion in rare paired oxidation, and iron accumulation.
cases. The age of disease onset is Nicotinamide has been shown to in-
inversely correlated with the number crease frataxin but no clinical benefit
has yet been demonstrated, and studies (eg, pancerebellar ataxia, isolated gait
with the iron chelator deferiprone and ataxia), associated manifestations, and
the antioxidant idebenone are unclear the cause of ataxia. Good history
on long-term benefit. Carbamylated taking will allow neurologists to predict
erythropoietin, interferon gamma-1b, the findings of the physical examination
pioglitazone, epoetin alfa, and a few with good accuracy. Detection of any
other clinical trials have been completed. surprising physical findings should
These studies have not shown convinc- warrant revisiting the history.
ing evidence of efficacy.17
History
EVALUATION OF THE PATIENT Ataxia may present with a variety of
WITH ATAXIA associated signs and symptoms that
The history should provide clues to the allow the neurologist to narrow the dif-
type of ataxia (eg, cerebellar ataxia, ferential diagnosis. The standard history
sensory ataxia) or vestibular dysfunc- and physical examination serve as a
tion, the affected parts of the body general framework for the evaluation
Continuum (Minneap Minn) 2016;22(4):1208–1226 www.ContinuumJournal.com 1217
FIGURE 9-4 Axial MRI of a 17-year-old girl with autosomal recessive spastic ataxia of
Charlevoix-Saguenay showing degeneration of the corticospinal tract in the
brainstem. The patient has had spasticity, ataxia, reduced fine motor function,
and abnormal plantar responses since she was 5 years old. The patient’s family history was
negative except for a cousin with spasticity. Consecutive axial T2-weighted MRI slices (A, B)
demonstrate linear hypointensity in the pons.
22
Reprinted with permission from Martin MH, et al, AJNR Am J Neuroradiol. B 2007 American Society of
Neuroradiology. www.ajnr.org/content/28/8/1606.short.
FIGURE 9-8 Atrophy of the cervical spinal cord in a patient with Friedreich ataxia shown on
T1-weighted sagittal section (A) and T2-weighted horizontal section (B) showing
the atrophic cervical spinal cord (arrow) on MRI.
26
Reprinted with permission from Mascalchi M, et al, AJR. B 1994 American Roentgen Ray
Society. www.ajronline.org/doi/abs/10.2214/ajr.163.1.8010211.
5. Whelan HT, Verma S, Guo Y, et al. Evaluation Scale for pharmacological assessment of
of the child with acute ataxia: a systematic the cerebellar syndrome. The Ataxia
review. Pediatr Neurol 2013;49(1):15Y24. Neuropharmacology Committee of the
doi:10.1016/j.pediatrneurol.2012.12.005. World Federation of Neurology. J Neurol
6. Koontz DW, Maddux B, Katirji B. Sci 1997;145(2):205Y211. doi:10.1016/
Evaluation of a patient presenting with S0022-510X(96)00231-6.
rapidly progressive sensory ataxia. J Clin 19. Schmitz-Hübsch T, du Montcel ST, Baliko L,
Neuromuscul Dis 2004;6(1):40Y47. et al. Scale for the assessment and rating
doi:10.1097/01.cnd.0000133065.28161.00. of ataxia: development of a new clinical
7. Dinolfo EA. Evaluation of ataxia. Pediatr Rev scale. Neurology 2006;66(11):1717Y1720.
2001;22(5):177Y178. doi:10.1542/pir.22-5-177. doi:10.1212/01.wnl.0000219042.60538.92.
8. Klockgether T. Sporadic ataxia with adult 20. Subramony SH, May W, Lynch D, et al.
onset: classification and diagnostic criteria. Measuring Friedreich ataxia: interrater
Lancet Neurol 2010;9(1):94Y104. doi:10.1016/ reliability of a neurologic rating scale.
S1474-4422(09)70305-9. Neurology 2005;64(7):1261Y1262.
9. Jayadev S, Bird TD. Hereditary ataxias: doi:10.1212/01.WNL.0000156802.15466.79.
overview. Genet Med 2013;15(9):673Y683. 21. Schmahmann JD, Gardner R, MacMore J,
doi:10.1038/gim.2013.28. Vangel MG. Development of a brief ataxia
10. van de Warrenburg BP, van Gaalen J, Boesch S, rating scale (BARS) based on a modified
et al. EFNS/ENS consensus on the diagnosis form of the ICARS. Mov Disord 2009;24(12):
and management of chronic ataxias in 1820Y1828. doi:10.1002/mds.22681.
adulthood. Eur J Neurol 2014;21(4):552Y562. 22. Martin MH, Bouchard JP, Sylvain M, et al.
doi:10.1111/ene.12341. Autosomal recessive spastic ataxia of
11. Subramony SH, Xia G. Ataxic and cerebellar Charlevoix-Saguenay: a report of MR imaging
disorders. In: Daroff RB, Jankovic J, in 5 patients. AJNR Am J Neuroradiol 2007;
Mazziotta JC, Pomeroy SL, editors. Bradley’s 28(8):1606Y1608. doi:10.3174/ajnr.A0603.
neurology in clinical practice. 7th ed. 23. Koshy B, Oommen SP, Jasper S, et al.
New York, NY: Elsevier, 2015:217Y222. Development and dysmorphism in Joubert
12. Chakor RT, Bharote H. Inherited ataxia with syndromeVshort case series from India.
slow saccades. J Postgrad Med 2012;58(4): J Trop Pediatr 2010;56(3):209Y212.
318Y325. doi:10.4103/0022-3859.105471. doi:10.1093/tropej/fmp084.
13. Srivastava T, Singh S, Goyal V, et al. ‘‘Hot 24. Hagerman PJ, Hagerman RJ. Fragile
cross bun’’ sign in two patients with multiple X-associated tremor/ataxia syndromeVand
system atrophy-cerebellar. Neurology older face of the fragile X gene. Nat Clin
2005;64(1):128. doi:10.1212/ Pract Neurol 2007;3(2):107Y112. doi:10.1038/
01.WNL.0000141862.49535.E1. ncpneuro0373.
14. Gilman S, Wenning GK, Low PA, et al. 25. van Gaalen J, van de Warrenburg BP. A
Second consensus statement on the diagnosis practical approach to late-onset cerebellar
of multiple system atrophy. Neurology ataxia: putting the disorder with lack of
2008;71(9):670Y676. doi:10.1212/ order into order. Pract Neurol 2012;12(1):
01.wnl.0000324625.00404.15. 14Y24. doi:10.1136/practneurol-2011-000108.
15. Reetz K, Dogan I, Costa AS, et al. Biological 26. Mascalchi M, Salvi F, Piacentini S, Bartolozzi
C. Friedreich’s ataxia: MR findings involving
and clinical characteristics of the European
the cervical portion of the spinal cord. AJR
Friedreich’s Ataxia Consortium for Translational
Am J Roentgenol 1994;163(1):187Y191.
Studies (EFACTS) cohort: a cross-sectional
doi:10.2214/ajr.163.1.8010211.
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S1474-4422(14)70321-7. et al. Whole-genome sequencing identifies
a novel ABCB7 gene mutation for X-linked
16. Lecocq C, Charles P, Azulay JP, et al.
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Delayed-onset Friedreich’s ataxia revisited.
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doi:10.1002/mds.26382.
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17. Abrahão A, Pedroso JL, Braga-Neto P, et al.
28. Pierson TM, Adams D, Bonn F, et al. Whole-exome
Milestones in Friedreich ataxia: more than a
sequencing identifies homozygous AFG3L2
century and still learning. Neurogenetics 2015;
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18. Trouillas P, Takayanagi T, Hallett M, et al. proteases. PLoS Genet 2011;7(10):e1002325.
International Cooperative Ataxia Rating doi:10.1371/journal.pgen.1002325.
Diagnosis and
Address correspondence to
Dr Vicki Shanker, Mount Sinai
Beth Israel, Phillips Ambulatory
Care Center, 10 Union Square
KEY POINTS
h Dystonia is a from the action as overflow (eg, foot group characterized as idiopathic is
hyperkinetic movement tapping on the right produces dysto- fluid, as causative genes may be dis-
disorder characterized nia in the resting left foot). When con- covered, and patients will subsequently
by involuntary muscle tractions are sustained, they produce be recategorized.
contractions often twisted or abnormal postures. These Diagnostic evaluation, including ge-
initiated or worsened by postures have a characteristic direction- netic testing, requires an understanding
voluntary action. ality, referred to as patterning. When of the clinical phenotypes associated
h In 2013 a consensus contractions are intermittent, they fre- with specific etiologies; this presents a
document presented a quently produce tremorlike activity or daunting challenge as we discover new
revised classification jerky movements.1 The amplitude of genetic etiologies and as we learn about
that categorized dystonic tremors is enhanced when the the variation in clinical expression of a
dystonia into two affected area is positioned against the genotype. DYT-TOR1A and DYT-THAP1
nonoverlapping axes. direction of the pull (ie, turning the neck are the most common genetic causes of
Axis I categorizes to the right in a patient with left cervical isolated dystonia, and commercial test-
dystonia by the clinical
dystonia). Likewise, dystonic movements ing is available for both. DYT-TOR1A
features and axis II
may subside when the affected area is has autosomal dominant inheritance
by etiology.
placed in the maximum direction of the with reduced penetrance estimated at
h DYT-TOR1A and pull. This placement is identified as the 30%. One recurring TOR1A mutation,
DYT-THAP1 are the
null point. Another characteristic, but a deletion of one of a pair of GAG triplets
most common genetic
not universal, feature in dystonia is the coding for glutamic acid, is responsible
causes of isolated
dystonia, and commercial
sensory trick, or geste antagoniste, which for almost all dystonia associated with
testing is available describes a tactile or proprioceptive this gene. TOR1A encodes the protein
for both. maneuver performed to minimize the torsinA that resides in the endoplasmic
dystonic movement.2 For example, plac- reticulum system. Its normal biological
ing a scarf around the neck may de- function is still under study and thought
crease cervical dystonia. Even the to involve protein trafficking; further-
thought of performing the trick can more, recent work using TOR1A mutant
reduce the dystonic movement.3 Pa- models demonstrated a loss of normal
tients may have several tricks, and tricks function with activation of endoplasmic
may vary among individuals. reticulum stress and discrete neurode-
generation.4 TOR1A dystonia is more
Classification common in the Ashkenazi Jewish pop-
Classification schemas for dystonia have ulation, which has a carrier mutation
evolved since first formulated in the frequency of 1:1000 to 1:3000, approx-
1980s. In 2013 a consensus document imately sixfold higher than the general
presented a revised classification that population. The mean age of onset is
categorized dystonia into two nonover- 13 years of age with an initial presen-
lapping axes.1 Axis I categorizes dysto- tation typically in an arm or a leg; leg
nia by the clinical features and axis II onset is often younger than arm onset
by etiology. Clinical features in axis I (mean of 9 years versus 15 years of age).
include the age of onset, affected body Spread to other limbs often occurs, al-
region, temporal pattern, and associ- though almost one-fourth of affected
ated features, as defined in Table 10-1. patients remain as focal dystonia; fur-
Axis II delineates the etiology of the thermore, the cranial muscles are usu-
dystonia and contains two approaches ally spared. DYT-THAP1 is also autosomal
to etiology: (1) Is there neuropathology dominant with reduced penetrance ap-
(degeneration, static/structural, or nei- proximated at 60% and is caused by
ther)? (2) Is there a cause (genetic, ac- mutations in THAP1 (Thanatos-associated
quired, or neither [idiopathic])? The protein domain containing apoptosis
1228 www.ContinuumJournal.com August 2016
associated protein 1). The mean age of been reported to cause isolated adult-
onset is 16 years, and the usual site of onset dystonia: DYT-CIZ1, DYT-ANO3,
onset involves brachial, cervical, or cra- and DYT-GNAL. Prior to these discov-
nial muscles, and unlike DYT-TOR1A, eries, little was known about the cause
speech is often affected. DYT-THAP1 of isolated adult-onset dystonia. All three
dystonia may remain as a focal dystonia; conditions have autosomal dominant
however, more commonly, it becomes inheritance. Commercial testing is not
segmental or generalized. currently available for these mutations.
