Neurologic Diseases

C H A P T E R
8
Neurologic Diseases
BENJAMIN K. SCOTT, MD n

DIMITRY BARANOV, MD n
Hereditary Peripheral Neuropathies KEY POINTS

Primary Hereditary Motor and Sensory Neuropathies, n Hereditary motor and sensory neuropathies (HMSNs) are
Including Charcot-Marie-Tooth Disease
disorders of myelination of the peripheral nervous sys-
Hereditary Sensory and Autonomic Neuropathies
tem resulting in progressive loss of motor and sensory
Neurodegenerative Disorders with Autonomic Failure
function.
Multiple System Atrophy
n In familial dysautonomia (HSAN-III), anesthesia manage-
Pure Autonomic Failure
ment is directed at prevention and prompt treatment of
Basal Ganglia and Cerebellar Disorders
dysautonomic crises.
Parkinson's Disease
n Multiple system atrophy is a new term synonymous with
Huntington's Disease (Chorea)
Shy-Drager syndrome, striatonigral degeneration, and
Sydenham's Chorea (Rheumatic Chorea)
olivopontocerebrellar atrophy.
Dystonias
n Parkinson's disease symptoms include tremor, bradykine-
Diseases of Myelin
sia, rigidity, and postural instability; medical management
Multiple Sclerosis
restores dopaminergic versus cholinergic balance.
Nitrous Oxide–Induced Subacute Combined Degeneration
n Huntington's disease is characterized by choreoathe-
Peripheral Nerve Disease and the Polyneuropathies
toid movements (butyrophenones and phenothiazines
Guillain-Barré Syndrome
may temporarily alleviate), dementia, and psychiatric
Motor Neuron Diseases
disturbances.
Amyotrophic Lateral Sclerosis
n Sydenham's chorea is an acute manifestation of rheumatic
Friedreich's Ataxia
fever.
Spinal Muscular Atrophy
n Dystonias are a broad group of movement disorders in
Neuroectodermal Disorders
which sustained involuntary muscle contractions lead to
Neurofibromatoses
abnormal postures or repetitive movements.
von Hippel–Lindau Disease
n Multiple sclerosis has an unpredictable pattern of relapse,
Tuberous Sclerosis
which may coincide with postoperative recovery.
Sturge-Weber Syndrome
n Guillain-Barré syndrome is characterized by ascending
Posterior Fossa Anomalies and Arnold-Chiari
Malformations paralysis with areflexia.
Chiari I Malformation n Neurofibromatosis is a multisystem disease requiring a
Chiari II Malformation, Myelomeningocele, and multidisciplinary surgical team for optimal outcomes.
Hydrocephalus n Multisystem von Hippel–Lindau disease is characterized by
Klippel-Feil Syndrome and Other Cervical Spine CNS lesions combined with pheochromocytoma and renal
Disorders of Childhood cell carcinoma; most patients require neurosurgical pro-
Mucopolysaccharidoses cedures or surgery for removal of pheochromocytoma or
renal cell carcinoma.
251
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252 ANESTHESIA AND UNCOMMON DISEASES
n Tuberous sclerosis is also a multisystem disease, ide- or are caused by exposure to various agents (e.g., heavy met-
ally requiring multidisciplinary team management; most als, alcohol, certain medications). As such, the hereditary
patients require surgical procedures or imaging studies neuropathies are a common and diverse group of genetically
during childhood and typically have various degrees of determined neurologic diseases. They are primarily charac-
mental retardation. terized by a dysfunction of peripheral sensory neurons in the
n Sturge-Weber syndrome is a rare congenital (not heritable) presence of additional muscle weakness or autonomic system
vascular disorder of unknown etiology marked by facial dysfunction. However, a dysfunction of the central nervous
angioma (port-wine stain) and leptomeningeal angioma. system (CNS) and other organ systems is more prominent in
n Chiari malformation type I patients should be evaluated some types of hereditary neuropathies, which is of special rel-
for degree of brainstem compression, cranial nerve involve- evance to the anesthesiologist treating these patients.
ment, spinal cord compression, and increased intracranial Historically, classification of the hereditary peripheral neu-
pressure. ropathies was primarily based on clinical manifestations and
n In patients with Klippel-Feil syndrome, main consideration eponyms were used to designate a specific combination of
is catastrophic cervical spinal cord injury during induction clinical symptoms (e.g., Riley-Day syndrome, Charcot-Marie-
of anesthesia and positioning. Tooth disease). However, significant phenotypic variability
n Mucopolysaccharidoses can trigger new, potentially cata- led to nosologic confusion. Modern classification of heredi-
strophic neurologic complications; a difficult to impossible tary neuropathies is based on clinical and electrophysiologic
airway is the central concern. characteristics, modes of inheritance, and underlying genetic
n Further anesthetic issues are detailed for specific neuro- mutations. The hereditary neuropathies are usually divided
logic diseases in the boxes. into three major groups according to their main clinical mani-
festation: predominantly motor involvement, predominantly
sensory or autonomic involvement, or neither. These major
Neurologic disorders represent a unique challenge to anesthe- groups are further divided into types (usually based on dif-
siologists by affecting the same biosubstrate targeted by anes- ferences in clinical presentation, pathology, nerve conductiv-
thetic agents to produce the state of anesthesia. The direct ity studies) and subtypes (based on genetic characteristics).
consequence of neurologic disorders is often dramatically Table 8-1 summarizes some of the more prevalent hereditary
altered pharmacodynamics of anesthetics. Anesthetic agents types of polyneuropathy; a comprehensive description can be
are also in essence reversibly neurotoxic, and thus their use found in a recent review.1
in patients with already-compromised neurologic function As in the previous edition of this textbook, this chapter con-
might lead to further deterioration of existing symptomatol- tinues to use the modern classification, with cross-referencing
ogy. Monitoring the recovery of neurologic function from the to traditional eponyms. All major medical reference databases
effects of anesthesia is further complicated in patients with use this classification, and patients in clinical anesthesia prac-
neurologic deficits. Many neurologic disorders also are very tice increasingly are diagnosed according to this terminol-
rare, with only minimal or no anesthesia experience reported ogy, which is widely accepted in the mainstream neurologic
in the literature. practice.
This combination of factors in neurologic patients demands
maximum caution and planning in the administration of anes-
Primary Hereditary Motor and Sensory
thesia. The last two decades have seen rapid development in
Neuropathies, Including Charcot-Marie-Tooth
the understanding of genetic mechanisms and the underlying
Disease
pathophysiology of many neurologic conditions, which in turn
has led to better management of these disorders. It also helped The hereditary motor sensory neuropathies (HMSNs) repre-
to create newer, more precise classifications for many classes sent a spectrum of disorders caused by a specific mutation in
of neurologic disorders, guided more by etiology and patho- one of several myelin genes that results in defects in myelin
physiology than by pure symptomatology. However, signifi- structure, maintenance, and formation. The association of dif-
cant overlap still exists between different classes of neurologic ferent mutations within the same gene with various clinical
disorders, which is further complicated by cross-referencing phenotypes is a common finding in this group of peripheral
to older eponymic classification. This chapter groups different neuropathies. This variability suggests that these disorders rep-
disorders by the commonality of their anesthesia and periop- resent a spectrum of related phenotypes caused by an under-
erative challenges. lying defect in peripheral nervous system myelination. The
HMSNs, otherwise known as Charcot-Marie-Tooth disease
(CMTD), have been classified as types 1 to 7, which are further
HEREDITARY PERIPHERAL NEUROPATHIES subdivided, thus consisting of close to 30 clinical syndromes;
Inherited disorders of peripheral nerves are a part of a much the vast majority are very rare and have never been reported
larger group of inherited or acquired polyneuropathies that in the anesthesia literature. Because of the paucity of rele-
often coexist with systemic, infectious, and metabolic diseases vant anesthesia data on currently identified phenotypes, only
(e.g., diabetes mellitus, thyroid disease, neoplastic syndromes) Charcot-Marie-Tooth types 1 and 2 (CMT-1 and CMT-2) and
Chapter 8 Neurologic Diseases 253
TABLE 8-1 n Hereditary Peripheral Neuropathies*
Clinical Manifestations/Underlying Electrophysiologic

HMSN/HSAN Type Pathology Inheritance Patterns Findings
HEREDITARY PRIMARY MOTOR AND SENSORY NEUROPATHIES (HMSNs)

HMSN type 1 (Charcot-Marie-Tooth Demyelinating disorder, distal weakness, Autosomal dominant Moderate to severe
disease type 1, CMT-1): five onset in 1st-2nd decade of life, slow reduction in nerve
subtypes identified progressing, “onion bulbs” conduction velocities
HMSN type 2 (Charcot-Marie-Tooth Neuroaxonal (not demyelinating) Autosomal dominant Normal to mildly reduced
disease type 2, CMT 2): eight disorder, distal weakness, slow nerve conduction
identified subtypes progressing velocities
HMSN type 3 (Dejerine-Scottas Demyelinating disorder, severe Autosomal dominant Severe reduction in nerve
or congenital hypomyelinating hypotonia in early childhood or at conduction velocities
syndrome): three identified subtypes birth, “onion bulbs”
HMSN type 4: seven identified Large group of disorders, typically Autosomal recessive Severe reduction
subtypes with early, severe presentation and or absent nerve
rapidly progressing, demyelinating, conduction velocities
sometimes prominent sensory deficit
HEREDITARY PRIMARY SENSORY AND AUTONOMIC NEUROPATHIES (HSANs)

HSAN type 1 (hereditary sensory Small axon loss, acromutilation Autosomal dominant
radicular neuropathy)
HSAN type 2 (congenital sensory Large and small axon loss Autosomal recessive
neuropathy)
HSAN type 3 (Riley-Day syndrome or Large and small axon loss, with Autosomal recessive
familial dysautonomia) dysautonomic crises, lack
lacrimation
HSAN type 4 (congenital insensitivity Congenital sensory neuropathy with Autosomal recessive
to pain with anhidrosis) anhidrosis, C-axon loss (see text)
*Inherited neuropathies other than HMSN/HSAN include hereditary neuropathy with pressure palsy, hereditary brachial plexopathy, and giant axonal neuropathy.
HMSN type 3, which together are the most common heredi- of the intrinsic hand and foot muscles, footdrop, palpable
tary peripheral neuropathies,2 are discussed here. Combined hypertrophy of the peripheral nerves, and possible scolio-
prevalence is almost 40 per 100,000 population. sis and kyphosis. Disease exacerbation may occur in preg-
nancy.5 Life expectancy is unaffected.
Pathophysiology and Diagnosis. HMSN type 1, or CMT-1, Type 2 HMSN, or CMT-2, also called axonal CMT, is a
is a demyelinating disorder of peripheral nerves that most heterogeneous disorder with normal or borderline nerve
often presents in the first or early-second decade of life, conduction velocity. It is primarily an axonal, not a demy-
although infants can also be affected.3 Significant family his- elinating, disorder, with neuropathy the result of neuro-
tory is typical. Diffuse slowing of nerve conduction veloc- nal death and wallerian degeneration (no onion bulbs on
ity and gradually progressing distal muscle weakness with biopsy). The clinical course is similar to that of CMT-1, but
early loss of coordination characterize CMT-1. It is associ- sensory symptoms predominate over motor symptoms, and
ated with loss of reflexes, talipes (pes) cavus, and hammer peripheral nerves are not palpable. Patients with CMT-2 C
toe. Later, distal calf atrophy develops (classic “stork leg” subtype display significant vocal cord and diaphragmatic
deformity), in combination with gradual loss of propriocep- weakness, resulting in OSA, which is of concern to the anes-
tion and sense of vibration. Abnormal concentric myelin for- thesiologist.6 Onset is usually in the second or third decade
mations are called “onion bulbs” and are found around the of life, but can be seen in early childhood, with rapid clinical
peripheral axons. These are a characteristic feature of CMT-1, progression.
usually revealed by sural nerve biopsy. The CMT-1A Type 3 HMSN includes two syndromes: D ejerine-Sottas
subgroup of patients may present with proximal muscle wast- syndrome and congenital hypomyelinating neuropathy (CHM).
ing and weakness. Dematteis et al.4 also observed obstructive Both are characterized by profound hypotonia, presenting in
sleep apnea (OSA) in this subtype of patients, with a high early infancy or at birth, in the case of CHM. Dejerine-Sottas
degree of correlation between the severity of neuropathy and syndrome is clinically similar to CMT-1, although its manifesta-
degree of obstruction. Even later changes include atrophy tions are more severe and appear in early childhood.
The preoperative evaluation and preparation of HMSNs ANESTHETIC CONSIDERATIONS