Since the advent of next-generation CIZ1 (cyclin-dependent kinase inhib-
sequencing, three additional genes have itor 1AYinteracting zinc finger protein 1)
KEY POINT
h The most common cause was identified in a large white kindred population screening, the mutation
of dopa-responsive with adult-onset cervical dystonia.4 accounts for only a very small propor-
dystonia is mutations in Subsequent screens have identified rare tion (1% to 2%) of cervical dystonia in
GCH1, which encodes or no pathogenic variants, suggesting adults. The full phenotypic spectrum and
the rate-limiting enzyme this gene very rarely underlies dysto- penetrance requires additional study.8,9
in the biosynthesis of nia.5,6 ANO3 (anoctamin 3) mutations Many of the combined dystonias have
tetrahydrobiopterin. manifest as tremor-predominant cervi- identified genes as well. Dopa-responsive
cal dystonia. Dystonia may also begin dystonia is due to deficiencies in en-
or spread to involve brachial, laryngeal, zymes involved in the biosynthesis of
or facial muscles. Some patients have dopamine. The most common cause
myocloniclike jerks in the head or arms of dopa-responsive dystonia is muta-
and the age of onset is broad, ranging tions in GCH1, which encodes the rate-
from childhood (4 to 5 years of age) to limiting enzyme in the biosynthesis of
adulthood (40 years of age).7 GNAL mu- tetrahydrobiopterin. Commercially
tations were first identified in two fam- available DNA tests include gene se-
ilies and then confirmed in about 15 quencing and also testing for deletions
additional families; this disorder is in- and duplications. CSF analysis and
herited in an autosomal dominant fash- phenylalanine loading testing are sup-
ion and produces a phenotype usually plementary tests that can assist in
marked by adult-onset cervical and cra- making the diagnosis. Most often,
nial dystonia (either focal or segmental, GCH1mutations cause a childhood
with rare early onset or generalization). onset disorder that is inherited domi-
The GNAL (G protein subunit alpha L) nantly with reduced penetrance.
encoded protein (G"olf) couples the Symptoms are predominantly dystonic
dopamine D1 receptor of the direct and often diurnal. Mean age of onset
pathway and adenosine A2A receptor ranges between 6 and 12 years of age,
of the indirect pathway to the activation with larger studies favoring an older age
of adenylate cyclase type 5 (ADCY5), re- of onset.10 Girls are more likely to be
sulting in adenosine 3¶,5¶-cyclic mon- affected. Case 10-1 illustrates a case of
ophosphate (cAMP) production.8 With dopa-responsive dystonia. Younger
Case 10-1
An 11-year-old girl presented for gait evaluation. Her mother had had a
normal pregnancy, and there were no complications at birth. The patient
walked at 9.5 months but her parents noted that her gait was clumsy and her
toes pointed inward. She walked better in the morning than in the evening.
Prior assessments included a diagnosis of femoral anteversion from a pediatric
orthopedist and cerebral palsy from a neurologist. When she was 6 years old,
she developed clenching of her left hand. The patient had a normal MRI of
her brain and spine. At the time of presentation, her parents noted new right
hand clenching and retrocollis when walking. Family history was significant
for a paternal grandfather with Parkinson disease. Neurologic examination
was pertinent for increased patellar reflexes. While sitting, there was mild
retrocollis and intoeing of both feet. There was dystonic posturing in both
arms (left greater than right) and legs when performing activities in the
limbs. Dystonic posturing was noted in all limbs when walking. She was
started on one-half of a 25 mg/100 mg tablet of carbidopa/levodopa per
day, and she was slowly increased to a whole 25 mg/100 mg tablet 2 times per
Continued on page 1231
KEY POINTS
h The movement disorder dominant with imprinting (the epige- PxMD-PNKD.17 Patients develop acute
examination is crucial to netic process that leads to inactivation dystonia, chorea, or ballistic movements
identifying dystonia of a paternal or maternal allele) with lasting minutes to hours. Attacks are
phenomenology and preferential expression of the paternal infrequent and are commonly triggered
includes several allele. Myoclonus (which is the promi- by alcohol, caffeine, or stress.
elements not routinely nent feature) and dystonia are most All of the axis I features of dystonic
included in the frequently present in the cervical area syndromes are obtained clinically. His-
neurologic examination. and the upper extremities. Symptoms tory should include a careful screen
h Additional studies such often improve with alcohol. However, for exposure to causative agents and a
as genetic testing and patients are at risk for developing detailed family history for movement
neuroimaging may be alcohol dependence, which is seen in disorders. Patients should be asked
required to characterize approximately one-fourth of manifest- about the presence of any ameliorat-
a patient with dystonia ing carriers. Comorbid psychiatric diag- ing or exacerbating features including
along axis II of the noses are common with social and sensory tricks. The presence of depres-
classification system.
specific phobias present in one-third sion and anxiety, which may be comor-
of manifesting carriers. An excess of bid with many forms of dystonia, should
major affective disorder and obsessive- be assessed as well. The movement
compulsive disorder have been re- disorder examination is crucial to iden-
ported.12 A missense mutation in tifying dystonia phenomenology and
CACNA1B was recently identified in includes several elements not routinely
one family with myoclonus-dystonia included in the neurologic examina-
and may also be associated with car- tion. Table 10-2 supplies features of
diac arrhythmias. Painful limb cramps patient history and examination find-
and continuous high-frequency leg my- ings that are helpful to the diagnosis.
oclonus were also present in some of Case 10-2 illustrates the importance
this population.13 of clinical assessment in achieving the
Paroxysmal kinesigenic dyskinesia correct diagnosis and treatment plan.
is a condition where frequent brief Additional studies may be required
(seconds to minutes) hyperkinetic to characterize the etiology of a pa-
movements, including dystonia, are tient’s dystonia, as listed in axis II of
triggered with activity. Attacks are often the revised classification system. Aside
preceded with a sensory warning. Mu- from neurologic signs, the clinical eval-
tations in PRRT2 (proline-rich trans- uation should include an ophthalmic
membrane protein 2) on chromosome and general medical examination that
16 can cause the disease state, which is may point to a specific etiology (eg,
usually autosomal dominant.14,15 This Kayser-Fleischer rings and Wilson dis-
mutation is also associated with infan- ease). When concern exists for vocal
tile convulsions with choreoathetosis cord involvement, ear, nose, and throat
with or without paroxysmal kinesigenic referral is recommended for fiberoptic
dyskinesia, benign familial infantile laryngoscopy. MRI of the brain or spinal
seizures, episodic ataxia, hemiplegic cord should be ordered if the history or
migraine, and benign paroxysmal tor- examination suggests an underlying
ticollis of infancy. Paroxysmal exertionY etiology associated with structural pa-
induced dyskinesia and epilepsy can be thology. In cases where the diagnosis of
caused by mutations in SLC2A1, the dystonia due to a parkinsonian condition
gene that encodes the glucose trans- is considered, a dopamine transporter
porter 1 (GLUT1) of the blood-brain scan may be helpful. If the dopamine
barrier.16 Paroxysmal nonkinesigenic dys- transporter scan shows reduced striatal
kinesia is associated with mutations in dopamine terminals, Parkinson disease
1232 www.ContinuumJournal.com August 2016
Case 10-2
A 65-year-old ambidextrous woman presented with a chief complaint of
head tremor, which developed when she was 30 years old. The tremor was
associated with an uncomfortable tightness in her neck muscles. She was
never exposed to dopamine-blocking medications prior to symptom onset.
The patient’s symptoms improved if she lightly touched her cheek and
when she turned her head to the left. She never had tremor in her voice or
in her limbs, and she denied symptoms of writer’s cramp. Her mother had a
neck tremor as an adult. The patient had been previously diagnosed with
essential tremor, and propranolol had been prescribed but did not improve
symptoms. On examination, there was hypertrophy in both sternocleidomastoid
muscles. She had a jerky, multidirectional neck tremor, notable for a null
point with head turn to the left and neck flexed. There was no tremor in the
arms (Supplemental Digital Content 10-2, links.lww.com/CONT/A199). She
was diagnosed with cervical dystonia with dystonic tremor. Symptoms improved
with botulinum toxin injections that were initially placed in the right
sternocleidomastoid muscle and left splenius cervicis muscle with EMG guidance.
Later injections sets were modified to include bilateral splenii muscles as
well as the right semispinalis capitis and right longissimus muscles.
Comment. The presence of a tremor in the neck is often associated with
essential tremor. However, essential tremor never presents with isolated
neck tremor. The presence of isolated neck tremor should raise suspicion
for an alternate diagnosis. In this case, the patient had a sensory trick, muscle
pain, muscle hypertrophy, and a null point, all suggestive of a diagnosis of
cervical dystonia. Early misdiagnosis led to an ineffective treatment plan.
Careful attention to history and the physical examination will allow the
clinician to offer effective treatments early in the disease.
KEY POINTS
h Targeted, disease-specific with low-dose levodopa for possible have a significant and sustained improve-
treatments are increasing dopa-responsive dystonia (see the ment to low-dose therapy. A gradual
as our understanding of following section on dopaminergic titration starting at 25 mg/d to 50 mg/d
the etiology for the medications). of levodopa for children and 50 mg/d
combined/complex For most patients with multifocal and to 100 mg/d of levodopa for adults is
dystonia syndromes generalized dystonia, oral medical ther- recommended. Slow titration reduces
expands (eg, apy is the first-line approach. Medica- the risk of side effects such as nausea
GLUT1 deficiency, tion options include carbidopa/levodopa, and transient dyskinesias. Usually, a ro-
cerebrotendinous anticholinergics (ie, trihexyphenidyl), bust response occurs with 200 mg/d
xanthomatosis, benzodiazepines, baclofen, and to 300 mg/d but, in rare cases, higher
manganese transport
dopamine-depleting agents. A sum- doses up to 1000 mg/d are needed.29
disorder, Wilson disease).
mary of these medications, along with Wearing-off symptoms and motor fluc-
h For most patients with common doses and side effects, are tuations are not commonly seen in re-
multifocal and listed in Table 10-4. With the exception sponse to long-term use as they are
generalized dystonia,
of a few special circumstances, no in patients with Parkinson disease. Pa-
oral medical therapy is
controlled or randomized studies are tients with nonYdopa-responsive dys-
the first-line approach.
available to guide clinicians to choose tonia, whether idiopathic, genetic, or
one drug over another. acquired, may also have a partial clin-
Dopaminergic medications. ical response to levodopa. Some cases
Carbidopa/levodopa is the standard of dystonic tremor worsen with levo-
of care treatment for dopa-responsive dopa.30 Patients with cerebral palsy may
dystonia as patients characteristically not benefit from levodopa.31
KEY POINTS
h Baclofen is a treatment of paroxysmal nonkinesigenic range from 1 g/d to 7.6 g/d. Sodium oxy-
+-aminobutyric acid B dyskinesia. Dosing is usually twice daily, bate is a Schedule III controlled substance,
receptor agonist although, when initiated, often begins which can cause significant central ner-
reported in several with evening doses to offset possible vous system and respiratory suppression.
retrospective studies to sedation. Titration should be slow. Im- Pharmacologic treatment in spe-
demonstrate benefit in paired mentation and nausea are com- cial circumstances. Antiepileptic drugs
dystonia management, mon side effects. Patients are instructed have variable benefit in dystonia. Car-
especially in children to avoid sudden discontinuation of the bamazepine is the exception, shown to
with comorbid dystonia medication as cessation of large doses be beneficial in cases of paroxysmal
and spasticity. can cause seizures and delirium. kinesigenic dyskinesia. In Wilson dis-
h Chemodenervation with Baclofen is a GABA-B receptor ago- ease, a disorder of copper metabolism,
botulinum neurotoxin is nist reported in several retrospective copper chelators such as peni-
first-line therapy for studies to demonstrate benefit in dys- cillamine and trientine are typically
most patients with focal tonia management, especially in chil- first-line therapy. For more information,
and segmental dystonia.