may be complicated because of similarity in clinical pre- The anesthetic experience for HMSN types 1, 2, and 3 is
sentation with other genetic or acquired polyneuropathies limited to a number of case reports9,10,12-21 and retrospective
(Box 8-1). reviews.22,23 Despite the absence of strong evidence advocating
No specific treatments for HMSNs are available. Symp for or against the use of specific anesthetic agents or particular
tomatic supportive care consists of orthopedic corrective joint anesthetic techniques, a number of important concerns have
procedures for talipes cavus and scoliosis deformities and been raised in the literature regarding anesthetic management
physical and occupational therapy. Orthopedic procedures are of these patients (Box 8-2).
usually staged, ranging from soft tissue procedures and osteot- Drugs triggering malignant hyperthermia (MH) have
omy to triple arthrodesis. Multiple administrations of general been used in patients with CMTD without complication.22,23
or regional anesthesia might be required. However, in two reports of MH during general anesthesia in
Preoperative preparation of patients with HMSNs is dic- CMTD patients, the authors advocate against the use of suc-
tated by the extent of clinical involvement and coexisting mor- cinylcholine and volatile agents.15 Furthermore, an approach
bidities. The degree of motor neurologic involvement should postulating that any patient with a neuromuscular disease
be evaluated and affected muscle groups noted. Atrophic should be considered to be at increased risk for MH adds to
denervated muscles usually display significant resistance to this controversy. The review of the available literature describ-
nondepolarizing muscle relaxants and are unreliable for mon- ing anesthesia management in patients with HMSN indicates
itoring of neuromuscular blockade (NMB). that most authors prefer to avoid administering MH-triggering
Patients with CMT-1 and CMT-2 C should be evaluated agents in patients with HMSN types 1, 2, and 3, partly because
for restrictive pulmonary disease related to scoliosis and dia- of medicolegal considerations.
phragmatic weakness and potential OSA. Respiratory insuf- Succinylcholine use in these patients is associated with
ficiency has been described in patients with CMT.7-9 Careful increased risk of malignant arrhythmias secondary to exag-
planning for extubation and a possible need for postopera- gerated hyperkalemic response.24 Although succinylcholine
tive respiratory support may be necessary in these patients. has been used in CMTD without untoward effects,22,23 it seems
Patients with HMSNs may have undetected cardiac conduc- appropriate to avoid its use in any patient with suspected mus-
tion abnormalities.10,11 Although this association is not strong, cular denervation.
all patients with an HMSN should have a preoperative ECG. Nondepolarizing muscle relaxants have been used success-
Pregnancy often leads to exacerbation of the symptoms of fully in patients with HMSNs without indications of prolonged
CMTD and, in combination with diaphragmatic splitting, can
lead to respiratory compromise.9
BOX 8-2 n HEREDITARY PERIPHERAL NEUROPATHIES:
ANESTHETIC ISSUES
BOX 8-1 n DIFFERENTIAL DIAGNOSIS OF HEREDITARY Hereditary Motor and Sensory Neuropathies (HMSNs)
MOTOR SENSORY NEUROPATHIES Informed consent regarding the effect of anesthetic agents on the
course of the disease is difficult to provide because of a lack of
Genetic Neuropathies conclusive evidence in the literature.
Refsum's disease Thorough preoperative interview and maximal patient participation
Metachromatic leukodystrophy regarding the choice of anesthetic technique are advisable,
Familial brachial plexus neuropathy combined with detailed documentation of these discussions.
Adrenomyeloneuropathy Neuroaxial and regional anesthesia are not contraindicated, but lower
Pelizaeus-Merzbacher disease concentrations of local anesthetic and careful titration are advisable.
Amyloid neuropathies Patients with advanced disease have increased risk of perioperative
respiratory depression and sleep apnea.
Acquired Neuropathies
Avoid monitoring neuromuscular blockade at the affected muscles to
Metabolic Disease
avoid overdose.
Diabetes mellitus
Use of depolarizing muscle relaxants should be avoided when
Thyroid disease
possible in patients with HMSNs.
Vitamin B12 deficiency
Hereditary Sensory and Autonomic Neuropathies: Familial
Infectious Disease
Dysautonomia (HSAN-III)
Neurosyphilis
Preoperative and intraoperative maintenance of euvolemia is critical
Leprosy
to prevent severe hypotonic episode.
Human immunodeficiency virus
Invasive intraoperative hemodynamic monitoring is recommended, as
Other Diseases dictated by degree of autonomic dysfunction and type of surgery.
Chronic alcoholism Prolonged postoperative ventilatory support might be needed,
Heavy-metal intoxications especially in patients with compromised respiratory function.
Vasculitis Rapid-sequence induction should be considered in patients with a
Neoplastic syndromes history of aspiration and gastroesophageal reflux.
Chronic inflammatory demyelinating polyneuropathy Tight body temperature control is important the HSAN-III patient.
duration of action.22,23,25,26 However, some authors express rea- histamine phosphate. The reported anesthetic experience for
sonable concern that adequate monitoring of NMB could HSANs is limited to anesthesia management of patients with
be complicated because of altered responses on the affected familial dysautonomia (HSAN-III) and CIPA (HSAN-IV).
muscles, which are not always obvious during clinical assess- The clinical presentation, diagnosis, and management of other
ment.27 Additionally, there is at least one case report of pro- HSANs have been reviewed.35
longed neuromuscular block with vecuronium.28 Inadequate
reversal of NMB in patients with pre-existing respiratory FAMILIAL DYSAUTONOMIA (HSAN TYPE III, OR RILEY-DAY
compromise can lead to serious complications. Some advocate SYNDROME)
avoiding the use of nondepolarizing muscle relaxants in such Familial dysautonomia (FD) is a rare genetic disorder that
patients whenever possible.12,14,18 affects, almost exclusively, persons of Ashkenazi Jewish
Neuroaxial anesthetic techniques have been success- extraction. It is the most prevalent and well studied of all
fully used in patients with HMSN without untoward effects, HSANs. Development of autonomic and sensory neurons is
including for vaginal delivery and cesarean section.9,17,18,20,29,30 impaired, resulting in reduced population of nonmyelinated
However, some authors correctly point out that medicole- and small-diameter myelinated axons. The sympathetic neu-
gal concerns must be considered when designing anesthesia rons are primarily affected, and sympathetic ganglia are small.
plans for these patients.9,18 Despite lack of evidence that anes- The parasympathetic neurons and large axons are generally
thesia affects the course of pre-existing neuromuscular dis- spared. FD presents at birth and progresses with age. In the
ease, regional anesthesia may be erroneously blamed for any past, more than 50% of patients died before 5 years of age.
subsequent deterioration in sensory or motor deficits. This is Currently, because of improvements in diagnosis and treat-
especially true in pregnancy, which as noted, is associated with ment, newborns diagnosed with FD have a greater than 50%
exacerbation of neurologic symptoms in women with CMTD. chance to live past age 30.
Additionally, the choice between general or regional/neurax- Although FD has close to 100% penetrance, the presen-
ial anesthesia in patients with CMTD complicated by respira- tation of the disease at different life stages is highly variable.
tory compromise is guided by the preservation of respiratory Autonomic dysfunction is the most prominent feature, present-
function in the perioperative period. In patients with phrenic ing the greatest impediment to normal functioning, and usu-
nerve involvement, whose respiration depends on accessory ally overshadows the sensory deficits. Dysautonomic crisis is
muscles, regional block involving intercostal muscles can lead the most dramatic feature of this syndrome, characterized by
to acute respiratory failure.31 In other case reports, however, episodes of severe nausea and vomiting associated with agita-
patients with CMTD required prolonged respiratory support tion, hypertension, tachycardia, excessive sweating, and sali-
after general anesthesia.32,33 vation, which are easily triggered by emotional or physical
Patients with CMT-1 have demonstrated increased sen- stress, or arousal from sleep.
sitivity to thiopental, correlating with the degree of motor The clinical diagnosis of FD is usually established soon
and sensory deficit.34 However, propofol and total intrave- after birth by demonstrating the presence of four main cri-
nous anesthesia (TIVA) have been successfully used in these teria: absence of tears with emotional crying, absence of
patients without untoward effects.13,16 lingual fungiform papillae, hypotonic or absent patellar
Anesthetic management in the vast majority of patients reflexes, and absence of axon flare to intradermal injection
with HMSN appears to be uncomplicated and should be of histamine in children of Ashkenazi Jewish descent. Many
directed to accommodate any coexisting systemic conditions. other systems are affected at various stages in life, and the
However, detailed preanesthesia assessment and thorough myriad of clinical manifestations of FD can be divided into
documentation of informed consent, with maximum patient two main groups: sensory dysfunction and autonomic dys-
participation in the decision-making process on choice of function (Box 8-3). Differential diagnosis typically does not
anesthesia technique, are crucial. present a problem, considering availability of genetic testing
and the fact that this disease is restricted to Ashkenazi Jews.
However, many other conditions have some similar symp-
Hereditary Sensory and Autonomic Neuropathies
toms of autonomic and sensory dysfunction. All HSANs,
The hereditary sensory and autonomic neuropathies (HSANs) cranial nerve and nuclear dysplasias, cri du chat (cat's cry)
are a diverse and constantly expanding group of disorders syndrome, and Möbius syndrome can have some of the fea-
affecting the development of autonomic and sensory neu- tures found in FD. Many eye conditions have similar ocular
rons. Until recently, seven such disorders have been described, manifestations with those of FD.
with familial dysautonomia (HSAN type III), also known as Treatment of FD patients is symptomatic. Diazepam is the
Riley-Day syndrome, and HSAN type IV, also known as con- most effective treatment for dysautonomic crisis with vomit-
genital insensitivity to pain with anhidrosis (CIPA), the most ing. It also normalizes blood pressure and heart rate in these
recognized and well understood. All HSANs are manifested patients. Increased salt and fluid intake is used to treat dehy-
by both sensory and autonomic dysfunction present at vari- dration and hyponatremia and associated postural hypoten-
able degrees, with a unique feature for all types being absence sion. Fludrocortisone and midodrine are also used for this
of a normal axon flare response after intradermal injection of purpose. Surgical procedures performed on these patients
BOX 8-3 n FAMILIAL DYSAUTONOMIAS: SENSORY AND AUTONOMIC DYSFUNCTION
Sensory System Postural hypotension.