dren with comorbid dystonia and refer to the article ‘‘Wilson Disease’’ by
spasticity. Because of its mild side effect Ronald F. Pfeiffer, MD, FAAN,44 in this
profile, oral baclofen is frequently tried issue of Continuum. Acute medication-
in adults as well. Patients are often induced dystonic reactions are dystonic
started on 10 mg/d to 15 mg/d given in movements that can occur within mi-
2 to 3 equally divided doses per day and nutes to hours of receiving a medi-
effective doses range from 30 mg/d to cation that causes a nigrostriatal D2
120 mg/d. Common side effects include dopamine blockade. These episodes
sedation, nausea, dizziness, hypotonia, are terminated commonly with the anti-
and impaired cognition. Continuous in- histamine diphenhydramine (25 mg to
trathecal baclofen is an alternative de- 50 mg IV or IM) or the anticholinergic
livery method considered for children benztropine (1 mg to 2 mg IV or IM).
with dystonia and leg spasticity or
cerebral palsy.41 Prior to surgical im- Chemodenervation
plementation, a trial is conducted where Chemodenervation with botulinum neu-
patient response to baclofen delivered rotoxin is first-line therapy for most
through a temporary catheter is as- patients with focal and segmental dys-
sessed. Intraventricular baclofen has tonia. Patients with generalized dysto-
shown benefit in patients with symp- nia can also receive therapy to targeted
tomatic generalized dystonia who are areas. Botulinum neurotoxin is a neu-
refractory to oral medications. Patients rotoxic protein that is produced by the
taking baclofen can also develop sei- bacterium Clostridium botulinum. The
zures, delirium, rebound muscle rigid- toxin is injected into the affected
ity, rhabdomyolysis, hyperpyrexia, and muscle(s) and taken up into associated
organ failure with abrupt discontinua- motor neurons. The toxin then blocks
tion of the baclofen; a slow taper off the vesicular release of acetylcholine
the medication is recommended. into the neuromuscular junction, ulti-
Sodium oxybate is the sodium salt mately reducing the involuntary activity
of +-hydroxybutyrate, a metabolite of of the affected muscles. Although
the neurotransmitter GABA. It is ap- seven distinct serotypes (A to G) exist,
proved for use in cataplexy and exces- only types A and B are used commer-
sive daytime sleepiness in narcolepsy. cially and have US Food and Drug Ad-
However there are reports that it is ministration (FDA) approval for clinical
helpful in myoclonus-dystonia and spas- use. Serotype A is available as onabotu-
modic dysphonia.42,43 Effective doses linumtoxinA, abobotulinumtoxinA, and
1238 www.ContinuumJournal.com August 2016
KEY POINT
h Substantial data instrument significantly improved injec- pallidus internus (GPi) is the target for
suggest that patients tion outcomes.50 most surgeries. In 2006, the first sham
with DYT1 and isolated In the future, mapping of muscle study, including a group of 40 patients
non-DYT1 generalized endplates may improve efficacy and re- with isolated segmental or generalized
dystonia are most duce the side effects of toxin injection. A dystonia, was published.52 Patients
responsive to deep brain study using high-density surface EMG receiving true stimulation had signifi-
stimulation intervention. found that patients with cervical dysto- cant improvement when compared to
nia had equal clinical benefit when the sham. Substantial data suggest that
toxin was injected at half dose in the patients with DYT1 and isolated non-
motor unit endplates of the splenius DYT1 generalized dystonia are most
capitis or sternocleidomastoid mus- responsive to DBS intervention.53 How-
cles compared to normal doses during ever, patients with DYT6 dystonia may
the patients’ traditional injections.51 not have as robust of a response.54
More recent studies have shown im-
Surgical Intervention provement in patients with isolated
In 2003, deep brain stimulation (DBS) cervical dystonia resistant to chemode-
received a humanitarian exemption by nervation, combined dystonia such as
the FDA for use in dystonia. Since this myoclonus-dystonia, and dystonia in
time, it has emerged as first-line sur- other identified genetic and central
gical therapy for dystonia. The globus nervous system diseases.55,56 Case 10-3
Case 10-3
A 51-year-old man presented with a chief complaint of involuntary tongue
protrusion, dysphagia, increased salivation, and impaired speech progressing
over a 1-year period. He had not been exposed to dopamine-blocking
medication prior to symptom onset. On physical examination he had severe
dysarthria and hypometric saccades on vertical gaze. Motor examination
was pertinent for involuntary tongue protrusion with improvement when a
tongue depressor rested on the tongue, diffuse rigidity, dystonic posturing
of all four limbs, and truncal tilt to the right with retropulsion when walking.
Imaging was normal, as was video laryngoscopy. There was no significant
clinical response to trihexyphenidyl or clonazepam. Genetic testing revealed
a mutated allele (T) at DSC3 and a mutated allele (G) at DSC12 on his X
chromosome. This confirmed a diagnosis of X-linked dystonia-parkinsonism
(DYT3). The patient received bilateral globus pallidus internus (GPi) deep
brain stimulation (DBS). Early improvements were seen in the limbs. Two
years after surgery the patient had no involuntary tongue protrusion,
improved dysarthria and dysphagia, no limb involvement, and improved
truncal movements. Supplemental Digital Content 10-3, links.lww.com/
CONT/A200 illustrates this case pre- and post-DBS.
Comment. X-linked dystonia-parkinsonism is a condition that typically
presents in adulthood. The disease is also called Lubag disease from first
descriptions of the disease in subjects from the island of Panay in the
Philippines. Patients may have a focal onset, but dystonia typically generalizes.
This case demonstrates clinical improvement in a patient with DYT3 dystonia.
A recent case report and review of the literature found significant clinical
improvement in other patients with DYT3 dystonia.57 Benefits of DBS for
DYT1 are well reported. However, growing evidence suggests that other
genetic forms of dystonia may improve with surgical intervention.
collis Association supports individuals 11. Sweney MT, Newcomb TM, Swoboda KJ. The
expanding spectrum of neurological
and families affected by the condition, phenotypes in children with ATP1A3 mutations,
promotes awareness, and advances Alternating Hemiplegia of Childhood,
research for treatment. Rapid-onset Dystonia-Parkinsonism, CAPOS
and beyond. Pediatr Neurol 2015;52(1):56Y64.
www.torticollis.org doi:10.1016/j.pediatrneurol.2014.09.015.
Spasmodic Torticollis Dystonia. The 12. Peall KJ, Dijk JM, Saunders-Pullman R, et al.
Psychiatric disorders, myoclonus dystonia
Spasmodic Torticollis Dystonia organiza-
and SGCE: an international study. Ann Clin
tion provides information and research Transl Neuro 2016;3(1):4Y11. doi:10.1002/
on the condition as well as doctor and acn3.263.
patient opinions on various treatments. 13. Groen JL, Andrade A, Ritz K, et al. CACNA1B
mutation is linked to unique myoclonus-dystonia
www.spasmodictorticollis.org syndrome. Hum Mol Genet 2015;24(4):
987Y993. doi:10.1093/hmg/ddu513.
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Clinical features of patients with blepharospasm: does not improve function in individuals with
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33. Luciano AY, Jinnah HA, Pfeiffer RF, et al.
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87Y100. doi:10.1007/s00415-014-7586-2. 1531-8257(199907)14:4G652::AID-
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40. Greene P, Shale H, Fahn S. Experience with
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42. Frucht SJ, Bordelon Y, Houghton WH,
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2006;21(10):1778Y1780. doi:10.1002/mds.21043. D8CJ8C5S
Wilson Disease
Address correspondence to
Dr Ronald F. Pfeiffer,
Department of Neurology,
Oregon Health & Science
University, 3181 SW Sam Ronald F. Pfeiffer, MD, FAAN
Jackson Park Rd, Portland,
OR 97239-3098,
pfeiffro@ohsu.edu.
Relationship Disclosure: ABSTRACT
Dr Pfeiffer received personal Purpose of Review: This article reviews the clinical features of Wilson disease,
compensation for serving on
the advisory boards of focusing on the neurologic and psychiatric abnormalities, and addresses the diagnostic
Acadia Pharmaceuticals Inc, workup and treatment approaches to managing the disease.
Lundbeck, and Pfizer Inc, Recent Findings: The list of known mutations causing Wilson disease continues to
as a consultant for Clintara
LLC, for serving as co-editor- grow, but advances in genetic testing may soon make it feasible to routinely perform
in-chief of Parkinsonism & genetic testing on individuals suspected of having Wilson disease.
Related Disorders, and for Summary: Wilson disease is a rare genetic disorder with protean manifestations that
serving on the speakers
bureau of Teva should be considered in the differential diagnosis of any individual presenting with
Pharmaceutical Industries Ltd. unexplained neurologic, psychiatric, or hepatic dysfunction. Appropriate diagnostic
Dr Pfeiffer served on the testing should be expeditiously performed and treatment promptly initiated and
editorial boards of the
International Journal of maintained since failure to diagnose and treat Wilson disease will result in progressive
Brain Science and the Journal and ultimately irreversible damage to the neurologic and other systems.
of Parkinson’s Disease and
receives publishing royalties
from CRC Press, Taylor & Continuum (Minneap Minn) 2016;22(4):1246–1261.
Francis Group, and Humana
Press/Springer. Dr Pfeiffer
served as principal
investigator of a study for the INTRODUCTION the incorporation of copper into
Michael J. Fox Foundation, the
Parkinson Study Group, and In 1912 S. A. Kinnear Wilson published apoceruloplasmin to form ceruloplas-
Rhythm Pharmaceuticals, Inc. a detailed description of the illness that min. In Wilson disease, the defective
Unlabeled Use of
Products/Investigational now bears his name.1 Over the years, ATP7B protein cannot perform this
Use Disclosure: many others have contributed to the function, resulting in abnormally low
Dr Pfeiffer discusses the levels of ceruloplasmin. When hepatic
unlabeled/investigational use
recognition and knowledge of Wilson
of zinc for the treatment of disease, leading to our current under- copper levels are elevated, ATP7B is
Wilson disease. standing that the fundamental abnor- redistributed to cytoplasmic vesicles
* 2016 American Academy where it facilitates copper transport into
of Neurology.
mality of Wilson disease is the impaired
biliary excretion of copper. This results the bile canaliculi.2 This function also
in a gradual accumulation of copper is impaired in Wilson disease, which
and consequent tissue damage, initially leads to a gradual increase in copper
within the liver but eventually also in levels within the liver, and when the
other organs, including the brain. Al- capacity of the liver to store the
though a genetic basis for Wilson relentlessly accumulating copper is
disease was documented within 10 exceeded, the copper spills out of the
years of Wilson’s initial publication and liver to inflict damage in other organs
subsequently identified as an autosomal as well. ATP7B dysfunction and hepatic
recessive disorder, it was not until 1993 dysfunction may also lead to accumu-
that the responsible gene, now known lation of other metals, such as iron and
as ATP7B, was identified on chromo- manganese, in the brains of individuals
Supplemental digital content:
Videos accompanying this ar- some 13. with Wilson disease, perhaps contrib-
ticle are cited in the text as The protein (also named ATP7B) uting to symptoms.3
Supplemental Digital Content.
Videos may be accessed by encoded by the gene typically resides Over 520 Wilson disease mutations
clicking on links provided in the within the trans-Golgi network in have been identified, and most in-
HTML, PDF, and app versions
of this article; the URLs are
hepatocytes and transports copper dividuals with Wilson disease are com-
provided in the print version. Video across organelle membranes, enabling pound heterozygotes. 4 Missense
legends begin on page 1259.