Decreased pain sensation, often with hypersensitivity of palms, sole, Postural hypertension can develop in older patients.
neck, and genital areas; decreased temperature sensation.
Dysautonomic Crisis
Visceral sensation is intact.
Episodes of severe nausea and vomiting associated with agitation,
Sense of vibration and proprioception is affected in older individuals;
hypertension, tachycardia, and excessive sweating/salivation.
ataxia.
Easily triggered by emotional or physical stress and arousal from sleep.
Hypotonia in younger children; often disappears with age; decreased
tendon reflexes. Other Manifestations
Prone to self-injury; unrecognized fractures; scoliosis and joint Renal System
deformities. Dehydration azotemia.
Progressive loss of renal function with age.
Autonomic System
Gastrointestinal System Central Nervous System/Developmental
Impaired oropharyngeal coordination and impaired swallowing, resulting Emotional lability, probably related to catecholamine imbalance.
in dysphagia and frequent aspirations in newborns and infants. Prolonged breath holding with crying, decerebrate posturing, syncope,
Abnormal esophageal motility; decreased lower esophageal sphincter cyanosis; may be misinterpreted as seizures.
pressure and esophageal reflux. Normal intelligence.
Gastrointestinal dysmotility, complicated by cyclic vomiting (part of Delayed development.
dysautonomic crisis).
Ocular Manifestations
Respiratory System Absence of overflow tears with emotional crying in all patients.
Recurrent pneumonias result from aspirations. Corneal insensitivity; abrasions and spontaneous injuries; ulcers.
Insensitivity to hypoxia and hypercapnia (no ventilatory response). Optic neuropathy increases with age.
Low tolerance for hypoxia; profound hypotension and bradycardia in
Laboratory Findings
response to hypoxia.
Elevated blood urea nitrogen (BUN).
Cardiovascular System Hyponatremia associated with excessive sweating.
Rapid, severe orthostatic hypotension without compensatory Catecholamine imbalance: elevated dopa/DHPG ratio.
tachycardia.
Episodes of severe hypertension and tachycardia as part of
dysautonomic crisis.
Syncopal episodes produced by various stimuli (e.g., full bladder, large
bowel movement). Dopa, 3,4-Dihydroxyphenylalanine; DHPG, 3,4-Dihydroxyphenylglycol.
include gastrostomy in the majority of patients before age these patients. Intravenous (IV) prehydration with crystalloids
5 years, to provide fluid and alimentation in patients with is often recommended to achieve euvolemic status preopera-
dysphagia; fundoplication for treatment of gastroesophageal tively.42,43 Patients are evaluated for the presence and severity of
reflux (GER) and associated pneumonia; and spinal fusions GER; antacids need to be administered preoperatively to affected
for severe scoliosis. patients. Renal function is assessed to rule out significant renal
failure, which can affect the choice of muscle relaxants. Patients
ANESTHETIC CONSIDERATIONS with FD are prone to anticipation anxiety that can trigger dysau-
Anesthesia for surgical procedures had been associated with tonomic crisis. Preoperative medication with benzodiazepines is
great risks in patients with FD.36-38 Recent progress in the recommended. Preoperative medication with opioids is contra-
understanding of existing risks and improved preoperative indicated because of possible increased sensitivity to the agents.
preparation resulted in significantly improved perioperative Intraoperative management of FD patients is directed
outcomes.39-42 Good working knowledge of FD manifesta- toward better cardiovascular stability, prevention of pulmo-
tions and a systematic approach to preoperative assessment nary aspiration, prevention of postoperative respiratory com-
are essential for successful anesthetic management of these promise, and adequate postoperative pain control. Invasive
patients (see Box 8-2). hemodynamic monitoring (intra-arterial line and central
The respiratory system should be evaluated for signs of venous catheters) has been advocated in the past but was
chronic or acute infections from repeated aspirations. Chest not used in one reported series without untoward effects.39,42
radiography is warranted in all patients. In patients with It appears reasonable to use invasive monitoring in patients
restrictive pulmonary disease caused by chronic pneumonias with postural hypotension and for extensive surgery with
and scoliosis, arterial blood gas (ABG) analysis is included. large fluid shifts. Immediate preinduction administration of
Severe intraoperative hypotonia is a well-recognized risk fluid bolus can reduce blood pressure (BP) variation. BP insta-
of general anesthesia.36-38 Cardiac output depends on preload bility intraoperatively is treated by additional fluid boluses
because of a lack of compensatory sympathetic response to and direct-acting vasopressors, if the patient is unresponsive
hypotonia. Correction of existing dehydration and hypona- to administration of fluids. Any episodes of desaturation are
tremia is essential for intraoperative hemodynamic stability in promptly addressed by increased oxygen concentration to
avoid profound hypotension and bradycardia from lack of with CIPA: anxiety alleviation, temperature control, and
hypoxic compensatory responses. adequate pain control. Despite congenital insensitivity to
Rapid-sequence induction with cricoid pressure should pain, general anesthesia was found to be necessary. Overall
be considered in patients with GER and a history of repeated requirements of general anesthetics necessary for maintain-
aspirations. ing stable hemodynamics have been only slightly reduced.
Careful planning for extubation, postoperative ventilatory General anesthesia was used in all patients in these reports
support, and weaning from the respirator in the intensive care without any adverse reactions to the IV or inhalational anes-
unit (ICU) should be part of the routine postoperative man- thetic agents, opioids, or succinylcholine. In one report, a
agement for these patients. In the past, FD patients frequently patient died after intraoperative cardiac arrest without clear
required prolonged ventilation in the ICU setting after general cause, although the authors suspected that the high concen-
anesthesia. Reports indicate that with alternative techniques, tration of halothane used (2%) could have been responsi-
such as epidural39 or local anesthesia, or deep propofol seda- ble.45 Previous recommendations against the use of atropine
tion with spontaneous ventilation,42 these patients can recover (or other anticholinergic drugs) to avoid hyperpyrexia in
from anesthesia quickly without need for postoperative respi- these patients was not supported by the results reported in
ratory support. this series. Many patients received atropine without untow-
Although patients with FD have decreased perception of ard effects.
pain and temperature, their visceral perception is intact, and
they need sufficient levels of anesthesia and postoperative
pain control. Postoperative pain should be promptly treated
NEURODEGENERATIVE DISORDERS WITH
to avoid dysautonomic crisis. Nonsteroidal anti-inflammatory
AUTONOMIC FAILURE
drugs (NSAIDs) or paracetamol will suffice in many cases. Autonomic failure (or dysautonomia), with its protean range
Opioids should be used cautiously to avoid respiratory depres- of manifestations and symptoms, is a common part of an
sion. Regional techniques can be useful.39 immensely diverse group of disorders in which some or all ele-
There have been no reports of adverse or prolonged ments of the autonomic nervous system are affected. Autonomic
responses of FD patients to any specific anesthetic agents or failure to varying degrees is a part of the presentation of many
muscle relaxants. For appropriate surgical procedures, regional systemic diseases (e.g., diabetes mellitus, amyloidosis), infec-
anesthesia is well tolerated.39 Use of deep propofol sedation for tious diseases (e.g., leprosy, human immunodeficiency virus
endoscopic outpatient procedures has been reported, with excel- [HIV], rabies), immune disorders (e.g., acute dysautonomia,
lent results.42 Body temperature needs to be carefully monitored Guillain-Barré syndrome), paraneoplastic disorders, hereditary
because of impaired temperature control in these patients. The autonomic disorders (e.g., all HSANs, dopamine β-hydroxylase
eyes should be lubricated and protected at all times. deficiency), and neurodegenerative disorders. A comprehen-
Familial dysautonomia is a serious anesthetic challenge that sive discussion on various aspects of autonomic dysfunction
can be hazardous in these patients without proper preopera- in these conditions can be found in most neurology and medi-
tive preparations and intraoperative management. However, cal textbooks. This section discusses only the most prevalent
current approaches have resulted in significantly reduced neurodegenerative disorders in which autonomic failure plays
mortality and morbidity in FD patients. a prominent role, presenting a significant anesthetic challenge.
Parkinson's disease (PD), dementia with Lewy body dis-
order (LBD), multiple system atrophy (MSA), and pure
CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS
autonomic failure disorder (PAF) are all neurodegenera-
Pathophysiology and Diagnosis. Congenital insensi- tive disorders of unclear etiology, presenting with variable
tivity to pain with anhidrosis, or HSAN type IV, is a rare degrees of autonomic dysfunction. Based on the differences
autosomal recessive neuropathy characterized by recur- in the neuropathology, these disorders can be divided into
rent episodic fever, anhidrosis (absence of sweating), pain two subgroups: Lewy body syndromes (PD, LBD, and PAF)
insensitivity, self-mutilating behavior, and mental retar- and multiple system atrophy. All these disorders are char-
dation.35 Death from hyperthermia has been reported in acterized by the presence of α-synuclein in the neuronal
infants with CIPA. Besides anhidrosis, it differs from FD cytoplasmic inclusions (Lewy bodies, as in Lewy body syn-
by complete insensitivity to superficial and deep painful dromes) or the glial cell inclusions (GCIs, as in MSA); thus
stimuli and normal lacrimation, much milder autonomic these disorders are often called synucleinopathies. In PD,
dysfunction, with absent postural hypotension or dyspha- neurodegeneration is predominant in the substantia nigra
gia. Self-inflicted multiple injuries are typical for these and other brainstem nuclei and in peripheral autonomic
patients. This is often accompanied by accidental trauma, neurons. Motor dysfunction is more prominent than auto-
burns, wound infections, skin ulcers, joint deformities, and nomic failure in PD patients. Neuronal degeneration in PAF
osteomyelitis. is restricted to peripheral autonomic neurons; thus the symp-
There is only limited anesthetic experience in patients toms of pure autonomic failure without other manifestations.
with CIPA.1,44-46 Okuda et al.44 suggest three important Extensive cortical involvement, in addition to degeneration
considerations in the anesthesia management of patients of brainstem nuclei and peripheral autonomic neurons, is
characteristic for LBD, which presents as severe dementia many patients. Other symptoms of autonomic dysfunction,
associated with parkinsonism and autonomic failure. as described for familial dysautonomia, can be present. The
In MSA, cytoplasmic inclusions are found in the glial cells differential diagnosis can be difficult because of frequent
(GCIs) and not neurons (Lewy body). These inclusions are overlapping of the clinical picture between these condi-
associated with degenerative changes in the central neurons tions, especially in the initial stages of the disease process.
in basal ganglia, cortex, and spinal cord, but not in periph- Definitive diagnosis in some disorders could be established
eral autonomic neurons. Two phenotypes of MSA are cur- only on postmortem histopathologic examination. However,
rently identified based on the predominant clinical picture of thorough clinical examination helps to distinguish between
parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). In PD, LBD, MSA, and PAF (Table 8-2). The subject of neu-
the past, the patients with a predominant picture of autonomic rodegenerative disorders with autonomic failure has been
failure were diagnosed with Shy-Drager syndrome. Currently, reviewed.47,48
this term is rarely used, because all patients with MSA have a Anesthetic management of PD is described later. Although
significant degree of autonomic dysfunction.47 LBD is the second most common cause of dementia after
Autonomic failure in patients with Lewy body syn- Alzheimer's disease, there are no reports of anesthetic man-
dromes and MSA typically manifests with orthostatic and agement in the literature. It appears reasonable to assume that
postprandial hypotension, bladder dysfunction, gastroin- the principles of anesthetic management of patients with LBD
testinal (GI) motility disorders, and erectile dysfunction are common to those in patients with other forms of dementia.
(ED). Orthostatic and postprandial hypotension is often In LBD patients with advanced dysautonomia, the same pre-
the earliest and most disabling aspect of dysautonomia in cautions should be taken as in patients with MSA.
TABLE 8-2 n Differential Diagnosis of Multisystem Atrophy, Parkinson's Disease, Pure Autonomic Failure, and Dementia
with Lewy Bodies
Characteristic Multisystem Atrophy Parkinson's Disease Pure Autonomic Failures Dementia with Lewy Bodies
Central nervous Multiple involvements Multiple involvements Unaffected Multiple involvements

system
involvement
Site of lesions Mainly preganglionic, Peripheral autonomic Mainly peripheral Cortex, brain stem,
central; degeneration postganglionic autonomic postganglionic peripheral autonomic
of interomediolateral neurons neurons; loss of postganglionic neurons
cell columns ganglionic neurons
Progression Fast; median survival, Slow Slow; up to 15 years and Slow

6-8 years after first longer
symptoms
Prognosis Poor Good Good Moderate to poor
Autonomic Early onset, severe Late onset, usually Severe, usually the only Unclear, but can be severe
dysfunction mild to moderate manifestation
Extrapyramidal Common Common Absent Common

involvement
Cerebellar Common Common Absent Common

involvement
Lewy bodies Mostly absent Primarily in substantia Present in autonomic Cortex, brainstem,
nigra neurons hippocampus
Glial cytoplasmic Present Absent Absent Absent

inclusions
(postmortem
staining)
Response to Poor Good Moderate

chronic levodopa
therapy
Dementia Uncommon Usually not severe, Uncommon Early, severe, rapidly

25%-30% of patients progressing
Modified from Marti MJ, Tolosa E, Campdelacreu J: Mov Disord 18(suppl 6):21-27, 2003; and Kaufmann H, Biaggioni I: Semin Neurol 23:351-363, 2003.
Multiple System Atrophy

BOX 8-4 n NEURODEGENERATIVE DISORDERS WITH
In 1998, consensus committees representing the American AUTONOMIC FAILURE: ANESTHETIC ISSUES
Autonomic Society and the American Academy of Neurology
Multiple System Atrophy (MSA)
defined multiple system atrophy as a sporadic, progres- Perioperative hemodynamic instability, related to autonomic failure
sive, neurodegenerative disorder of undetermined etiology, with orthostatic hypotension and sometimes severe supine
characterized by features in the three clinical domains of hypertension, is to be expected. Invasive hemodynamic monitoring
parkinsonism, autonomic failure, and cerebellar or pyramidal may be of benefit in perioperative management of patients with
severe symptoms.
dysfunction. In the past, the terms striatonigral degeneration,
Obstructive and central sleep apnea and sleep-related inspiratory
olivopontocerebellar atrophy, and Shy-Drager syndrome were stridor may occur. The risk of postoperative airway obstruction and
used, depending on the predominance of clinical symptoms in apneic episodes is increased in patients with MSA.
any of these three domains. In patients with advanced dementia and parkinsonism, anesthetic
Multiple system atrophy is a fatal disease that typically pres- considerations are similar to those in patients with other forms of
dementia and Parkinson's disease.
ents in the fourth to sixth decade of life, with mean disease
No specific anesthetic techniques or agents are contraindicated in
duration of 6 years from onset of symptoms. Because of the MSA patients.
significant similarity of clinical presentation to other neuro-
degenerative disorders, MSA is often not diagnosed until later Anesthetic considerations are similar to those in patients with MSA.
stages. Parkinsonism is a predominant symptom in 80%, and
cerebellar dysfunction in 20%, of all patients. Parkinsonism is
usually not responsive to antiparkinsonian medications, which
helps to differentiate MSA from PD. The most common and controversy surrounds the potentially unpredictable response
early presentation of autonomic dysfunction is urinary inconti- to vasopressor amines because of sympathetic hypersensitivity
nence and ED. Orthostatic hypotension is found in half of MSA caused by autonomic denervation.52,61 Therefore, it is recom-
patients and is usually mild. Reduced heart rate variability and mended to administer vasoactive medications very cautiously
absence of compensatory tachycardia during hypotension is in much smaller doses than usual. However, vasopressors have
characteristic. Paradoxically, supine hypertension is present in been used without adverse effects for treatment of hypoten-
more than half of patients and complicates their management. sion intraoperatively, when titrated judiciously.53,54,60
Recurrent syncope is a sign of severe orthostatic hypotension. Significant intraoperative supine hypertension has been
Severe constipation, fecal incontinence, and decreased sweat- reported, with minimal response to labetalol but profound
ing are other signs of autonomic dysfunction in MSA. hypotension after hydralazine administration.62 The hypo-
Obstructive sleep apnea or central sleep apnea and sleep- tension responded only to vasopressin infusion. Short-acting
related inspiratory stridor associated with bilateral vocal cord vasodilators such as sodium nitroprusside may be a better
paresis or dysfunction have been reported in MSA patients.49 choice for intraoperative supine hypertension. The hyperten-
There are no currently available treatments that can mod- sive episodes in autonomic failure are particularly responsive
ify the clinical course or address the underlying pathologic to transdermal nitroglycerin.63
MSA process. All the treatments are symptomatic, intended Neuraxial anesthesia techniques have been successfully
for improving the quality of life in these patients. Orthostatic employed in patients with MSA, including for labor and
hypotension is treated with administration of fludrocortisone delivery, with a greater degree of hemodynamic stability,
or milrinone (oral adrenergic vasoconstrictor). The presence also avoiding possible difficulties with extubation in these
of significant supine hypertension limits the use of vasopres- p
atients.51,56,57,59,64 It is speculated that patients with autonomic
sors. Erythropoietin has been reported to be useful in the failure are less likely to respond with hypotension to sympa-
treatment of patients with associated anemia and severe hypo- thectomy caused by neuraxial block because they are already
tension. Tracheostomy and respiratory support is reserved for sympathectomized. The data in the literature support this
the patients with stridor and central sleep apnea. hypothesis.
When general anesthesia is chosen, careful planning for
ANESTHETIC CONSIDERATIONS extubation and postoperative monitoring of the respiration in
Perioperative management of patients with MSA is a formi- the ICU setting is warranted, especially in MSA patients with a
dable challenge because of potential hemodynamic instabil- history of stridor or central or obstructive sleep apnea.
ity and respiratory compromise in the postoperative period
(Box 8-4). A few case reports in the literature indicate no
adverse effects to most of the common anesthetic agents.50-60
The management is directed at ensuring hemodynamic sta- Pure autonomic failure is a sporadic, slow-progressing neuro-
bility through invasive hemodynamic monitoring, adequate degenerative disorder of the autonomic nervous system (ANS)
preoperative hydration, and maintenance of normovolemia that typically affects individuals in the sixth decade of life. PAF
with fluid replacement intraoperatively. Preoperative opti- is characterized by an isolated impairment of the peripheral
mization of fludrocortisone therapy is recommended. Some and central ANS. No symptoms of parkinsonism, cerebellar
dysfunction, or dementia are usually present. The orthostatic thalamus, which suppresses both the cortical motor system,
hypotension in this syndrome is typically severe and more leading to bradykinesia and tremor, and the brainstem motor
disabling than in other neurodegenerative disorders with areas, leading to gait and postural instability.
autonomic failure. Other symptoms of autonomic failure are The precise mechanism of degeneration in PD has yet to
similar to those seen in MSA. The prognosis in PAF patients, be elucidated. Programmed cell death, protein misfolding and
however, is much better. aggregation, abnormal proteosomal degradation, oxidative
There is only one case report in the literature of general stress, mitochondrial dysfunction, and immunomodulation
anesthesia without complications in a patient with PAF;65 it is and inflammation have all been proposed. Although no uni-
unclear whether the patient also had epidural anesthesia per- versally accepted pathologic criteria exist for the diagnosis of
formed. However, the authors advocate the use of epidural PD, one hallmark of the disease appears to be the presence of
anesthesia and invasive hemodynamic monitoring for greater eosinophilic, intracytoplasmic inclusions known as Lewy bod-
hemodynamic stability. ies. Composed primarily of α-synuclein, in association with
The same principles of anesthetic management used for ubiquitin, complement, and numerous cytoskeletal proteins,
patients with MSA should be applied when managing PAF Lewy bodies are found in the substantia nigra, locus ceruleus,
patients. cerebral cortex, and sympathetic ganglia of PD patients, as well
as in the cardiac sympathetic plexus, dorsal vagal nucleus, and
myenteric plexus of the intestines. Importantly, Lewy bodies
BASAL GANGLIA AND CEREBELLAR
are not specific for PD and are found in other neurodegenera-
DISORDERS
tive diseases (e.g., MSA, progressive supranuclear palsy, Lewy
Parkinson's Disease body dementia), in Down syndrome, in amyloidopathies (e.g.,
Alzheimer's disease), in tau-protein–associated diseases
Parkinson's disease is a chronic progressive neurodegener-
(e.g., frontotemporal dementia), and even in a small percent-
ative disease characterized by resting tremor, bradykinesia,
age of normal elderly brains.68 It remains unclear whether
rigidity, and postural instability. In addition to these cardi-
Lewy bodies represent a pathologic neurotoxic process, or as
nal signs, many patients with PD will experience secondary
recent evidence suggests, play a neuroprotective role.69
symptoms attributable to the disease or its pharmacother-
apy. Dementia is common, especially in advanced stages, as Medical Management. Pharmacologic management of PD
are fatigue and depression. Hallucinations, psychosis, anos- patients seeks to balance dopaminergic and cholinergic effects
mia, and autonomic instability are also well-described in the striatum and thus preserve motor function and qual-
nonmotor features of the disease. Diagnosis is clinical, ity of life while minimizing medication-related side effects.
requiring at least two of the four cardinal signs. Prevalence Current therapies attempt to achieve these goals by blocking
has been estimated at approximately 1% of the population acetylcholine transmission, enhancing dopamine production,
over 60.66 To date, attempts to identify risk factors have or stimulating central dopamine receptors (Table 8-3).70-72
produced contradictory results. Older age has been per- Motor symptoms generally respond better to treatment than
sistently associated with increased risk of PD. Other puta- extramotor symptoms, but effectiveness diminishes in later
tive risk factors include environmental exposure to heavy stages. Although several agents have shown possible neuro-
metals, pesticides, and herbicides; dietary factors; and body protective effects in human and animal studies, currently no
weight. Although most cases appear sporadic, several genes treatment significantly reverses or delays PD progression.
have recently been linked to PD, particularly in those cases
Surgical Management. Surgical treatment of PD began in
manifesting before age 50.67
the early 20th century and was originally based on the inten-
Pathophysiology. Coordination of movement depends on tional lesioning of deep brain structures. Thalamotomy was
a complex feedback loop in which the cortex sends informa- performed to ameliorate tremor and pallidotomy to con-
tion to the basal ganglia and cerebellum and in turn receives trol both parkinsonism and levodopa-induced dyskine-
information from these structures through the thalamus. sias. Although the introduction of stereotactic localization
Because of their anatomic location, these pathways are often improved outcomes and reduced complications from these
referred to as “extrapyramidal.” PD is characterized by neu- surgeries, the continued risk of permanent paresis, visual field
ronal loss, depigmentation, and gliosis in the substantia nigra cuts, gait disturbances, dysarthria, and hypersalivation, com-
pars compacta and pontine locus ceruleus, as well as degen- bined with the development of deep-brain stimulation tech-
eration of the putamen, globus pallidus, hippocampus, and niques, have led to a pronounced shift away from permanent
brainstem nuclei. The result of this degeneration is a relative surgical lesioning.
dopamine deficiency, particularly in the striatum and puta- Drawing on the intraoperative observation that focal
men, and unopposed cholinergic activation of inhibitory electric stimulation of the brain induced a functional but
γ–aminobutyric acid (GABA) transmission from the striatum. reversible “lesion,” implantable deep-brain stimulation of
The end result of this imbalance is excessive inhibition of the the subthalamic nucleus (STN), globus pallidus (GPi), and
TABLE 8-3 n Pharmacologic Therapy of Parkinson's Disease
Drug Features Side Effects Contraindications
DOPAMINE PRECURSORS
Levodopa Converted to dopamine by dopa Nausea, somnolence, dizziness, History of psychosis
decarboxylase headache, confusion Narrow-angle glaucoma
Combined with carbidopa (see Hallucinations/delusions Concurrent monoamine
Sinemet) Agitation oxidase inhibitor (MAOI)
Treats akinetic symptoms, tremor, Pyschosis therapy
and rigidity Motor fluctuations (“wearing-off
Not as effective for postural phenomenon”)
instability Dyskinesias/dystonias
Motor fluctuations and dyskinesias Homocysteine elevation (proposed)
often become impediments to Peripheral neuropathy if concomitant
therapy. elevated methylmalonic acid
Evidence for both neurotoxic and
neuroprotective effects70
Carbidopa Decarboxylase inhibitor that does not Rebound hypertension with

cross blood-brain barrier withdrawal
Prevents peripheral conversion of
levodopa to dopamine
Reduces nausea, vomiting, orthostatic
hypotension
Sinemet Combination of carbidopa/levodopa

Available in 1:10 and 1:4 ratio
Controlled-release formulation also
available
DOPAMINE AGONISTS
Bromocriptine Sometimes used as levodopa-sparing Similar to levodopa History of psychosis
Cabergoline monotherapy in younger patients Dopaminergic dysregulation Recent myocardial infarction
Pramipexole Fewer “on-off” fluctuations and less syndrome (compulsive use, cyclic Severe vascular disease
Ropinirole dyskinesia than levodopa mood disorder) Breastfeeding
Apomorphine Apomorphine used as parenteral Impulse control disorders
“rescue” therapy for levodopa- Dopamine withdrawal syndrome
induced motor fluctuations (resembling cocaine withdrawal)
Valvular heart disease (cabergoline)
Angina and orthostasis
(apomorphine)
Acute somnolence (pramipexole)
ANTICHOLINERGICS
Trihexylphenidyl Most useful in patients under age 70 Common and may limit use Relatively contraindicated
Benztropine without significant akinesia or gait Memory impairment, confusion, in elderly or cognitively
disturbance hallucinations impaired patients
May be used adjunctively for persistent Peripheral antimuscarinic effects Prostatic hypertrophy
tremor Closed-angle glaucoma
Improve DA/Ach balance
Rapid withdrawal may precipitate
exacerbation of symptoms
CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS

Tolcapone Prolong and potentiate levodopa effect Dyskinesia Liver disease may be a relative
Entacapone by increasing plasma half-life Hallucinations contraindication.
Confusion Liver function must be
Nausea monitored for the first
Orthostatic hypotension 6 months in all patients.
Hepatotoxicity (tolcapone)
Diarrhea
Continued
TABLE 8-3 n Pharmacologic Therapy of Parkinson's Disease—Cont'd
Drug Features Side Effects Contraindications
MONOAMINE OXIDASE B (MAO-B) INHIBITORS

Selegiline Modest effect in some patients Nausea Use caution with concomitant
Rasagiline Inhibit breakdown of DA Headache SSRIs or TCAs
May be neuroprotective Diarrhea Does not precipitate
Insomnia (selegiline's amphetamine hypertension with
metabolites) concomitant tyramine
Confusion in elderly ingestion
ANTIVIRALS
Amantadine Mild antiparkinsonian activity Side effects are rare in monotherapy
Mechanism unclear (likely but include livedo reticularis,
dopaminergic, anticholinergic, and ankle edema, hallucinations,
NMDA mediated) confusion, and nightmares.
Short-term monotherapy for mild Central nervous system side effects
disease are more likely when used
May reduce levodopa-induced adjunctively.
dyskinesia and motor fluctuations
May reduce impulse control disorders in
patients taking dopamine agonists71
HORMONE REPLACEMENT
Estrogen Adjunctive therapy in postmenopausal Adverse effects associated with long-
women term estrogen use
Effect may be indirect through improved
subjective well-being.
Improved “on time,” but not objective
scales of ADLs in one study72
Few data on estrogen/progesterone
DA, Dopamine; Ach, acetylcholine; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; ADLs, activities of daily living.
ventralis intermedius (Vim) have all been successful in ame- ANESTHETIC CONSIDERATIONS
liorating PD symptoms. Vim stimulation appears to be most Preoperative Concerns. A thorough history of the patient's
effective for tremor-predominant cases. Evidence from ran- symptoms, disease severity, and medication regimen should be
domized controlled trials (RCTs) suggests that both STN and obtained. The patient's prescribed medication regimen should
GPi are effective for treatment of motor symptoms and bra- be optimized before scheduling surgery. Because several med-
dykinesia. STN stimulation appears to provide a greater dose- ications used to treat PD have a relatively short half-life, doses
sparing effect in terms of future medication use, and GPi may should be continued through the morning of surgery, and
provide superior control of dyskinesias as well as fewer altera- until as close to induction of anesthesia as feasible for after-
tions of mood, cognition, and behavior.73 noon or unscheduled procedures (Box 8-5).
In addition to its reversibility, deep-brain stimulation
appears safer than lesioning, even when bilateral. The treat- Preoperative Evaluation. Cognitive impairment may pre-
ment effect may be modulated; it causes less permanent collat- dispose patients to postoperative delirium, and baseline men-
eral damage to the surrounding brain, without ruling out the tal status should be assessed. Neurologic symptoms, including
possibility of new medical or surgical therapies as they become tremor, muscle rigidity, and bradykinesia, should also be
available. Drawbacks include increased time and expense, assessed. Patients with PD are particularly vulnerable to respi-
including specialized intraoperative and postoperative device ratory complications, and the preoperative evaluation should
management, the infection risk of indwelling hardware, elicit evidence of swallowing dysfunction, retained or exces-
potential magnetic resonance imaging (MRI) incompatibility, sive oropharyngeal secretions, dyscoordination or rigidity of
and the need for periodic battery replacement. Anesthesia for accessory muscles of respiration, and recent or active respi-
deep-brain stimulation is discussed later. ratory infection. From a cardiovascular standpoint, patients
Future directions for surgical management include neu- should be evaluated for arrhythmia and hypertension, as
ral transplantation of dopaminergic cells, targeted infusion of well as evidence of hypovolemia and orthostatic hypoten-
glial cell line–derived neurotrophic factor (GDNF), gene ther- sion, which are common medication side effects. Autonomic
apy, and continuous duodenal levodopa infusion. dysfunction, including abnormal micturition, salivation, GI
nausea and vomiting, and facilitate earlier ability to resume