KEY POINTS
h Neurologic dysfunction TABLE 11-1 Multisystem TABLE 11-1 Continued
is the initial clinical Involvement in
manifestation of Wilson Wilson Disease b Musculoskeletal
disease in 40% to 60%
Osteoporosis
of patients, with a b Hepatic
typical appearance at Slowly progressive hepatic Osteomalacia
approximately 20 years failure with cirrhosis Osteoarthritis
of age.
Mimicking acute viral hepatitis Spontaneous fractures
h Basal gangliaYbased
abnormalities, especially Mimicking autoimmune b Myocardial
chronic active hepatitis
tremor and dystonia, Cardiac hypertrophy
are the most common Acute fulminant hepatic failure
neurologic features of Cardiomyopathy
b Neurologic
Wilson disease. Electrocardiographic
Basal ganglia dysfunction abnormalities
Tremor b Renal
Dystonia Renal impairment
Chorea Nephrocalcinosis
Athetosis Hematuria
Parkinsonism Proteinuria
Myoclonus b Dermatologic
Cerebellar dysfunction Hyperpigmentation of
Combined dysfunction the legs
Risus sardonicus, the fixed facial gri- Wilson disease, but upper motor neu-
mace or smile, is produced by dysto- ron signs, lower motor neuron signs,
nia of the facial muscles. Parkinsonism sensory loss, and sphincter dysfunction
is evident in approximately 40% of all are unusual.19,21
persons with Wilson disease.19 Chorea,
athetosis, and myoclonus are less com- Psychiatric Manifestations
mon, but do occur.18,20 Most reports indicate that psychiatric
Cerebellar dysfunction develops in symptoms are evident at or prior to
approximately 30% of individuals with diagnosis in approximately 30% to
Wilson disease.20 Dysarthria may be 40% of individuals with Wilson
cerebellar or hypokinetic in character disease.22 Psychiatric dysfunction in
and eventually develops in the vast Wilson disease may range from subtle
majority of individuals with Wilson personality changes to frank psychosis
disease. Dysarthria may progress to the (Table 11-1). Depression is common,
point of complete anarthria. Dysphagia and suicidal behavior has been reported.
also may develop during the course of Acute psychosis may be the present-
Wilson disease and may be present in ing feature of Wilson disease and is
up to 50% of individuals at the time of characterized by paranoid ideation, de-
diagnosis.18 Some disturbance of gait is lusional thinking, hallucinations, and
evident in 45% to 75% of patients with even catatonia.23 Psychosis may first
Wilson disease at the time of diagnosis appear during recovery of motor func-
and may range in character from par- tion following initiation of copper
kinsonian to cerebellar.12,18 chelation therapy and in that setting
Other neurologic abnormalities, is attributed to improved motor func-
such as autonomic dysfunction, sei- tion unveiling previously masked psy-
zures, and headaches, may occur in chosis.10 Dementia is uncommon in
KEY POINTS
h Kayser-Fleischer rings Wilson disease but may develop in ent in only 2% to 17% of individuals
may not be present in individuals with advanced disease. Mild with untreated Wilson disease. They
persons with Wilson cognitive impairment is present more are produced by deposition of copper
disease who are frequently.24 in the anterior capsule and have a
asymptomatic or sunflower or sunburstlike appearance.
who have only Ophthalmic Manifestations Sunflower cataracts do not interfere
hepatic dysfunction; Although various ophthalmic abnor- with vision and typically require slit-
furthermore, they may malities have been described in pa- lamp examination to be seen.
occur in other tients with Wilson disease, two classic
conditions characterized findings are important to remember Other Manifestations
by hepatic dysfunction.
(Table 11-1). Formed by the deposi- Coombs-negative hemolytic anemia
h Coombs-negative tion of copper within Descemet mem- may be the initial manifestation of
hemolytic anemia in brane in the cornea, Kayser-Fleischer Wilson disease in 10% to 15% of cases.26
combination with liver rings are the best known ophthalmic The combination of unexplained
disease should always
abnormality in Wilson disease. They Coombs-negative hemolytic anemia
prompt evaluation for
usually are gold, brown, or green in and liver disease should always prompt
Wilson disease.
color and almost always are bilateral. evaluation for possible Wilson dis-
Slit-lamp examination often is necessary ease.12 Osteoporosis and bone fractures
to visualize Kayser-Fleischer rings, es- are quite common in Wilson disease.27
pecially in brown-eyed individuals. Be- Joint involvement also is frequent,
cause they first appear in the superior possibly the result of copper and iron
and then the inferior aspect of the deposition within joints producing free
cornea, lifting the eyelid during exami- radicalYinduced synovial and cartilage
nation is important to make sure early damage. Myocardial involvement in
Kayser-Fleischer rings are not over- Wilson disease is not widely recognized,
looked. Kayser-Fleischer rings may not but also is surprisingly common and
yet have formed in persons who are includes cardiac hypertrophy and elec-
presymptomatic or have only hepatic trocardiographic abnormalities. Renal
involvement. In one study, Kayser- involvement may also occur in Wilson
Fleischer rings were evident in 100% disease and is the presenting feature in
of patients with neurologic dysfunction, rare instances. Hyperpigmentation of
but in 86% of persons with just hepatic the legs may occur and be mistaken
involvement, and in only 59% of for Addison disease.
presymptomatic individuals.20 Others
have reported that Kayser-Fleischer DIAGNOSTIC EVALUATION OF
rings are evident at the time of diag- WILSON DISEASE
nosis in only 44% to 62% of patients Accurate and affordable genetic test-
presenting with hepatic dysfunction.25 ing, which would permit diagnosis of
Kayser-Fleischer rings are not patho- Wilson disease by a single simple test,
gnomonic for Wilson disease, and may soon become routinely available,
pigmented corneal rings indistinguish- but until then diagnosis is still depen-
able from Kayser-Fleischer rings have dent upon the judicious and expedi-
been described in a number of condi- tious employment of a constellation of
tions characterized by hepatic dysfunc- diagnostic studies (Table 11-2).6 A
tion, including primary biliary cirrhosis scoring system has been devised to
and others. assist in the diagnosis of Wilson dis-
The sunflower cataract is another ease.9 Wilson disease should be con-
classic, but much less frequent, ocular sidered in the differential diagnosis of
manifestation of Wilson disease, pres- any individual, particularly any young
1250 www.ContinuumJournal.com August 2016
KEY POINTS
h Ceruloplasmin is not an
adequate sole screening
Case 11-2
An 11-year-old girl was brought in for evaluation by her parents following
test for Wilson disease
her 15-year-old brother’s recent diagnosis of Wilson disease. The patient
because it be may
felt completely normal, had not experienced any symptoms of hepatic,
normal or only slightly
neurologic, or psychiatric dysfunction, and her general physical and
low in 5% to 15%
neurologic examinations were completely normal. She had no
of persons with
Kayser-Fleischer rings on ophthalmologic examination. Hepatic function
Wilson disease.
studies, ceruloplasmin, and 24-hour urinary copper levels were all within
h Elevated 24-hour urine normal limits. Formal genetic testing was performed, however, and
copper is not demonstrated the same ATP7B mutation as her brother. She was placed on
pathognomonic for treatment with zinc.
Wilson disease because Comment. Screening laboratory studies may be entirely normal in
it may be elevated in individuals with Wilson disease who have not yet developed symptoms.
obstructive liver diseases Therefore, all asymptomatic siblings of individuals with Wilson disease
and in carriers of should undergo genetic testing and, if test results are positive, should be
Wilson disease. placed on therapy with zinc.
KEY POINTS
h In individuals with Neuropsychiatric presentation. In ping results in a small, but significant,
neurologic or psychiatric individuals presenting with either neu- negative copper balance.
dysfunction, a rologic or psychiatric dysfunction, a Initially, its use was limited to pre-
combination of combination of Kayser-Fleischer rings, symptomatic individuals, but with fur-
Kayser-Fleischer rings, elevated 24-hour urinary copper, and ther experience, the use of zinc as
elevated 24-hour urine reduced ceruloplasmin essentially maintenance therapy following initial
copper, and reduced confirms the diagnosis of Wilson dis- treatment of neurologically symptom-
ceruloplasmin confirms ease, and liver biopsy is unnecessary. atic individuals with other more potent
the diagnosis of Wilson However, in the occasional situa- decoppering agents also has become
disease, and liver biopsy tion where either the 24-hour urine accepted.12,25,31 Some, although cer-
is not necessary.
or the ceruloplasmin level is inconclu- tainly not all, investigators now even
h Zinc, penicillamine, and sive, liver biopsy may still be neces- consider zinc to be first-line therapy for
trientine for treatment sary. Once again, genetic testing will Wilson disease.4,31,32
of Wilson disease eventually become the diagnostic test Zinc may be administered as zinc
should be taken on an
of choice. acetate, sulfate, or gluconate and
empty stomach.
should always be taken on an empty
TREATMENT stomach. Adverse effects are rare, but
A variety of treatment approaches gastric irritation may occur; zinc acetate
have been utilized in the treatment is less likely to cause this than zinc
of Wilson disease. Treatment also will sulfate. The typical dose of zinc used
vary depending on the clinical presen- for both presymptomatic and symp-
tation of the patient. tomatic patients with Wilson disease
is 50 mg of elemental zinc 3 times daily
Dietary Therapy (zinc sulfate is often marketed as
Dietary restriction of copper intake containing 220 mg of zinc sulfate salt,
has not been a successful treatment but this translates to 50 mg of elemen-
approach in Wilson disease, although tal zinc).
some investigators recommend avoid-
ance of foods such as shellfish, liver, Copper Chelation Therapy
nuts, chocolate, and mushrooms, In contrast to decreasing absorption,
which have particularly high cop- the other treatment approach for
per content.12,25 Wilson disease entails increasing the
elimination of copper from the body
Inhibition of Intestinal Copper by means that circumvent the dam-
Absorption aged and inactive hepatic route. Che-
Limiting the accumulation of copper lation of copper with subsequent renal
by inhibiting its absorption from the excretion of the chelated compound
gastrointestinal tract is one approach has been the standard treatment of
that may be taken in the treatment of Wilson disease. Two agents currently
Wilson disease. The agent currently are used.
used for this is zinc. Penicillamine. Penicillamine is a
Zinc. Zinc is absorbed by intestinal metabolic byproduct of penicillin that
enterocytes and induces metallothionein avidly chelates copper. Penicillamine
formation within them. The induced should always be given on an empty
metallothionein binds dietary copper stomach because its bioavailability is
and traps it within the enterocytes until reduced by approximately 50% if it
the cells are eventually sloughed and is ingested with food. Pyridoxine sup-
excreted in the feces. This zinc-induced, plementation sometimes is recom-
metallothionein-mediated copper trap- mended because penicillamine is a
1254 www.ContinuumJournal.com August 2016
KEY POINT
h Liver transplantation available medications should they be- topic liver transplantation has been
typically is necessary come available. reported, presumably due to massive
in individuals with Tetrathiomolybdate. Ammonium release of copper from the liver dam-
Wilson disease who tetrathiomolybdate was first tested aged by Wilson disease just prior to
develop acute for the treatment of Wilson disease in and during its removal.
fulminant hepatic 1984, but it remains an experimental The potential utility of orthotopic
failure. Following treatment modality, unavailable for liver transplantation in treating the
successful transplantation, general use. patient with Wilson disease with stable
ongoing pharmacologic liver function but severe neurologic
treatment is not Liver Transplantation dysfunction who is advancing despite
necessary.
Historically, the mortality rate of ful- optimal medical management has
minant hepatic failure in the setting of been proposed, but is still considered
Wilson disease has been virtually 100% to be experimental and not routine
if treatment is confined to medical standard of care.
management, although in a recent Living related liver transplantation,
report, six out of nine patients treated in which the donor is a living relative
with a combination of a corticosteroid, of the affected patient and donates
a copper chelating agent, and thera- part of his or her liver, has been suc-
peutic plasma exchange recovered.37 cessfully employed in Wilson disease.
Orthotopic liver transplantation still More temporary or bridging methods
remains the definitive treatment for this also are being investigated to support
complication of Wilson disease and individuals until a donor liver becomes
also may be appropriately employed in available, such as exchange transfusion,
patients with chronic severe hepatic plasma exchange, hemofiltration, albu-
insufficiency who are unresponsive to min dialysis, and the molecular absor-
medical management. With growing bent recirculating system.16
experience and surgical refinements,
the 5-year survival rate following ortho- Deep Brain Stimulation
topic liver transplantation for Wilson For patients with Wilson disease with
disease is now 85% to 90%.16 Since the neurologic dysfunction who do not
transplanted liver is free of the genetic achieve a satisfactory outcome from
defect that characterizes Wilson dis- medical treatment, evidence is emerg-
ease and contains normally functioning ing that deep brain stimulation (DBS)
ATP7B protein, copper metabolism may be useful in some instances, such
normalizes following orthotopic liver as refractory tremor or dystonia, but
transplantation, and continued chela- experience is still limited.38
tion or other medical therapy generally
is no longer necessary. However, the Treatment Guidelines
genetic abnormality remains in all Recommended treatment approaches
other body tissues and, thus, will be to Wilson disease differ, depending on
passed on to all children, and if the the clinical presentation of the patient.
transplanted liver was received from a These are summarized in the follow-
parent as a living related donor, the ing paragraphs and in Table 11-3.
transplanted liver will bear the genetic Asymptomatic patients. In the indi-
makeup of a heterozygote for Wilson vidual who is still asymptomatic, most
disease and may not have entirely investigators now recommend that
normal liver function. therapy be initiated with zinc alone.
The appearance of neurologic Hepatic presentation. In the indi-
symptoms shortly following ortho- vidual who has hepatic but not
1256 www.ContinuumJournal.com August 2016
KEY POINT
h Copper deficiency may important, but often neglected, aspect stable penicillamine therapy, the
develop during of Wilson disease management. Even 24-hour urinary copper level should
long-term therapy with with close follow-up, compliance be in the range of 200 mcg/d to
chelating agents in problems become evident in a signif- 500 mcg/d; levels below 200 mcg/d
individuals with Wilson icant portion of patients with Wilson may indicate either noncompliance
disease, and anemia disease, which makes it vital that or overtreatment.25 The serum free
may be the initial sign of compliance be monitored regularly. (nonceruloplasmin-bound) copper level
copper deficiency. Strict compliance is so vital that some can also be a useful monitoring tool;
authorities recommend supervised elevation above 15 mcg/dL suggests
medication administration and weekly inadequate compliance.12
or biweekly clinic visits during the It is important to remember that
initial treatment stages.33 Compliance prolonged treatment with zinc and
with zinc therapy can be assessed by chelating agents poses the risk of
measurement of 24-hour urinary zinc actually inducing a copper deficiency
and copper levels. A 24-hour urinary state in the patient with Wilson dis-
zinc level of less than 2 mg (normal is ease (Case 11-3). Anemia, sometimes
0.1 mg to 0.4 mg) indicates inadequate with associated leukopenia, may be
compliance. Monitoring compliance the initial sign of copper deficiency.
with trientine or penicillamine therapy In patients on zinc maintenance ther-
is somewhat more difficult, but a spike apy, a 24-hour urinary copper level
in a previously gradually decreasing below 35 mcg/d is suggestive of
24-hour urinary copper level may copper deficiency due to over-
indicate inadequate compliance. In treatment.12 For individuals on trien-
patients with Wilson disease on chronic, tine or penicillamine, a serum-free
Case 11-3
A 27-year-old man presented in routine follow-up to the neurology clinic.
He had been diagnosed with Wilson disease 6 years previously. After his
initial diagnosis, the patient was placed on treatment with penicillamine
and both neurologic and hepatic function improved markedly. This
improvement had been maintained. Two years ago he was switched to
zinc maintenance therapy. Periodic monitoring with 24-hour urine copper
determinations demonstrated a level of 200 mcg/d to 300 mcg/d when he
was on penicillamine, but his most recent level was only 20 mcg/d. A recent
blood test documented the presence of both anemia and leukopenia.
Comment. The presence of anemia and leukopenia in an individual with
Wilson disease on chronic treatment with either a chelating agent or zinc
should raise the question of acquired copper deficiency. In addition to
hematologic dysfunction, prolonged copper deficiency can result in
progressive neuropathy and myelopathy that may be irreversible. There
are no firm guidelines on how to treat acquired copper deficiency in the
setting of Wilson disease. The zinc or chelating agent should be
temporarily stopped. Copper supplementation, as would be employed in
other copper deficiency syndromes, would not be prudent in most
instances in this setting, but if myelopathy has developed subacutely,
copper should be administered to more rapidly replenish copper to normal
levels. Monitoring copper status and resuming chelation or zinc therapy
at a lower dose once copper status has reached normal levels is a
reasonable treatment approach.
13. Merle U, Schaefer M, Ferenci P, Stremmel W. 25. Roberts EA, Schilsky ML; American Association
Clinical presentation, diagnosis, and for Study of Liver Diseases (AASLD). Diagnosis
long-term outcome of Wilson’s disease: a and treatment of Wilson disease: an
cohort study. Gut 2007;56(1):115Y120. update. Hepatology 2008;47(6):2089Y2111.
doi:10.1136/gut.2005.087262. doi:10.1002/hep.22261.
14. Kim JW, Kim JH, Seo JK, et al. Genetically 26. Roberts EA, Schilsky ML; Division of
confirmed Wilson disease in a 9-month old Gastroenterology and Nutrition, Hospital
boy with elevations of aminotransferases. for Sick Children, Toronto, Ontario, Canada.
World J Hepatol 2013;5(3):156Y159. A practice guideline on Wilson disease.
doi:10.4254/wjh.v5.i3.156. Hepatology 2003;37(6):1475Y1492.
doi:10.1053/jhep.2003.50252.
15. Członkowska A, Rodo M, Gromadzka G.
27. Quemeneur AS, Trocello JM, Ea HK, et al.
Late onset Wilson’s disease: therapeutic
Bone status and fractures in 85 adults with
implications. Mov Disord 2008;23(6):
Wilson’s disease. Osteoporos Int
896Y898. doi:10.1002/mds.21985.
2014;25(11):2573Y2580. doi:10.1007/
16. Schilsky ML. Liver transplantation for s00198-014-2806-2.
Wilson’s disease. Ann N Y Acad Sci
28. Ferenci P, Steindl-Munda P, Vogel W, et al.
2014;1315:45Y49. doi:10.1111/nyas.12454.
Diagnostic value of quantitative hepatic
17. Ala A, Borjigin J, Rochwarger A, Schilsky M. copper determination in patients with
Wilson disease in septuagenarian siblings: Wilson’s disease. Clin Gastroenterol Hepatol
raising the bar for diagnosis. Hepatology 2005;3(8):811Y818. doi:10.1016/S1542-
2005;41(3):668Y670. doi:10.1002/ 3565(05)00181-3.
hep.20601.
29. McMillin GA, Travis JJ, Hunt JW. Direct
18. Machado A, Chien HF, Deguti MM, et al. measurement of free copper in serum or
Neurological manifestations in Wilson’s plasma ultrafiltrate. Am J Clin Pathol
disease: report of 119 cases. Mov Disord 2009;131(2):160Y165. doi:10.1309/
2006;21(12):2192Y2196. doi:10.1002/ AJCP7Z9KBFINVGYF.
mds.21170.
30. Sinha S, Taly AB, Ravishankar S, et al.
19. Dusek P, Litwin T, Czlonkowska A. Wilson Wilson’s disease: cranial MRI observations
disease and other neurodegenerations and clinical correlation. Neuroradiology
with metal accumulations. Neurol Clin 2006;48(9):613Y621. doi:10.1007/
2015;33(1):175Y204. doi:10.1016/ s00234-006-0101-4.
j.ncl.2014.09.006.
31. Hoogenraad TU. Paradigm shift in treatment
20. Taly AB, Meenakshi-Sundaram S, Sinha S, of Wilson’s disease: zinc therapy now
et al. Wilson disease: description of 282 treatment of choice. Brain Dev 2006;28(3):
patients evaluated over 3 decades. Medicine 141Y146. doi:10.1016/j.braindev.2005.08.008.
(Baltimore) 2007;86(2):112Y121. doi:10.1097/
32. Weiss KH, Gotthardt DN, Klemm D, et al.
MD.0b013e318045a00e.
Zinc monotherapy is not as effective as
21. Berger B, Mader I, Damjanovic K, et al. chelating agents in treatment of Wilson
Epileptic status immediately after initiation disease. Gastroenterology
of D-penicillamine therapy in a patient with 2011;140(4):1189Y1198. e1. doi:10.1053/
Wilson’s disease. Clin Neurol Neurosurg j.gastro.2010.12.034.
2014;127:122Y124. doi:10.1016/
33. Aggarwal A, Bhatt M. The pragmatic
j.clineuro.2014.09.030.
treatment of Wilson’s disease. Mov Disord
22. Zimbrean PC, Schilsky ML. Psychiatric aspects Clin Pract 2014;1:14Y23. doi:10.1002/
of Wilson’s disease: a review. Gen Hosp mdc3.12003.
Postreading
Self-Assessment and
CME Test
James W. M. Owens Jr, MD, PhD; Joseph E. Safdieh, MD, FAAN
b 23. A 10-year-old girl presents for evaluation of muscle stiffness and abnormal
gait. Her symptoms began at age 8 and have been progressing. Initially, her
feet would turn inward when walking, and more recently she reports that her
thighs feel very tight. A family history of dystonia exists in her mother and a
maternal aunt. On examination, she demonstrates dystonic posturing of her
left foot, and when walking, she develops dystonic posturing in both lower
extremities. What is the most appropriate initial therapy?
A. benztropine
B . levodopa
C. onabotulinumtoxinA
D. tetrabenazine
E . trihexyphenidyl
b 24. A 55-year-old right-handed man reports right hand clumsiness, which has
progressed over the past 2 years. He reports no weakness or clear sensory
disturbance of the hand but reports increasing difficulty holding objects or
using utensils. He now uses his left hand more than his right. Over the last
6 months he has begun to notice a right hand tremor that has been slowly
worsening in intensity. A trial of levodopa up to a dose of 1200 mg/d provided no
noticeable improvement. On examination he has a coarse 6 Hz tremor at the
right wrist at rest and with action. His motor examination reveals normal
strength throughout, with rigidity of the right arm at the wrist and elbow
and dystonic posturing of the hand. Primary sensory modalities are intact but
he exhibits agraphesthesia and astereognosis of the right hand. He also is
unable to mime tasks or imitate gestures with his right hand, although he has
no difficulty doing so with his left. His Montreal Cognitive Assessment (MoCA)
score is 25 out of 30; he is unable to complete the Trails test, draw a cube,
and has difficulty drawing a clock face. What is the most likely diagnosis for
this patient?
A. corticobasal degeneration
B . dementia with Lewy bodies
C. idiopathic Parkinson disease
D. multiple system atrophy
E . progressive supranuclear palsy
b 33. Which of the following patients with Parkinson disease is most likely to
develop an impulse control disorder from dopamine agonist therapy?
A. a 42-year-old man
B . a 42-year-old woman
C. a 71-year-old man
D. a 71-year-old woman
E . an 87-year-old man
b 34. A 17-year-old boy presents for evaluation of tremor. His symptoms started
6 months ago and have been progressively worsening. He reports a tremor
in his arms and a sense of tightness in his limbs and face. He has no family history
of neurologic disease. Neurologic examination is notable for facial dystonia,
proximal, bilateral upper extremity high-amplitude tremor, and mild symmetric
rigidity. Which of the following additional neurologic signs is most likely to be
present in this patient?