BOX 8-5 n BASAL GANGLIA AND CEREBELLAR enteral medications. When tremor is a serious impediment to
DISORDERS: ANESTHETIC ISSUES
the safe performance of a procedure (e.g., ophthalmologic sur-
Parkinson's Disease (PD) gery), diphenhydramine may be a useful adjunct for reducing
Medication effects are common and include motor fluctuations tremor in the awake or sedated patient.
and dyskinesias, orthostatic hypotension, and antimuscarinic
In the absence of hypovolemia or cardiac dysfunction,
symptoms.
Deep-brain stimulation is a safe, reversible treatment for patients
propofol is a good choice for induction of general anesthe-
without cognitive impairment; implantation requires patient sia because of its rapid metabolism and predictable offset.
cooperation with intraoperative neurologic examination. Risks Although case reports have linked propofol to dyskinesias,
include air embolism and intracerebral hemorrhage. it has also been noted to diminish tremor in the postopera-
Patients with PD undergoing any surgery should continue their
tive period.74,75 Thiopental has been associated with dyskine-
medication regimen until immediately before surgery and should
resume their medications as soon as possible postoperatively.
sias in several reports.76,77 Although ketamine may increase
Medications with potential extrapyramidal side effects should be oral secretions and is relatively contraindicated because of its
avoided. potential to cause hypertension through an exaggerated sym-
Patients with PD are particularly vulnerable to aspiration, respiratory pathetic response, it has been used without incident.78 Inhaled
compromise, and postoperative delirium.
anesthetics have been associated with an increase in postop-
Huntington's Disease (HD) erative rigidity.
Patients with advanced disease are at risk for aspiration and Nondepolarizing neuromuscular blockers may mask
respiratory complications.
tremor, but patients with PD appear to have normal sensitivity
Patients with HD may have decreased pseudocholinesterase activity.
to these drugs. Hyperkalemia has been reported in one patient
Sydenham's Chorea (SC) with presumed denervation from chronic PD who received
Preoperative evaluation must include ECG and evaluation for carditis
and valvular disease.
succinylcholine.79 However, a subsequent case series found
Procedural sedation may be difficult because of patient movement no evidence of hyperkalemia in PD patients exposed to succi-
and may be facilitated by the use of neuroleptics, benzodiazepines, nylcholine.80 Anticholinesterase agents have been used in the
or propofol. treatment of some parkinsonian symptoms and are presumed
Patients with SC should receive long-term prophylaxis against
safe to use for the reversal of NMB. Because it does not cross
recurrent group A streptococcal pharyngitis.
the blood-brain barrier, glycopyrrolate is the preferred anti-
Dystonias cholinergic, particularly in patients with cognitive deficits.
Dystonic symptoms may complicate positioning and in severe cases,
Opioid medications should be used with caution in patients
airway management.
Dystonic symptoms are often relieved by sedation. who are unlikely to tolerate respiratory depression. Fentanyl
Dystonic patients may be managed using anticholinergic or and remifentanil may exacerbate muscle rigidity, although this
dopaminergic therapy, leading to possible drug-drug interactions. effect is amenable to treatment with neuromuscular blockers
There are no specific contraindications to any particular anesthetic and may be blunted by coadministration of propofol. At low
agent, although many have been implicated in acute dystonic
doses, morphine has been reported to decrease dyskinesias,
reactions.
but at high doses it may actually precipitate them.81 NSAIDs
may be beneficial as part of an opioid-sparing strategy.
Medications that may precipitate extrapyramidal symptoms
or dystonic reactions, including phenothiazines (prometha-
zine), butyrophenones (droperidol), and metoclopramide are
function, and temperature regulation should be considered.
contraindicated in patients with PD. Benzodiazepines may
Seborrheic dermatitis of the face, ears, and skin folds is com-
diminish tremor, but may also exacerbate delirium and should
mon in PD patients and should be recognized as a manifes-
be avoided in patients with significant dementia. Vasodilators
tation of underlying autonomic dysfunction. Weight loss and
should be used with caution in patients at risk for hypovole-
malnutrition are also common in patients with more advanced
mia, and hypotension should be treated with volume resusci-
disease, and GI dysmotility and esophageal reflux disease can
tation and direct-acting agents such as phenylephrine rather
increase the risk of aspiration. Glucose utilization is often dis-
than ephedrine.
rupted, and preoperative serum glucose should be measured.
Intraoperative Management. As suggested, intraoperative Postoperative Concerns. Patients with PD should be
challenges in the management of patients with PD include watched closely for postextubation respiratory failure. These
increased aspiration risk, potential for autonomic instability patients are at increased risk of laryngospasm, inability to han-
and arrhythmia, and relatively high incidence of orthostatic dle oral and respiratory secretions, and aspiration pneumonia.
hypotension. Tremor and rigidity may make positioning and Respiratory reserve is likely to be diminished, especially in
cooperation difficult for patients undergoing sedation or pre- patients with preoperative muscle rigidity and dyscoordina-
induction vascular access or monitor placement. On the other tion. Intraoperative atelectasis and medication effects are likely
hand, regional anesthesia may reduce the risk of aspiration and to impair respiratory function further. Oral secretions may be
respiratory complications, minimize the risk of postoperative a contraindication to noninvasive ventilation. In patients who
fail to meet criteria for extubation or who are reintubated for yet to be fully elucidated, HD appears to develop from the
respiratory failure, antiparksinonian medications should be neurotoxicity of an abnormal variant of the protein hunting-
continued via gastric tube to maximize chances of successful tin, arising from an autosomal dominant mutation involving
extubation. a trinucleotide expansion (CAG) in the Huntington gene on
chromosome 4p.86 Onset typically occurs in middle age, with
ASSOCIATED PROCEDURES the development of chorea, which is often accompanied by
Anesthesia for Deep-Brain Stimulator Placement. Deep- insidious progression of cognitive and personality changes.
brain stimulation (DBS) surgery is generally accomplished Choreatic movements are often subtle initially, but progress
using two separate procedures. In the first stage, a stereotactic to the point of interference with normal movement. In late
head frame is placed with the patient in a semi-upright posi- stages, chorea begins to affect the diaphragm and the muscles
tion, and leads are then placed through burr holes using ste- of the aerodigestive tracts, leading to dysphagia, dysarthria,
reotactic guidance and patient cooperation. Several techniques and involuntary phonation. Onset and severity of the dis-
have been used to facilitate lead placement; all share the goal ease are influenced by the number of inherited trinucleotide
of protecting the airway, providing adequate patient comfort, repeats; because somatic instability can increase the number
and allowing patient cooperation with intraoperative neuro- of repeats each generation, inheritance is subject to anticipa-
logic examination to optimize lead positioning. Monitored tion, the genetic phenomenon in which subsequent genera-
anesthesia care, scalp block, IV sedation, and general anes- tions may experience earlier onset and worsened severity of
thesia using an asleep-awake-asleep technique have all been the disease. Patients with juvenile-onset HD typically experi-
described. Maintenance of airway patency and ventilation are ence a rapidly progressive course. Prevalence of HD in Europe
particularly important, given the difficulties of airway man- and North America has been estimated at 5 to 8 per 100,000
agement once the head frame is in place. In addition to their population.87
potential for disinhibition or confusion in patients with cogni- Although the huntingtin protein is expressed throughout
tive deficits, the effects of GABAergic medications on electro- the body, it appears that only a subset of neurons are affected
physiologic brain monitoring and their tendency to suppress by the abnormal variant.88 The typical pathologic finding in
tremor and rigidity may contraindicate their use. patients with HD is diffuse atrophy of the caudate and puta-
Intraoperative risks include an increased potential for men. Early onset is also associated with atrophy of cerebellar
venous air embolism in the semi-upright position and intra- Purkinje cells.89 At the cellular level, cytoplasmic and intranu-
cerebral hemorrhage (2%-4% of DBS cases).82 Maintenance clear aggregates of the amino-terminus of mutant huntingtin
of systolic BP less than 140 mm Hg has been suggested in an are characteristic; whether these aggregates are causative or
effort to reduce the risk of hemorrhage.82 Stimulator implan- protective remains unclear. Huntingtin is necessary for nor-
tation is usually performed 1 to 4 weeks after lead placement. mal embryonic development, and the presence of trinucleotide
Because neuromonitoring is not required, DBS is usually per- expansion does not seem to affect this process. In the adult, its
formed under general anesthesia and carries risks similar to role is less clear, although huntingtin is known to interact with
permanent pacemaker implantation. multiple proteins and may play a role in protein trafficking,
vesicular transport and anchoring, endocytosis, postsynaptic
Anesthesia for Patients with Implantable Deep-Brain
signaling, or cell survival.90 Conversely, the abnormal variant
Stimulators. Anesthesia for patients with implantable deep-
in HD may disrupt a wide variety of processes and pathways,
brain stimulators has not been well studied. MRI compat-
including protein degradation, axonal transport, and synap-
ibility varies slightly by device, and the manufacturer should
tic transmission, and may lead to excitotoxicity, cellular meta-
be consulted before proceeding with MRI in these patients.
bolic dysfunction, and abnormal apoptosis.90
Electrocautery has the theoretic potential to cause generator
To date, management of patients with HD remains support-
malfunction and inappropriate electrode activation or CNS
ive. Physical and occupational therapy, nutrition, and psychoso-
burns, but a recent review found no evidence of such complica-
cial counseling are important strategies for maximizing quality
tions.83 If possible, bipolar diathermy eliminates this concern.
of life. Chorea may respond to treatment with tetrabenazine,
Scant evidence is available to guide intraoperative device man-
which blocks dopamine transport. However, use of this agent
agement. Turning off the device intraoperatively seems a safe
may worsen bradykinesia, cognition, and mood. Neuroleptic
approach,84 but whether it is necessary is unclear. Postoperative
agents may also be useful in controlling chorea as well as agi-
akinesia may respond to levodopa, but some recommend turn-
tation and psychosis. Depression is common in patients with
ing the generator back “on” before emergence from anesthesia.85
HD and may respond to tricyclic antidepressants (TCSs) or
selective serotonin reuptake inhibitors (SSRIs). Recent stud-
ies have evaluated the possible disease-modifying effects of
Huntington's Disease (Chorea)
vitamin E, creatine, coenzyme Q10, highly unsaturated fatty
Huntington's disease (HD; Huntington's chorea) is an inher- acids (HUFAs), ethyl eicosapentaenoate (fatty acid derivative),
ited progressive neurodegenerative condition whose hall- minocycline (antiapoptotic), and riluzole (inhibitor of striatal
marks include choreoathetoid movements, dementia, and glutamine). None of these agents has demonstrated a robust
psychiatric disturbances. Although the exact mechanism has benefit, but trials are ongoing.91 Gene therapy, vaccination with
the huntingtin protein, DBS, and surgical delivery of fetal tis- The pathogenesis of SC remains incompletely understood.
sue or neurotrophic factors have been proposed, and in some Group A streptococcal infection stimulates the formation of
cases studied in animals or small human trials.92,93 antibodies against the N-acetyl-β-d-glucosamine (NABG
or GlNAc) streptococcal antigen. These antibodies appear
ANESTHETIC CONSIDERATIONS to cross-react with host antigens, leading to valvular injury
Data regarding anesthetic management of HD patients are in rheumatic endocarditis, for example. Some of these anti-
limited. Patients with HD may have difficulty holding still bodies bind to lysoganglioside on the surface of neurons, ini-
during procedures performed with sedation (see Box 8-5). tiating a calcium-mediated cell-signaling cascade.102 Others
Butyrophenones and phenothiazines may alleviate chorei- cross-react with tubulin, suggesting a link to the pathogenesis
form movements, and benzodiazepines may be used to treat of other antibody-mediated motor neuropathies.103,104 At the
acute anxiety. However, caution should be used in patients gross anatomic level, small studies using MRI, positron emis-
with dementia, who are at increased risk for postoperative sion tomography (PET), and single-photon emission com-