A. Babinski sign
B . distal symmetric sensory loss
C. fasciculations
D. Kayser-Fleischer rings
E . reduced rectal tone
b 35. A 64-year-old man with early Parkinson disease has been maintained on
rasagiline for 10 months. He presents because his symptoms, which had initially
stabilized, seem to be worsening over the past 2 months. He describes a sense of
stiffness in his left arm as well as difficulty keeping up with his spouse when they
are walking outside. On examination, he is noted to have decreased blink rate,
bilateral upper extremity rigidity and bradykinesia (left greater than right), mild
resting tremor in the left hand, and mildly stooped posture with no retropulsion.
Which of the following is the most appropriate next step?
A. add amantadine
B . add benztropine
C. add droxidopa
D. add rotigotine
E . change rasagiline to selegiline
b 39. Which of the following is the most sensitive diagnostic test for Wilson disease?
A. 24-hour urinary copper excretion
B . liver biopsy
C. serum ceruloplasmin
D. serum copper
E . slit-lamp examination
b 40. Two days after returning from a family vacation to Korea, a 6-year-old girl
develops a high fever, headache, and significant dystonic movements. Which
of the following infectious agents is most likely responsible for her presentation?
A. Cryptococcus neoformans
B . herpes simplex virus type 1
C. Japanese B encephalitis virus
D. Mycobacterium tuberculosis
E . poliomyelitis virus
Postreading
Self-Assessment and
CME Test—Preferred
Responses
James W. M. Owens Jr, MD, PhD; Joseph E. Safdieh, MD, FAAN
b 4. A 56-year-old man who was diagnosed with Parkinson disease 5 years ago
presents with increased stiffness. He is maintained on carbidopa/levodopa
25 mg/100 mg 4 times a day and pramipexole 1.5 mg 3 times daily. Initially,
he found the treatment to be extremely effective, but the patient notes
that over the past year he can feel when he needs the next dose. The patient
feels very stiff and slow with worsening tremor about an hour before his
next dose of carbidopa/levodopa. What is the most appropriate next step?
A. deep brain stimulation
B . entacapone
C. infusional levodopa/carbidopa intestinal gel
D. ropinirole
E . trihexyphenidyl
b 13. A 69-year-old man presents with a tremor in his right hand that developed
1 week ago and has become quite disabling. On examination, he has a
mild resting tremor in the right hand. The tremor worsens when he holds
his arms outstretched and is especially exacerbated by performing a task
with his right hand, such as drawing a spiral or pouring water into a cup.
What is the most likely cause of the tremor?
A. dystonic tremor
B . essential tremor
C. fragile X tremor-ataxia syndrome
D. midbrain infarct
E . Parkinson disease
The preferred response is A (botulinum toxin). This patient has a focal neck
dystonia that is interfering with his work. Botulinum toxin injection would
be considered first-line therapy for this condition. Carbamazepine
is beneficial for paroxysmal kinesigenic dyskinesia, among other conditions.
Carbidopa/levodopa is optimal for patients with dopa-responsive dystonia.
Trihexyphenidyl may be considered for dystonic tremor if botulinum toxin
fails to adequately control the symptoms. Tetrabenazine, which inhibits
presynaptic vesicular uptake of dopamine, would not be considered first-line
therapy in a patient with a focal neck dystonia, but would be considered in
a patient with a more persistent, and particularly tardive, dystonia. For more
information, refer to page 1238 of the Continuum article ‘‘Diagnosis and
Management of Dystonia.’’
b 23. A 10-year-old girl presents for evaluation of muscle stiffness and abnormal
gait. Her symptoms began at age 8 and have been progressing. Initially,
her feet would turn inward when walking, and more recently she reports that
her thighs feel very tight. A family history of dystonia exists in her mother
and a maternal aunt. On examination, she demonstrates dystonic posturing
of her left foot, and when walking, she develops dystonic posturing in
both lower extremities. What is the most appropriate initial therapy?
A. benztropine
B . levodopa
C. onabotulinumtoxinA
D. tetrabenazine
E . trihexyphenidyl
b 30. A 57-year-old man is referred for evaluation of right hand tremor that he
has experienced for the past year. The tremor is most prominent at rest
and has gradually worsened since onset. He also is experiencing increasingly
impaired dexterity in the right hand, such as when typing. He and his wife
agree that his sense of smell has decreased. He reports no balance changes or
cognitive symptoms. On examination, he has a 4 Hz to 6 Hz resting tremor
in the right hand. He has a decrease in blink rate and facial expression, and
his finger taps on the right side are hypokinetic with decrement. He has mild
rigidity of his right wrist when tested with augmentation, but otherwise his
tone, bulk, and strength are normal. Right arm swing is reduced, but he has
otherwise normal gait. What is the most likely diagnosis?
A. corticobasal syndrome
B. dementia with Lewy bodies
C. multiple system atrophy
D. Parkinson disease
E. progressive supranuclear palsy
b 32. A 44-year-old woman presents for evaluation of head tremor that began
3 years ago. The tremor is present throughout the day and also occurs
when she lies down to go to sleep. She notes associated neck pain and a
pulling sensation in her neck. Examination demonstrates an irregular
tremor of the head with a slight head tilt to the left. The patient can
improve the tremor when she touches her chin with her left hand. What is
the most likely diagnosis?
A. dystonic tremor
B . essential tremor
C. orthostatic tremor
D. Parkinson disease
E . psychogenic tremor
b 33. Which of the following patients with Parkinson disease is most likely to
develop an impulse control disorder from dopamine agonist therapy?
A. a 42-year-old man
B. a 42-year-old woman
C. a 71-year-old man
D. a 71-year-old woman
E. an 87-year-old man
b 35. A 64-year-old man with early Parkinson disease has been maintained on
rasagiline for 10 months. He presents because his symptoms, which had initially
stabilized, seem to be worsening over the past 2 months. He describes a
sense of stiffness in his left arm as well as difficulty keeping up with his
spouse when they are walking outside. On examination, he is noted to have
decreased blink rate, bilateral upper extremity rigidity and bradykinesia
(left greater than right), mild resting tremor in the left hand, and mildly
stooped posture with no retropulsion. Which of the following is the most
appropriate next step?
A. add amantadine
B . add benztropine
C. add droxidopa
D. add rotigotine
E . change rasagiline to selegiline
The preferred response is A (analysis of the HTT gene). This patient has
late-onset chorea with no other significant neurologic findings or issues,
a presentation that has been called senile chorea. The majority of these
cases appear to be late-onset Huntington disease and, therefore, analysis
of the HTT gene is likely to be diagnostic. Ceruloplasmin levels will screen
for aceruloplasminemia and Wilson disease, neither of which would be
likely in this patient given the age of onset of symptoms and the isolated
choreiform nature of his movement disorder. Review of a fresh peripheral
blood smear would be helpful in conditions such as chorea-acanthocytosis,
McLeod syndrome, or Huntington diseaseYlike 2. While hyperthyroidism
can be associated with chorea, this patient has no other constitutional or
neurologic signs or symptoms pointing to this condition. For more information,
refer to page 1192 of the Continuum article ‘‘Chorea.’’
b 37. A 46-year-old man presents for evaluation of tremor that began 2 years
ago. The tremor initially did not bother him, but has worsened to the point
where it interferes with his handwriting. He takes no medications and has a
family history of Parkinson disease in his grandfather. Neurologic examination is
significant for asymmetric, bilateral postural tremor of the outstretched hands.
The tremor is also noted while the patient draws a spiral and holds a cup. No
rigidity or bradykinesia is seen. What is the most likely diagnosis?
A. dystonic tremor
B . essential tremor
C. Parkinson disease
D. psychogenic tremor
E . Wilson disease
b 38. A 56-year-old man presents for evaluation of gait instability and frequent
falls. His symptoms started 4 years ago and have been progressively worsening.
The patient also reports several episodes of syncope with standing, erectile
dysfunction, and reduced voice volume. He has no family history of neurologic
disease. Neurologic examination demonstrates masked face, reduced blink
rate, scanning dysarthria, nystagmus, symmetric appendicular rigidity, titubation,
and wide-based unsteady gait. On orthostatic blood pressure testing, his systolic
blood pressure drops 30 points when going from supine to standing, without
any change in pulse. Brain MRI demonstrates brainstem and cerebellar atrophy.
What is the most likely diagnosis?
A. Friedreich ataxia
B . multiple system atrophy
C. paraneoplastic cerebellar degeneration
D. Refsum disease
E . spinocerebellar ataxia type 6
b 39. Which of the following is the most sensitive diagnostic test for
Wilson disease?
A. 24-hour urinary copper excretion
B . liver biopsy
C. serum ceruloplasmin
D. serum copper
E . slit-lamp examination
b 40. Two days after returning from a family vacation to Korea, a 6-year-old girl
develops a high fever, headache, and significant dystonic movements.
Which of the following infectious agents is most likely responsible for
her presentation?
A. Cryptococcus neoformans
B . herpes simplex virus type 1
C. Japanese B encephalitis virus
D. Mycobacterium tuberculosis
E . poliomyelitis virus
Patient Management
Address correspondence to
Dr Susan H. Fox, Toronto
Western Hospital, 399
Bathurst St, Movement
The patient’s primary care provider is contacted and reports that the
patient had been taking risperidone for nighttime agitation for the past
year, but she had stopped taking the medication 1 month ago and then
switched to quetiapine.
The primary care provider also reports having noticed some mild
movements in the patient’s mouth but attributed these to her dentures
and felt that her vocalizations were due to agitation. The primary care
provider did not believe that risperidone caused these movements and
therefore requests further etiologic investigations.
The patient’s blood work for hematologic, renal, liver, and thyroid
functions are normal, and brain MRI shows mild periventricular white
matter changes but no basal ganglia lesions. The patient and family are
advised that the MRI findings are not likely the primary cause of her
symptoms but are related to her history of vascular disease.
b 6. What is the best treatment option for this patient at this time?
A. add clonazepam at night for sleep
B. add tetrabenazine
C. add vitamin E
D. stop amlodipine
E. switch from quetiapine to olanzapine
The patient returns for neurologic follow-up 2 months later with extreme
daytime drowsiness and no change in her orofacial movements. The
patient would like to try an alternative method of treatment.
b 8. What is the most likely explanation for the patient’s new complex of
symptoms?
A. akathisia
B. anxiety
C. depression
D. parkinsonism
E. worsening tardive dyskinesia
The patient remains clinically unchanged. She has a slow gait but does not
need any help with her activities of daily living. She is started on
mirtazapine 15 mg at night to help her sleep. She presents for follow-up
3 months later and reports some slowness and mild problems turning in
bed at night as well as increased constipation. She is slower while eating and
has slightly excessive salivation. The patient and her family are reluctant
for her to take more medications.
b 12. What management strategy is the best course of action at this time?
A. no changes in medications required
B. start carbidopa/levodopa
C. start pramipexole
D. start rasagiline
E. stop mirtazapine
The patient agrees not to start any new medications as she is worried
about side effects in view of the prior problems she has experienced. The
mirtazapine did seem to help her at night. One year later she returns for
follow-up, and she has ongoing slowness of all her activities of daily living,
with a slower gait. She uses a walker as she has had a few falls. Her voice is
quieter, and she has some mild dysphagia with liquids. She has intermittent
tremor in her hands that is worse on the right side, especially if she gets
anxious. She also reports stiffness and cramps in her legs overnight that wake
her up. However, she prefers to continue without medications. Her primary
care provider contacts the neurology office a few months later as the
family has expressed concern and anger at the problems their mother has
Patient Management
Address correspondence to
Dr Susan H. Fox, Toronto
Western Hospital, 399 Bathurst
St, Movement Disorders Clinic,
1. Jankovic J. Tardive syndromes and other drug-induced movement disorders. Clin Neuropharmacol
1995;18:(3):197Y214.
2. Jeste DV. Tardive dyskinesia rates with atypical antipsychotics in older adults. Clin Psychiatry
2004;65(suppl 9):21Y24.
1. Cardoso F. How to examine a patient with chorea. Movement Disord Clin Practice 2015;1(4):397.
doi:10.1002/mdc3.12107.
2. Gooneratne IK, Weeratunga PN, Gamage R. Teaching video neuroimages: orofacial dyskinesia
and oral ulceration due to involuntary biting in neuroacanthocytosis. Neurology 2014;82(8):e70.
doi:10.1212/WNL. 0000000000000144.
The patient’s primary care provider is contacted and reports that the
patient had been taking risperidone for nighttime agitation for the past
year, but she had stopped taking the medication 1 month ago and then
switched to quetiapine.
The primary care provider also reports having noticed some mild movements
in the patient’s mouth but attributed these to her dentures and felt that her
vocalizations were due to agitation. The primary care provider did not
believe that risperidone caused these movements and therefore requests
further etiologic investigations.
The preferred response is A (brain MRI). Brain MRI is the single most useful
test in directing further investigation in a patient with chorea.1 The most
common structural cause of chorea in the elderly is small vessel ischemic disease.
Less common causes of chorea include diabetic nonketotic hyperglycemia,
antiphospholipid antibody syndrome, and polycythemia rubra vera. HD and
HDL disorders (HDL1, HDL2) may have caudate atrophy on MRI. Rare
metabolic and storage disorders would also have abnormalities on MRI
(eg, copper or iron on the basal ganglia). Metabolic disorders including
liver, renal, and thyroid disorders are important to exclude. Liver disease
can cause acquired hepatolenticular degeneration with dyskinesia with
T1 hyperintensity in the pallidum. Increasingly recognized are
paraneoplastic disorders (eg, antiYN-methyl-D-aspartate [NMDA]) and
non-neoplastic autoimmune disorders (eg, antiYleucine-rich, glioma inactivated
1 [LgI1]) that can cause orofacial dyskinesia, usually in the setting of a
patient with an encephalitis. Blood and CSF examination for the presence
of these autoantibodies (eg, anti-NMDA) may be useful, but an MRI remains
the most useful test in this patient prior to further investigation.
1. Hermann A, Walker RH. Diagnosis and treatment of chorea syndromes. Curr Neurol Neurosci
Rep 2015;15(2):514. doi:10.1007/s11910-014-0514-0.
The patient’s blood work for hematologic, renal, liver, and thyroid
functions is normal, and brain MRI shows mild periventricular white matter
changes but no basal ganglia lesions. The patient and family are advised
that the MRI findings are not likely the primary cause of her symptoms but
are related to her history of vascular disease.
b 6. What is the best treatment option for this patient at this time?
A. add clonazepam at night for sleep
B . add tetrabenazine
C. add vitamin E
D. stop amlodipine
E . switch from quetiapine to olanzapine
The patient returns for neurologic follow-up 2 months later with extreme
daytime drowsiness and no change in her orofacial movements. The
patient would like to try an alternative method of treatment.
b 10. What is the best management option for this patient at this time?
A. increase tetrabenazine
B . reduce quetiapine
C. reduce tetrabenazine
D. stop quetiapine
E . stop tetrabenazine
The patient remains clinically unchanged. She has a slow gait but does not
need any help with her activities of daily living. She is started on
mirtazapine 15 mg at night to help her sleep. She presents for follow-up
3 months later and reports some slowness and mild problems turning in
bed at night as well as increased constipation. She is slower while eating and
has slightly excessive salivation. The patient and her family are reluctant for
her to take more medications.
b 12. What management strategy is the best course of action at this time?
A. no changes in medications required
B . start carbidopa/levodopa
C. start pramipexole
D. start rasagiline
E . stop mirtazapine
1. Lim TT, Ahmed A, Itin I, et al. Is 6 months of neuroleptic withdrawal sufficient to distinguish
drug-induced parkinsonism from Parkinson’s disease? Int J Neurosci 2013;123(3):170Y174.
doi:10.10.3109/00207454.2012.732976.
2. Morley JF, Pawlowski SM, Kesari A, et al. Motor and non-motor features of Parkinson’s disease
that predict persistent drug-induced Parkinsonism. Parkinsonism Relat Disord
2014;20(7):738Y742. doi:10.1016/j.parkreldis.2014.02.024.
The patient agrees not to start any new medications as she is worried
about side effects in view of the prior problems she has experienced. The
mirtazapine did seem to help her at night. One year later she returns for
follow-up, and she has ongoing slowness of all her activities of daily living,
with a slower gait. She uses a walker as she has had a few falls. Her voice
is quieter, and she has some mild dysphagia with liquids. She has intermittent
tremor in her hands that is worse on the right side, especially if she gets
anxious. She also reports stiffness and cramps in her legs overnight that
wake her up. However, she prefers to continue without medications. Her
primary care provider contacts the neurology office a few months later as
the family has expressed concern and anger at the problems their mother
has experienced over the past few years. The primary care provider is keen to
try and learn from the experience.1,2
1. Esper CD, Factor SA. Failure of recognition of drug-induced parkinsonism in the elderly. Mov
Disord 2008;23(3):401Y404.
2. Canadian Clinical Practice Guidelines for the Treatment of Schizophrenia. Can J Psychiatry
2005;50(suppl 1):7S.
Copper chelation therapy, 1249, 1254Y1255, for Parkinson disease, 1064, 1065, 1079Y1080,
1257, 1257t, 1259, 1260rY1261r 1081c, 1082t, 1085r
combination agents, 1255Y1256 apathy after, 1094
copper deficiency induced by, 1258, 1258c cognitive impairment and, 1083, 1093
liver transplantation and, 1256 diphasic dyskinesia induced by, 1079
penicillamine, 1254Y1255 drug-resistant tremor and, 1082
trientine, 1255 patient selection for, 1079
CORE PD (Consortium on Risk for Early-Onset psychiatric considerations for, 1087, 1100r
Parkinson Disease), 1057, 1062r for resting tremor, 1155
Corticobasal degeneration (CBD), 1048t, 1117, for urinary dysfunction, 1111
1119t, 1128Y1132, 1141rY1142r suicidality after, 1080, 1087
age at onset of, 1128 for Tourette syndrome, 1162
clinical features of, 1128Y1130 for tremor
diagnostic criteria for, 1131 cerebellar tremor, 1151
differentiation from Parkinson disease, 1057 dystonic neck tremor, 1150
neuroimaging in, 1132 essential tremor, 1148
DAT-SPECT, 1262 midbrain tremor, 1154, 1158r
neuropathology of, 1131Y1132 neuropathic tremor, 1154
treatment in advanced stages of, 1104 orthostatic tremor, 1151, 1157r
treatment of, 1128, 1129t, 1132 parkinsonian resting tremor, 1155
video of, 1140 for Wilson disease, 1256, 1261r
Corticobasal syndrome (CBS), 1128, 1131, 1131t Deferiprone, 1217
Corticosteroids Delirium, 1097, 1262c
for antiYNMDA receptor encephalitis, 1164c drug-related, 1105, 1111, 1237, 1238
for basal ganglia encephalitis, 1165 Delusions
for opsoclonus myoclonus ataxia syndrome, 1165 in anti-NMDA receptor encephalitis, 1164c
for peripheral neuropathyYrelated tremor, 1154 in dementia with Lewy bodies, 1137
for Wilson disease, 1247, 1252, 1256 in Parkinson disease, 1097Y1098
CP gene, 1188t, 1189t depression and, 1087
CPR (cardiopulmonary resuscitation), 1110 dopamine agonistYinduced, 1073, 1075t
CPT (Current Procedural Terminology) codes in Wilson disease, 1249
for botulinum toxin injections, 1266, Dementia. See also Cognitive impairment
1269Y1272, 1271t, 1273Y1275 antipsychotic risks in elderly patients with, 1100
Cranial nerve dysfunction, ataxia and, 1212t, 1219 in atypical parkinsonian syndromes, 1119,
Creatine, 1065, 1066t, 1235t 1121t, 1141r
Creatine kinase elevation, 1187t, 1194cY1195c corticobasal syndrome, 1128, 1129t, 1130, 1131t
Creatine metabolism disorders, 1176t, 1179 multiple system atrophy, 1134, 1134t
Creutzfeldt-Jakob disease, 1121t, 1191t, 1197, progressive supranuclear palsy syndromes,
1201, 1207r, 1213t 1120, 1122, 1123t, 1125, 1128, 1129t
CT. See Computed tomography in dentatorubral-pallidoluysian atrophy, 1188t
Current Procedural Terminology (CPT) codes frontotemporal, 1055t, 1058, 1120f, 1121t, 1186
for botulinum toxin injections, 1266, CBS variant of, 1131t
1269Y1272, 1271t, 1273Y1275 PSP variant of, 1121t, 1123, 1123t, 1125, 1141r
Cyclophosphamide, 1154, 1164 hospice care for, 1114t
in Parkinson disease, 1083r, 1086, 1091Y1093,
1101rY1102r, 1115r, 1116t
D
apathy and, 1093, 1094
hospice guidelines for, 1114t
DAT-SPECT imaging. See Dopamine long-term care placement for, 1105, 1110c
transporter-SPECT imaging patient evaluation for, 1113
DBS. See Deep brain stimulation psychosis and, 1097, 1099, 1100, 1105
DDC gene, 1174t in spinocerebellar ataxias, 1188t, 1214t
Deep brain stimulation (DBS) in Wilson disease, 1249Y1250
for chorea or ballismus, 1203 Dementia with Lewy bodies (DLB), 1117, 1119t,
for dystonia, 1180, 1185r, 1227, 1240Y1241, 1121t, 1137Y1139, 1142r
1240c, 1245r clinical features of, 1137
video of, 1242 diagnostic evaluation of, 1138Y1139
for genetic childhood movement disorders, neuroimaging in, 1138
1180, 1182 DAT-SPECT, 1138Y1139
in multiple system atrophy, 1136 neuropathology of, 1138, 1138f
Head nodding in children, 1161t Hyperglycemia, nonketotic, chorea due to, 1191t,
Headache 1192, 1193, 1196, 1197, 1198c
ataxia and, 1218, 1223 MRI in, 1198c, 1198f, 1201
botulinum toxin for, 1244r Hypertension, 1055c, 1071c, 1072c, 1130c, 1219
in Wilson disease, 1249 drug-induced
Helicobacter pylori, 1077 midodrine, 1136
Hemiballismus, 1190t, 1195, 1197, 1205r mirabegron, 1111
Hepatic dysfunction, in Wilson disease, 1246, supine, 1111, 1112, 1137
1247, 1248t, 1249c, 1259 Hyperthyroidism