delirium. In advanced stages, patients with HD are vulnerable puted tomography (SPECT) suggest that the basal ganglia
to dysphagia, aspiration, and respiratory complications. No and s triatum are subject to reversible changes consistent with
clear contraindications seem to exist to the use of the common hypermetabolism and hyperperfusion.105-107
induction agents, neuromuscular blockers, or inhaled anes- Initial treatment of acute rheumatic fever involves anti-
thetics. One case of delayed recovery from thiopental has been biotic therapy to eliminate carriage of group A streptococci,
reported, but others have used this drug without incident.94 anti-inflammatory therapy (aspirin) for patients with cardi-
Patients with HD may have decreased pseudocholinesterase tis, and heart failure management for those with severe val-
activity, but only a single case of delayed recovery from succi- vular lesions. Evidence suggests that treatment with steroids
nylcholine has been reported.95,96 may hasten resolution of SC.108,109 Numerous agents have been
used in the pharmacologic management of chorea symptoms,
ASSOCIATED PROCEDURES including valproic acid, carbamazepine, haldol, benzodiaz-
Although there are no procedures specifically related to the epines, and pimozide. Intravenous immune globulin (IVIG)
treatment or management of HD, patients with advanced and plasma exchange have also been used. All have shown
disease may require gastric feeding tube placement. These benefit in small studies, but no conclusive evidence supports
patients are also at high risk for falls. Orthopedic procedures, any of these treatments. Antibiotic prophylaxis against recur-
in particular hip and femur fixation, may be required. rent group A streptococcal pharyngitis is indicated for second-
ary prevention of recurrent episodes of rheumatic fever.110,111
Sydenham's Chorea (Rheumatic Chorea)
ANESTHETIC CONSIDERATIONS
Sydenham's chorea (SC) is an acute manifestation of rheu- Preoperative evaluation of the patient with Sydenham's cho-
matic fever, occurring in approximately one third of cases. rea or a history of rheumatic fever should include electrocar-
Chorea is often asymmetric and occasionally unilateral, and diogram (ECG) and evaluation for endocarditis and valvular
it is generally accompanied by muscular weakness and emo- disease (see Box 8-5). As with other movement disorders,
tional lability. Although the incidence of rheumatic fever has procedural sedation may be challenging, and symptomatic
declined to 2 to 14 cases per 100,000 people in Europe and treatment of chorea with neuroleptics, benzodiazepines, or
North America,97 almost 500,000 new cases occur each year, propofol may be helpful. A lack of published experience with
primarily in the nonindustrialized world.98 Children ages 5 to SC patients precludes any list of contraindications other than
13 years are most likely to be affected by SC, and girls are twice those related to cardiac complications of acute rheumatic fever
as likely to develop SC as boys.99 A familial predisposition to and possible interactions involving the drugs used for symp-
both acute rheumatic fever and to SC has been suggested. Onset tom management.
of chorea is typically gradual, occurring 1 to 8 months after
the inciting group A streptococcal infection. Emotional labil-
Dystonias
ity may precede motor symptoms, which often progress from
subtle hand movements to irregular writhing movements of Dystonias are a broad group of movement disorders in which
the arms. Ballistic movements, facial grimacing, tongue fascic- sustained involuntary muscle contractions lead to abnormal
ulations, and diffuse hypotonia are also common. Psychiatric postures or repetitive movements. Classification schemes have
manifestations include irritability, inappropriate laughing or centered on age of onset (early vs. late), anatomic distribution,
crying, and obsessive-compulsive behaviors. Symptoms, both and etiology (primary vs. secondary). Numerous genetic sub-
motor and psychiatric, generally resolve in 3 to 4 months, and types have also been identified. Prevalence estimates for dys-
most patients recover completely. However, persistent symp- tonias as a group have varied widely. The most-often cited
toms have been described more than 2 years after onset,100 and figures for the United States come from a 30-year study of
up to 20% to 30% of SC patients have relapses, particularly Rochester, Minnesota, which found an incidence of 2 cases of
those who do not receive antibiotic prophylaxis against recur- generalized dystonia per 1 million persons per year, and 24
rent streptococcal infection.101 cases of focal dystonia per 1 million per year.112
Etiology. Primary dystonias are generally characterized by examples include Wilson's, Huntington's, and Leigh's dis-
a gradual onset and progression of symptoms, and occur in eases; corticobasal degeneration; and cyanide or manga-
the absence of other neurologic, imaging, or laboratory abnor- nese toxicity.
malities. Early-onset dystonias present in childhood or young
Pathophysiology. Primary dystonias are not associated
adulthood, often beginning in one leg, and become general-
with specific neuropathology and do not appear to involve
ized in a majority of patients. Late-onset dystonias (occurring
neuronal cell degeneration. They have also been difficult to
in adulthood) typically present in the neck, arms, or face, and
localize anatomically. PET and functional MRI studies have
are likely to remain focal or segmental (involving contiguous
suggested abnormal metabolic activity in the motor cortex
body areas).
and supplementary motor areas, the cerebellum, and the basal
Cervical dystonia, also referred to as “spasmodic torticol-
ganglia.118,119 DBS recordings have implicated abnormal func-
lis,” is the most common primary focal dystonia.113 Dystonia
tion of the globus pallidus.120 Functionally, electrophysiologic
may involve rotation, lateral flexion, or anterior flexion of
studies suggest that dystonia involves loss of normal inhibi-
the head and is painful in 50% of patients. Dystonic con-
tory signals, abnormal plasticity of the motor cortex, and sub-
tractions may lead to finer movements of the head that may
tle abnormalities of sensory function.121 The neurochemistry
resemble tremor.114,115 Oromandibular and facial dystonias
of dystonia remains poorly understood. The overlap between
involve the muscles of the jaw, tongue, and larynx and may
dystonia and parkinsonism, as well as the acute dystonic
cause difficulty with speech and swallowing. Spasmodic
reactions that can accompany pharmacologic antagonism of
dysphonia refers to a focal dystonia of the laryngeal mus-
dopamine receptors, suggest the importance of dopaminer-
cles, most often involving the adductor muscles, and there-
gic pathways in the neurochemistry of dystonia. The clinical
fore causing difficulty with vocalization rather than airway
observation that anticholinergic therapy can be effective in
occlusion. Blepharospasm involves the periocular muscles
treating childhood dystonia suggests the importance of cho-
and may impact vision when severe enough to cause pro-
linergic pathways as well.
longed involuntary eye closure. Blepharospasm may also
occur in conjunction with oromandibular and facial dysto- Treatment. Treatment of dystonia is symptomatic.
nias, a constellation referred to as Brueghel's or Meige's syn- Appropriately, dopa-responsive dystonia can be almost com-
drome. Focal or segmental dystonias of the upper extremity pletely abolished with levodopa therapy. This response is gen-
are also common. These are generally unilateral, are often erally sustained, and required doses are often small enough to
absent at rest, and may produce an apparent tremor in addi- prevent motor side-effects. Up to 15% of other dystonias will
tion to abnormal posturing. Repetitive performance of spe- also respond to levodopa therapy.122 Anticholinergic drugs,
cific muscular tasks may produce occupational dystonias, including trihexyphenidyl and tetrabenazine, have also been
such as writer's cramp or the embouchure dystonia that widely used in the treatment of dystonia, but evidence for their
has affected players of woodwind or brass instruments. An efficacy is equivocal.123 Anecdotal evidence also suggests that
interesting feature of many focal dystonias is the presence some patients may benefit from benzodiazepines, baclofen,
of a geste antagoniste, or specific maneuver, such as a light carbamazepine, zolpidem, or dopamine receptor blockers.
touch to the overlying skin, which will relieve the dystonic Injection of affected muscle groups with botulinum toxin
contractions. (BoNT-A and BoNT-B) has proved safe and effective and is
Several hereditary dystonias have been identified, and now considered a first-line therapy for patients with cervi-
genetic predisposition or vulnerability likely plays a role in cal dystonia, blepharospasm, focal upper limb dystonias, and
many cases. Mutation of the TOR1A gene, which encodes tors- spasmodic dysphonia.124,125 Although sustained benefits are
inA, an ATP-binding protein, may account for as many as half possible using botulinum toxin, not all patients will respond,
of all cases of early-onset primary dystonia.116,117 Other heredi- and some will develop resistance to BoNT-A.126 These patients
tary dystonias include dopa-responsive dystonia, an early-onset may respond to the alternate serotype BoNT-B, but some
form often associated with parkinsonian features and notable patients will fail treatment with either type. In patients with
for its responsiveness to levodopa therapy; various forms of medication-resistant segmental or generalized primary dys-
dystonia plus parkinsonism; several types of paroxysmal dystonia, DBS of the globus pallidus has been effective in con-
kinesia; and myoclonus dystonia, an autosomal dominant controlling symptoms for a majority of patients.127 Long-term
dition involving myoclonic upper body jerks with dystonic follow-up data are limited. Although some evidence indicates
features. a benefit in focal dystonia treated with DBS, data for the treat-
Secondary dystonias occur as a result of an alternative ment of secondary dystonia are mixed.128
primary process. In these cases, dystonia is generally asso-
ciated with additional neurologic, laboratory, or imaging ANESTHETIC CONSIDERATIONS
abnormalities. Stroke, medication effects, and muscu- Preoperative evaluation of the patient with dystonia should
loskeletal or CNS trauma are common causes. Atypical focus on the severity of the dystonic movements, known trig-
presentations should also prompt further investigation. gers or sensory tricks to break spasm, and potential interac-
Numerous degenerative, genetic, and metabolic disease tions with levodopa or anticholinergic therapy (see Box 8-5).
processes have been associated with dystonia; notable Although symptoms are often relieved with sedation, cervical
or oropharyngeal dystonias may complicate airway manage- disorders in this group may vary significantly in their presen-
ment, and in severe cases, fiberoptic intubation techniques tation, all tend to have a broad range of symptoms involving
may be indicated for patients with limited mobility of the many sensory, motor, and cognitive functions, which usually
neck or jaw. Spasms are abolished by NMB and also appear progress with time, leading to various degrees of disability.
to be relieved by inhaled nitrous oxide (N2O) concentrations For most of the myelin disorders, no anesthesia experiences
greater than 50%.129 No anesthetic agents are contraindicated, have been reported. Therefore the focus here is on the most
although there are numerous case reports of acute dystonia common conditions in this group for which a sufficient num-
during and immediately after general anesthesia using various ber of reports address various aspects of perioperative care in
techniques including N2O/sevoflurane, N2O/propofol, and these patients. The same anesthetic considerations could be
propofol/fentanyl/vecuronium.130-133 extrapolated when providing anesthesia care for patients with
similar conditions.
DISEASES OF MYELIN
Multiple Sclerosis
The myelin diseases are a large group of neurodegenerative
disorders associated with abnormal myelinization of either Multiple sclerosis (MS) is an acquired inflammatory autoim-
the central or the peripheral nervous system and also referred mune disorder possibly caused by an interplay of genetic and
to as “demyelinating diseases.” This group can be subdivided environmental factors, although its exact etiology is unknown.
into dysmyelinating and demyelinating disorders. The dysmy- MS is characterized by widespread, initially partially revers-
elinating subgroup includes disorders associated with inher- ible, demyelination of axonal sheaths in the CNS and sub-
ited defective production of myelin, often manifesting at birth, sequent development of sclerotic lesions in the brain, which
whereas demyelinating disorders are acquired later in life eventually results in permanent neurodegeneration. MS pres-
and are characterized by a loss of normal myelin (Box 8-6). ents with a wide variety of signs and symptoms involving sen-
Regardless of the exact cause, abnormal myelinization of the sory, motor, autonomic, and cognitive functions (Box 8-7).
nervous system leads to impairment of nerve conduction MS characteristically first manifests in patients in their 20s to
and eventual loss of function in the affected nerves across the 40s, with a twofold to threefold higher prevalence in women.
whole spectrum of the nervous system. Although different
BOX 8-7 n MULTIPLE SCLEROSIS: CLINICAL SIGNS/

BOX 8-6 n DISEASES OF MYELIN SYMPTOMS*
Central Nervous System Sensory Symptoms
Multiple sclerosis Numbness, “pins and needles,” tingling in limbs
Leukodystrophies Swelling, tightness, coldness of limbs
Central pontine myelinosis Proprioceptive deficits
Subacute combined degeneration Facial sensory symptoms
Tabes dorsalis
Ophthalmic Symptoms
Multifocal leukoencephalitis
Visual loss related to optic neuritis
Devic's disease
Diplopia
Acute disseminated encephalomyelitis
Internuclear ophthalmoplegia
Peripheral Nervous System
Motor Symptoms
Hereditary primary motor sensory neuropathies
Subacute paraparesis or paraplegia, more in lower extremities
Acute (Guillain-Barré syndrome) or chronic inflammatory
Spasticity and possible contractures
demyelinating polyneuropathy
Coordination
Demyelinating (Acquired)
Vertigo
Multiple sclerosis
Gait imbalance
Central pontine myelinosis
Limb ataxia
Subacute combined degeneration (vitamin B12 deficiency)
Tabes dorsalis Autonomic Nervous System Dysfunction
Acute disseminated encephalomyelitis Bladder, bowel, and sexual dysfunction
Progressive multifocal leukoencephalopathy Possible orthostatic hypotension
Mercury intoxication
Other Symptoms/Signs
Dysmyelinating (Congenital/Hereditary) Temperature and exercise insensitivity (Uhthoff phenomenon or
Hereditary primary motor sensory neuropathies heating reaction)
Leukodystrophies Pain
Krabbe's disease Fatigue
Alexander's disease Depression
Pelizaeus-Merzbacher disease Seizures
Canavan's disease
Others *From most common to less common.
Many of these patients develop severe disability over time, and phases, but many patients fail to respond to corticosteroids
many die from complications related to MS. The etiology, epi- as their number of exacerbations increases. Patients with
demiology, pathophysiology, clinical presentation, and treat- optic neuritis respond to oral and IV adrenocorticotropic
ment of MS have been recently reviewed.134 hormone (ACTH) and prednisone in the acute phases and
None of the signs or symptoms listed in Box 8-7 is diag- experience fewer relapses. Other immunosuppressive agents,
nostic of or unique to MS, which can present with neuro- such as cyclophosphamide, cytarabine, and azathioprine,
logic symptoma found in other nervous system disorders. The have shown intermittent success at preventing the number
combination of these symptoms and the clinical course of MS and severity of relapses, but do carry side effects. Patients
progression eventually leads to the diagnosis. The following with severe motor spasticity and bladder dysfunction are
subtypes of the disease progression have been identified: treated with antispastic medications, which provide some
relief. Alternative therapies not clinically proven but tried in
n The relapsing-remitting subtype is characterized by acute
severely resistant cases include plasmapheresis, hyperbaric
onset of new symptoms (relapses, or exacerbations) fol-
oxygen therapy, linoleate supplementation, and interferons.
lowed by long periods of remission, during which most
The most recent, controversial development is related to the
symptoms tend to abate or completely reverse. Timing of
“vascular hypothesis,” suggesting that MS could be caused
relapses is unpredictable, and often no precipitating factor
by the chronic cerebrospinal venous insufficiency frequently
can be identified. Up to 80% of patients have this pattern as
found in these patients.138 Cerebral venous balloon angio-
initial presentation of MS.
plasty result in significant improvement in the course of
n Secondary progressive MS is characterized by progression of
MS in preliminary reports. The results of these series are
the clinical picture without periods of obvious remission.
inconclusive until proper blinded randomized studies can be
Many patients with relapsing-remitting disease eventually
conducted. However, if this treatment were to gain a wider
convert to secondary progressive MS.
acceptance, administering anesthesia for this procedure may
n The primary progressive subtype is found in patients
significantly increase exposure to patients with MS among
whose clinical symptomatology continues to accumulate
anesthesiologists.
without significant improvements in symptoms after ini-
tial onset of MS.
n The progressive-relapsing subtype is the rarest form and is ANESTHETIC CONSIDERATIONS
characterized by steady, progressive development of dis- Case reports and observational studies are limited regarding
ability with superimposed acute episodes of new neurologic anesthesia effects and perioperative management in patients
symptoms. with multiple sclerosis.135,139-150 Some of the earlier reports
implicated a possible connection between the use of general
The MS progression patterns may have a significant effect
or neuroaxial anesthesia and relapse of MS or worsening of
on the decision making in the perioperative management
existing symptoms.141,143 Despite these reports providing scant
of these patients. Although relapses in patients with near-
conclusive evidence to support this claim, it has been diffi-
complete remission or sudden worsening of existing symp-
cult to disprove this connection because of the unpredictable
toms can be precipitated by perioperative events, they are not
nature of relapses and the potential for the temporary wors-
necessarily synonymous with poor prognosis, but have a pow-
ening of existing neurologic deficits, even in the absence of
erful emotional effect on MS patients and may dramatically,
a new demyelinating event. This worsening can be caused by
even if only temporarily, affect their quality of life.
relatively benign perioperative derangements of homeostasis,
Factors clinically established as exacerbating MS include
such as hyperthermia or hyponatremia, or administration of
stressful events such as emotional and physical trauma, infec-
anesthetic agents. This usually brief deterioration is most likely
tions, surgery, and the peripartum period.135 Hormonal and
caused by an enhanced effect of these conditions on already-
temperature fluctuations appear to be clinically correlated
impaired but clinically silent conduction delay in previously
with exacerbations as well. Even small elevations in body core
demyelinated nerves. Current opinion in anesthesia literature
temperature above normal, as occur in the perioperative set-
does not support the idea that administration of anesthesia
ting, can block nerve conduction in previously demyelinated
can be linked to a new demyelinating event in patients with
nerve fibers and produce new neurologic deficits or worsen
MS. In the absence of large, controlled prospective studies, it
others.136 Previously, Edmund and Fog137 documented clini-
is impossible to resolve this issue. Given this lack of conclusive
cal deterioration with temperature elevations in 75% of MS
evidence, designing an anesthetic plan for patients with MS,
patients. However, it is important to emphasize that no evi-
even currently asymptomatic, poses a number of unique chal-
dence indicates that exposure to these precipitating factors
lenges (Box 8-8).
affects the overall prognosis of the disease in these patients.
Patients with MS presenting for surgery and anesthesia
Treatment. Current therapies for MS are not curative but may typically fit a number of distinct clinical scenarios, which
attempt to ameliorate acute or chronic symptoms and dis- require different approaches to perioperative management.
ability and reduce the number of future exacerbations. Most In patients with the relapsing-remitting pattern in a remis-
MS relapses respond to glucocorticoid therapy in the early sion presenting for elective or emergency surgery, the main
BOX 8-8 n MULTIPLE SCLEROSIS (MS): ANESTHETIC centrally, because the blood-brain barrier may be more perme-
ISSUES able as a result of chronic inflammatory changes. Therefore,
many believe that lower concentrations of local anesthetics
Patients with MS have an unpredictable pattern of relapse that may
coincide with postoperative recovery.
should be used and combined with narcotics, because there
Informed consent regarding the effect of anesthetic agents on have been no reports of significant adverse events with epidural
the course of the disease is difficult to provide due to lack of or intrathecal opioids. In a few anecdotal reports, regional or
conclusive evidence in the literature. neuroaxial anesthesia precipitated MS episodes in previously
Thorough preoperative interview and maximal patient participation undiagnosed patients, and temporary worsening of symptoms
regarding choice of anesthetic technique is advisable, combined
with detailed documentation of these discussions.
followed neuroaxial block for labor.
Neuroaxial and regional anesthesia are not contraindicated in MS The prevailing view is that administration of spinal anes-
patients, but lower concentrations of local anesthetic and careful thetic exposes the spinal cord to higher, potentially toxic con-
titrations are advisable. centrations compared with epidural anesthesia.139 Despite
Epidural anesthesia may be preferable to spinal anesthesia. these concerns and the limited evidence available, the exist-
Patients with MS are at increased risk of intraoperative autonomic
dysfunction.
ing literature largely supports the view that use of regional
Patients with advanced disease are at increased risk of perioperative anesthesia does not lead to true relapses of MS and should be
respiratory depression and sleep apnea. strongly considered in willing patients. This topic has been
Avoid monitoring neuromuscular blockade at the affected muscles to recently reviewed.149
avoid overdose. The paucity of conclusive evidence regarding the effects of
Use of depolarizing muscle relaxants should be avoided when
possible in MS patients.
local and regional anesthesia on the course of MS, combined
with a higher probability of postpartum relapse requires very
thorough prenatal discussion of anesthetic choice, including
careful documentation of these discussions. A recent survey of
concern is a possible postoperative relapse, either precipitated practicing anesthesiologists in the United Kingdom indicates a
by perioperative events or merely coincidental. It is of particu- majority would perform epidural or spinal anesthesia in preg-
lar importance to inform these often asymptomatic but fearful nant MS patients, provided special consideration were given
patients regarding the lack of conclusive evidence connecting to the relevant issues.154
the use of anesthetic agents and MS exacerbation episodes. In a patient with the relapsing-remitting pattern scheduled
Thorough preoperative interview, detailed anesthesia con- for an elective procedure who is found to have new neurologic
sent, and maximal engagement in the decision-making pro- deficits, it is prudent to delay surgery for neurologic consul-
cess regarding the choice of anesthetic technique and agents tation and therapeutic intervention. In patients with progres-
are crucial in this group of patients. Asymptomatic pregnant sive patterns of MS, anesthetic considerations are generally
patients with a history of MS pose a special challenge regarding governed by the disease progression and severity, associated
the use of epidural or spinal anesthesia for labor or cesarean degree of disability, and comorbidities. Patients with advanced
section. Because MS mainly affects women in their child- disease should be evaluated for signs of autonomic dysfunc-
bearing years, many of these women will likely need anesthe- tion, which would warrant the use of invasive monitoring to
sia for cesarean birth or ask for analgesia for labor. A further guide hemodynamic support intraoperatively. Compensatory
complication is that late pregnancy is associated with relief mechanisms in response to intraoperative events, anesthetic
of MS symptoms and reduced number of relapses. However, agents, and vasopressors may be altered in these patients.
the possibility of postpartum relapse increases compared with Patients with cranial nerve involvement and history of upper
nonpregnant patients, although pregnancy does not seem to airway obstruction and compromised respiratory function
adversely affect the overall prognosis of the disease. should be considered for postoperative ventilatory support in
Use of neuraxial blockade in patients with MS is controver- the ICU. Intraoperative positioning of patients with spasticity
sial because of the potential for direct neurotoxicity exerted and contractures can be challenging and may require advance
by local anesthetics, especially on demyelinated nerves. Local planning. Increases in body temperature are known to lead to
and regional anesthesia remains a controversial topic in MS dramatic increases in symptoms and may precipitate an onset
patients because of the potential pharmacodynamic effects of new symptoms. As a result, hyperthermia must be carefully
on nerve conduction. With the pathology of demyelination in avoided. Even mild fevers should be actively pre-empted and
MS, one might expect that the potential for neurotoxicity with aggressively treated when detected.
local anesthetics administered in the epidural or intrathecal Anesthetic induction agents and inhaled gases have no
space would be higher. However, several retrospective studies demonstrable adverse effects on nerve conduction and
have not demonstrated a significant increase in MS exacerba- have not been implicated in the literature as contributing
tions with either epidural or spinal local anesthetic administra- to MS progression. Drugs often administered under anes-
tion.139,143,151-153 Although unproved, many clinicians believe that thesia, including anticholinergics, atropine, and glycopyr-
repeated doses of local anesthetics for regional anesthesia carry rolate, may also lead to increases in body temperature and
a potentially increased risk for neurotoxicity, both locally and should be used with caution. The use of depolarizing muscle
relaxants also carries theoretic risks in MS patients, more PERIPHERAL NERVE DISEASE AND THE
specifically those with profound neurologic deficits that POLYNEUROPATHIES
often cause upregulation of motor-end-plate acetylcholine
receptors and the hyperkalemic response to depolarization. Peripheral nerve disease covers a wide variety of causation
We have not found any studies that implicate nondepolariz- and clinical entities (Box 8-9). The peripheral nervous sys-
ing muscle relaxants in neurologic sequelae perioperatively; tem (PNS), which encompasses all neural structures out-
thus their use appears to be safe. Drugs used to treat MS and side the spinal cord and brainstem, includes a broad variety
associated disorders need to be taken into consideration, of cell types, nerve fibers, anatomic variability, and function.
especially corticosteroids and antiepileptic medications. Likewise, the pathologic conditions capable of affecting the
PNS at multiple points also vary greatly. Signs and symptoms
of polyneuropathies can therefore include impaired motor
Nitrous Oxide–Induced Subacute Combined function, spasm and fasciculations, reflex changes, sensory
Degeneration loss, pain and paresthesias, dysesthesias, ataxia, tremor, tro-
Subacute combined degeneration (SCD) is a neurodegener- phic changes, and autonomic dysfunction. These can all have
ative demyelinating disorder of the spinal cord observed in acute or chronic onset and duration.
patients with vitamin B12 deficiency usually suffering from Guillain-Barré syndrome (GBS) is an example of a poly-
pernicious anemia, various conditions leading to malnu- neuropathy with motor, sensory, and autonomic components.
trition, tropical sprue, or HIV infection. A wide range of It is also an example of demyelinating PNS disease discussed
neurologic symptoms consistent with myelopathy, such as in the preceding section. The anesthetic considerations of the
progressive weakness, sensory ataxia, paresthesias, spastic- polyneuropathies in general are discussed here using GBS as
ity, paraplegia, incontinence, dementia, and visual loss result an illustrative example. However, diagnosis of a specific etiol-
from progressive degeneration of the dorsal and lateral white ogy for a mixed polyneuropathy can be challenging. In large
matter of the spinal cord and in the brain. Neurologic symp- studies, a sizable number of patients remain without a specific
toms may occur in patients without megaloblastic anemia. diagnosis of causative agent. Polyneuropathies encountered by
This condition is of particular interest to an anesthesiologist anesthesia providers include those caused by ischemia, diabe-
because of the unique role that N2O can play in the develop- tes, drugs, rheumatoid arthritis, lupus, sarcoid, Sjögren's dis-
ment of this condition. By oxidizing the cobalt in the cobola- ease, paraneoplasm, acquired metabolic syndrome, uremia,
min, N2O inactivates vitamin B12 and consequently reduces and alcohol. Of particular interest are the polyneuropathy
methionine synthase activity. Inadequate production of of critical illness162,163 and acute quadriplegia and myopathy
methionine leads to failure of myelin maintenance in spinal attributed to prolonged NMB and corticosteroid use.164 The
cord and axonal degeneration.155 inherited polyneuropathies are covered later in this chapter.
Subacute combined degeneration has been reported in pre- Individual neuropathies caused by trauma, radiation, reflex
viously healthy recreational N2O abusers with normal blood sympathetic dystrophy (RSD), or inflammation of individual
levels of B12.156 However, even single use of N2O for anesthesia peripheral nerves are not covered here.
in asymptomatic patients with subclinical deficiency of vita-
min B12 may lead to delayed SCD development.157-160 Repetitive
Guillain-Barré Syndrome
and prolonged exposure to N2O in patients with B12 deficiency
increases the probability of SCD development. Additionally, Guillain-Barré syndrome, also known as acute idiopathic
SCD tends to develop days or even weeks after uncomplicated polyneuritis or acute inflammatory polyneuropathy, is a cell-
anesthesia with N2O, rendering it difficult to make a con- mediated immunologic response against peripheral nerves
nection between the use of N2O and the progressive neuro- with a number of variant forms (Table 8-4).165-169 GBS is found
logic deterioration.161 Classic signs of developing myelopathy, worldwide, in both genders and all ages, with an incidence
often in combination with personality changes and intellectual of about 1.5 per 100,000 population. Pathologic examina-
impairments, after recent surgery in patients with pre-existing tion demonstrates perivascular lymphocytic and inflamma-
disorders predisposing to vitamin B12 deficiency should assist tory cell infiltration, segmental demyelination, and wallerian
in arriving at correct diagnosis. degeneration along entire peripheral nerves and scattered
Prompt treatment with vitamin B12 and methionine supple- throughout the PNS. Damage is primarily axonal and thought
mentation usually lead to rapid stabilization and often gradual to result from an immune-mediated response to myelin pro-
improvement and although not necessarily complete, reversal teins.170 In 60% to 70% of patients, GBS is preceded by a mild
of symptoms. In patients with known vitamin B12 deficiency GI or respiratory influenza-like illness by 1 to 3 weeks, with
or predisposing conditions such as malnutrition, gastritis, or Campylobacter jejuni, Epstein-Barr virus (EBV), or cytomega-
gastrectomy, N2O should not be used for anesthesia. With the lovirus (CMV) most frequently identified.171 Other preceding
availability of newer inhalational and intravenous agents char- events statistically associated with GBS include surgery, other
acterized by low context-sensitive decrement times, N2O can viral illness, vaccination, and lymphomatous disease. GBS is
be easily replaced without sacrificing the speed of emergence characterized by paresthesias, numbness, and progression to
from general anesthesia. mainly symmetric weakness. Distal extremities are affected
BOX 8-9 n PRINCIPAL NEUROPATHIC SYNDROMES
I. Syndrome of acute motor paralysis with variable disturbance of 7. Connective tissue diseases
sensory and autonomic function 8. Amyloidosis
A. Guillain-Barré syndrome (GBS; acute inflammatory polyneuro 9. Leprosy
pathy; acute autoimmune neuropathy) 10. Hypothyroidism
B. Acute axonal form of GBS 11. Benign sensory form in elderly patients
C. Acute sensory neuro(no)pathy syndrome B. Syndrome of more chronic polyneuropathy, genetically deter-
D. Diphtheritic polyneuropathy mined forms
E. Porphyric polyneuropathy 1. Inherited polyneuropathies of predominantly sensory type
F. Certain toxic polyneuropathies (thallium, triorthocresyl phosphate) a. Dominant mutilating sensory neuropathy in adults
G. Rarely, paraneoplastic b. Recessive mutilating sensory neuropathy of childhood
H. Acute pandysautonomic neuropathy c. Congenital insensitivity to pain
I. Tick paralysis d. Other inherited sensory neuropathies, including those
J. Critical illness polyneuropathy associated with spinocerebellar degenerations, Riley-Day
II. Syndrome of subacute sensorimotor paralysis syndrome, and universal anesthesia syndrome
A. Symmetric polyneuropathies C. Inherited polyneuropathies of mixed sensorimotor types
1. Deficiency states: alcoholism (beriberi), pellagra, vitamin B12 1. Idiopathic group
deficiency, chronic gastrointestinal disease a. Peroneal muscular atrophy (Charcot-Marie-Tooth; heredi-
2. Poisoning with heavy metals and solvents: arsenic, lead, mer- tary motor and sensory neuropathy [HMSN], types I and II)
cury, thallium, methyl n-butyl ketone, n-hexane, methyl bromide, b. Hypertrophic polyneuropathy of Dejerine-Sottas, adult and
ethylene oxide, organophosphates (e.g., TOCP), acrylamide childhood forms
3. Drug toxicity: isoniazid, ethionamide, hydralazine, nitrofuran- c. Roussy-Levy polyneuropathy
toin and related nitrofurazones, disulfiram, carbon disulfide, d. Polyneuropathy with optic atrophy, spastic paraplegia,
vincristine, cisplatin, paclitaxel, chloramphenicol, phenytoin, spinocerebellar degeneration, mental retardation, and
pyridoxine, amitriptyline, dapsone, stilbamidine, trichloethyl- dementia
ene, thalidomide, clioquinol, amiodarone, adulterated agents e. Hereditary liability to pressure palsy
such as l-tryptophan 2. Inherited polyneuropathies with a recognized metabolic
4. Uremic polyneuropathy disorder
5. Subacute inflammatory polyneuropathy a. Refsum's disease
B. Asymmetric neuropathies (mononeuropathy multiplex) b. Metachromatic leukodystrophy
1. Diabetes c. Globoid-body leukodystrophy (Krabbe's disease)
2. Polyarteritis nodosa and other inflammatory angiopathic d. Adrenoleukodystrophy
neuropathies (Churg-Strauss, hypereosinophilic, rheumatoid, e. Amyloid polyneuropathy
lupus, Wegener's granulomatosis, isolated peripheral nervous f. Porphyric polyneuropathy
system vasculitis) g. Anderson-Fabry disease
3. Mixed cryoglobulinemia h. Abetalipoproteinemia and Tangier disease
4. Sjögren-sicca syndrome IV. Neuropathy associated with mitochondrial disease
5. Sarcoidosis V. Syndrome of recurrent or relapsing polyneuropathy
6. Ischemic neuropathy with peripheral vascular disease A. Guillain-Barré syndrome
7. Lyme disease B. Porphyria
C. Unusual sensory neuropathies C. Chronic inflammatory demyelinating polyneuropathy
1. Wartenberg's migrant sensory neuropathy D. Certain forms of mononeuritis multiplex
2. Sensory perineuritis E. Beriberi or intoxications
D. Meningeal-based nerve root disease (polyradiculopathy) F. Refsum's disease, Tangier disease
1. Neoplastic infiltration VI. Syndrome of mononeuropathy or plexopathy
2. Granulomatous and infectious infiltration (e.g., Lyme, sarcoid) A. Brachial plexus neuropathies
3. Spinal diseases (e.g., osteoarthritic spondylitis) B. Brachial mononeuropathies
4. Idiopathic polyradiculopathy C. Causalgia
III. Syndrome of chronic sensorimotor polyneuropathy D. Lumbosacral plexopathies
A. Less chronic, acquired forms E. Crural mononeuropathies
1. Paraneoplastic: carcinoma, lymphoma, myeloma, and other F. Migrant sensory neuropathy
malignancies G. Entrapment neuropathies
2. Chronic inflammatory demyelinating polyneuropathy (CIDP)
3. Paraproteinemias
4. Uremia (occasionally subacute)
5. Beriberi (usually subacute) Data from Adams RD, Victor M, Ropper AH, editors: Principles of neurology,
6. Diabetes New York, 1997, McGraw-Hill.
first, followed by proximal upper extremities and cranial mus- paresthesias and autonomic dysfunction (hypotension and
cles in 50% of patients. Pain and paresthesias may accompany hypertension, sinus tachycardia or bradycardia, diaphoresis
variable sensory loss and areflexia. or anhidrosis, and orthostatic hypotension). Hyponatremia,
Signs and symptoms can be limited to lower extremities the syndrome of inappropriate secretion of antidiuretic hor-
or can involve progression to total muscular paralysis with mone (SIADH), and diabetes insipidus can also occur. Nerve
TABLE 8-4 n Guillain-Barré Syndrome and Its Variant Forms
Incidence/Occurrence Motor or Sensory Characteristic Signs Suspected Etiology
ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Most common in developed Both motor and sensory 85%-90% of cases; peripheral Cell-mediated immune, and
countries of Europe and North nerve demyelination humoral; attacks myelin
America and Schwann cells
ACUTE MOTOR AXONAL NEUROPATHY