diagnostic evaluation of, 1251, 1251t, 1252c, chorea and, 1191t
1253, 1260r tremor and, 1143, 1147
fulminant hepatic failure, 1247, 1248t, 1249c, Hypokinesia
1255, 1256, 1257, 1257t in aromatic L-amino acid decarboxylase
Kayser-Fleischer rings and, 1250, 1252 deficiency, 1174t
liver transplantation for, 1256 in multiple system atrophyYparkinsonism, 1134t
treatment guidelines for, 1255, 1256Y1257, 1257t in Parkinson disease, 1048
Herpes simplex virus encephalitis, 1163 in tyrosine hydroxylase deficiency, 1231
HIV. See Human immunodeficiency virus infection Hypomimia, facial
Hockey stick sign, 1201 in corticobasal syndrome, 1130c
Hoehn and Yahr staging scale, 1105, 1105t, 1107, in genetic parkinsonism, 1173
1110, 1115r in multiple system atrophyYparkinsonism, 1135c
Holmes tremor. See Midbrain (rubral) tremor in Parkinson disease, 1048, 1146
Homocystinuria, 1175t Hypophonia
Hospice guidelines, 1113, 1114t botulinum toxinYinduced, 1239
Hospital Anxiety and Depression Scale, 1088, 1090 in Parkinson disease, 1048, 1056c, 1070,
Hot cross bun sign, 1213, 1217c, 1217f, 1221 1071c, 1082
HPRT1 gene, 1176t in progressive supranuclear palsy, 1123t
HTT gene, 1187t, 1199 Hypotension. See Orthostatic hypotension
Human immunodeficiency virus (HIV) infection Hypothyroidism
ataxia in, 1213t, 1218, 1220 ataxia and, 1213t
chorea in, 1191t, 1196, 1197 benign hereditary chorea and, 1169
Huntington disease (HD), 1119t, 1121t, 1186,
1187t, 1205rY1207r. See also Chorea
I
age at onset of symptoms of, 1186, 1192
C9orf72-related, 1186, 1187t, 1196, 1199t, 1200,
1203, 1295r Iatrogenic causes of movement disorders, 1166
clinical features of, 1186, 1187t, 1197 ICARS (International Cooperative Ataxia Rating
genetic testing for, 1186, 1187t, 1192c, Scale), 1220, 1226r
1199Y1200, 1199t ICD-10-CM (International Classification of
juvenile (Westphal variant), 1186, 1196 Diseases, Tenth Revision, Clinical Modification)
late-onset, 1192, 1192c diagnosis codes for botulinum toxin injections,
video of, 1204 1269, 1270t, 1275
management of, 1202Y1203 Imipramine, 1059t
MRI in, 1187t, 1200, 1201f Immunosuppressive therapy
prevalence of, 1186, 1187t for antiYNMDA receptor encephalitis, 1164
videos of chorea in, 1204 for basal ganglia encephalitis, 1165
Huntington disease (HD) phenocopies, 1186, 1187t for opsoclonus myoclonus ataxia syndrome, 1165
C90rf72I-related, 1196 for peripheral neuropathyYrelated tremor, 1154
clinical features of, 1195 for Sydenham chorea, 1165
undiagnosed, 1200 for Wilson disease, 1256
Huntington diseaseYlike (HDL) syndromes Impulse control disorders
HDL1, 1188t, 1195, 1196 in Parkinson disease, 1095Y1097, 1096c
HDL2, 1187t, 1195, 1196, 1200 neurobiology of, 1096
HDL3, 1196 patient evaluation for, 1096Y1097
HDL4, 1186, 1187t prevalence of, 1095
Hydralazine, 1112 risk factors for, 1095
Hydrocephalus treatment of, 1097
chorea induced by, 1191t rating scales for, 1097
normal pressure, 1055t, 1056, 1058, 1062r Inborn errors of metabolism, 1173Y1179,
papilledema and, 1219 1174tY1178t, 1180c, 1183t
PRRT2 gene, 1167t, 1171t, 1194t, 1200, 1232 side effects of, 1068t
PRX002, 1066t with wearing off, 1076t, 1077, 1081c
Pseudobulbar affect, 1122, 1128, 1129t, 1140r Refsum disease, 1215t, 1221
Pseudoephedrine, 1059t, 1149 Rehabilitation therapy
PSP. See Progressive supranuclear palsy for corticobasal degeneration, 1132
Psychogenic movement disorders for multiple system atrophy, 1136
in children, 1181, 1182c for Parkinson disease, 1065Y1066, 1083
chorea, 1193 for pediatric psychogenic movement disorders,
tremor, 1152, 1152c, 1157r 1181, 1182c
Psychosis. See also Delusions; Hallucinations REM sleep behavior disorder. See Rapid eye
in dementia with Lewy bodies, 1137, 1139 movement sleep behavior disorder
in Huntington disease, 1193 Respite care, 1108
levodopa and, 1139 Resting tremor, 1117, 1154Y1155
in Parkinson disease, 1097Y1100, 1098c differentiation from action tremor, 1143,
clinical features of, 1097Y1099 1144Y1145, 1155
neurobiology of, 1099 drug-induced, 1143, 1155
patient evaluation for, 1099 essential tremor and, 1145
prevalence of, 1097 in genetic parkinsonism, 1173
risk factors for, 1099 in midbrain tremor, 1154
treatment of, 1099Y1100 in Parkinson disease, 1047, 1049t, 1050Y1051,
rating scales for, 1099 1051c, 1055c, 1064, 1067c, 1071c, 1090c,
in Wilson disease, 1249 1098c, 1143, 1154Y1155
Psychostimulants, discontinuation before absence of, 1052
DAT-SPECT, 1059t anxiety and, 1090c
PTS gene, 1174t levodopa-resistant, 1082, 1082t
Pull test, 1051, 1056c, 1067c, 1071c, 1072c, 1080, pill-rolling type, 1050, 1133, 1156
1105t, 1124c, 1130c, 1135c, 1140 reemergent tremor, 1147, 1154, 1155, 1158r
Punding, 1095 video of, 1156
Purine metabolism disorders, 1176t, 1179 in PSPYparkinsonism, 1123t, 1124c
PxMD-PNKD gene, 1232 in Wilson disease, 1152
Pyridostigmine, 1137, 1237 video of, 1259
Pyridoxine, 1218 Richardson syndrome, 1123, 1123t, 1124. See also
Pyruvate carboxylase deficiency, 1176t Progressive supranuclear palsy
6-Pyruvoyl tetrahydropterin synthase Rigidity, 1117
deficiency, 1174t baclofen-induced, 1238
in corticobasal degeneration, 1128, 1129t, 1130,
1130c, 1131t, 1132
Q differential diagnosis of, 1050
drug-induced resting tremor and, 1155
QDPR gene, 1174t in GCH1 deficiency, 1231
Quantitative sudomotor axon reflex test in genetic parkinsonism, 1173
(QSART), 1136 in multiple system atrophyYcerebellar type, 1217c
Questionnaire for Impulsive-Compulsive in multiple system atrophyYparkinsonism,
Disorders in Parkinson’s Disease, 1097 1133, 1134t, 1135c, 1140
Questionnaire for Impulsive-Compulsive in Parkinson disease, 1047, 1049t, 1050, 1051,
Disorders in Parkinson’s DiseaseYRating Scale, 1051c, 1055c, 1056c, 1064, 1071c, 1072c,
1097, 1103r 1145, 1146
Quetiapine, 1097, 1100, 1110c, 1139, 1237 fluctuations in response to levodopa for,
1073, 1074
palliative care for, 1111
R
postural deformities and, 1082
psychosis and, 1099
Rapid eye movement (REM) sleep behavior disorder progressive encephalopathy with rigidity and
in dementia with Lewy bodies, 1137 myoclonus, 1165
in multiple system atrophyYparkinsonism, in progressive supranuclear palsy, 1050, 1120,
1134t, 1135c, 1136 1121, 1122
in Parkinson disease, 1052, 1053t, 1071c PSP variants, 1123, 1123t, 1124, 1124c.1125
Rasagiline, for Parkinson disease, 1065, 1066t, in TUBB4A-related diseases, 1179
1067c, 1068t, 1069, 1084r in X-linked dystoniaYparkinsonism, 1240c, 1242
coprescribing with antidepressants, 1077 Risperidone, 1162.1234
benzodiazepines for, 1091, 1100 Spinocerebellar ataxias (SCAs), 1172t, 1173, 1208,
in children 1212Y1213
ADCY2-related disease, 1169, 1170c clinical features of, 1214t
aromatic L-amino acid decarboxylase chorea, 1188tY1189t, 1197
deficiency, 1180c extrapyramidal signs, 1219Y1220
benign neonatal sleep myoclonus, 1161t saccades in, 1188t, 1197, 1210, 1214t, 1216c
in Parkinson disease, 1052, 1053t, 1071c, 1078c, differentiation from essential tremor, 1147
1084r, 1096c gene mutations in, 1214t
anxiety and, 1089 genetic testing for, 1212Y1213, 1221Y222
cognitive impairment and, 1092, 1093 response to levodopa, 1219
depression and, 1087, 1088 SCA with axonal neuropathy type 1, 1215t
psychosis and, 1099 SCA1, 1188t, 1196, 1197, 1198, 1214t, 1221
REM sleep behavior disorder SCA2, 1188t, 1196, 1197, 1198, 1200, 1210,
in dementia with Lewy bodies, 1137 1216c, 1219, 1221
in multiple system atrophyYparkinsonism, video of, 1225
1134t, 1135c, 1136 SCA3 (Machado-Joseph disease), 1189t, 1196,
in Parkinson disease, 1052, 1053t, 1071c 1197, 1198, 1214t, 1219, 1221Y1222
Slit-lamp examination, for Wilson disease, 1153, SCA5, 1214t, 1222
1178t, 1189t, 1250, 1251Y1252, 1252t SCA6, 1214t, 1222
Smell testing, 1057 SCA7, 1196, 1197, 1214t, 1222
SNCA gene, 1174t SCA8, 1214t
Sniffin’ Sticks, 1057 SCA10, 1214t
SNRIs (serotonin norepinephrine reuptake SCA11, 1214t
inhibitors), 1089, 1129t, 1234 SCA12, 1214t, 1222
Social phobia, 1089 SCA13, 1214t, 1222
Sodium oxybate, 1238 SCA14, 1197, 1214t, 1222
Spasmodic Torticollis Dystonia, 1243 SCA15, 1214t
Spasmus nutans, 1161t SCA16, 1214t
Spastic ataxia of Charlevoix-Saguenay, 1172t, SCA17, 1186, 1187t, 1196, 1197, 1200, 1203,
1173, 1215t, 1221f, 1226r 1214t, 1219, 1222
SPECT. See Single-photon emission computed SCA20, 1214t
tomography SCA27, 1214t
Speech disturbances. See also Dysarthria; SCA34, 1214t
Hypophonia SCA36, 1214t, 1219, 1222
in antiYNMDA receptor encephalitis, 1164c SPR gene, 1174t, 1231
ataxias with, 1210, 1212t, 1216c, 1218, 1219, 1224f SPTBN2 gene, 1214t
Friedreich ataxia, 1172 Square-wave jerks, 1122, 1210, 1215t, 1219
spinocerebellar ataxias, 1173 SSRIs. See Selective serotonin reuptake inhibitors
in corticobasal syndrome, 1128, 1130c, 1131t Stereotypies in children, 1162
dystonia with, 1229, 1240c, 1241 Striatal disorders, 1176t
video of, 1242 Striatonigral degeneration, 1132, 1133t. See also
in multiple system atrophyYparkinsonism, Multiple system atrophy
1133, 1135c Stroke
video of, 1140 ataxia due to, 1213t, 1218, 1223
in Parkinson disease, 1048, 1065, 1070, 1079, chorea due to, 1189, 1191t, 1192, 1193, 1196,
1080, 1082, 1085r 1201, 1207r
in progressive supranuclear palsy, 1120, 1122, CT for, 1221
1123t, 1124c, 1125, 1127 hospice guidelines for, 1114t
video of, 1139 midbrain tremor and, 1154
scanning speech, 1151, 1210, 1212t, 1216c Parkinson disease and, 1049t, 1071c, 1092,
tremor with 1093, 1099
cerebellar tremor, 1151 pediatric movement disorders and, 1166
jaw tremor, 1146 Study of Antidepressants in Parkinson’s
voice tremor, 1150 Disease, 1089
Speech therapy STX6 gene, 1126
for Parkinson disease, 1065, 1070, 1080, Substantia nigra
1082, 1114t in corticobasal syndrome, 1132
for pediatric movement disorders, 1181 in multiple system atrophy, 1135
for progressive supranuclear palsy, 1127, 1129t in pantothenate kinaseYassociated
Spielberger State-Trait Anxiety Inventory, 1090 neurodegeneration, 1189t