Mainly northern China Motor only; axonal damage Seasonal; higher incidence of Immune, motor axons;
respiratory failure higher association with
Campylobacter jejuni
ACUTE MOTOR-SENSORY NEUROPATHY

Prolonged course Resembles pure variant Axonal damage of both motor —
but with some sensory and sensory
MILLER-FISHER VARIANT
— No significant weakness, Ataxia, ophthalmoplegia, Often C. jejuni as well;
but can involve cranial areflexia antibodies to cranial nerve
nerves myelin
conduction studies show reduced amplitude of motor evoked reduced likelihood and duration of mechanical ventilation,
potentials, slowed conduction, prolonged latency, and pro- and improved recovery.173,174 Multiple studies also support the
longed F waves. Diagnosis is made with an increased find- use of IVIG, which seems as effective as plasma exchange.174-177
ing of protein in the cerebrospinal fluid (CSF) with a normal Interestingly, no data support the use of these two therapies
cell count. The differential diagnosis includes the muscu- in combination or in conjunction with steroids, and choice of
lar dystrophies, acute spinal cord injury, chronic inflam- treatment is often guided by locally available experience and
matory demyelinating polyneuropathy, transverse myelitis resources.
or myelopathy, renal failure, polyneuropathy of critical ill- A majority of patients will experience progression of
ness, prolonged corticosteroid use, chronic NMB, and acute GBS for up to 2 weeks and begin remission at 4 weeks. Most
hyperphosphatemia. patients experience a complete recovery. Up to 15% have per-
Supportive care is an important component of the manage- sistent, mild neurologic deficits, and 5% to 10% have a pro-
ment of GBS. Up to one third of patients will require some tracted course with significant permanent neurologic deficits.
period of mechanical ventilation because of neuromuscular Mortality, generally from prolonged mechanical ventilation,
respiratory insufficiency. Paroxysmal hypertension and ortho- fatal arrhythmia, pulmonary embolism or other sequelae of
static hypotension are both common in patients with GBS. critical illness, is estimated at 5%.178 Up to 10% of patients
Although these patients are at increased risk for arrhythmia, will experience relapses, generally responsive to resumption
sustained sinus tachycardia is common and generally does not of immunotherapy, and 2% progress to a diagnosis of chronic
require treatment. Patients with significant autonomic dys- inflammatory demyelinating polyneuropathy (CIDP).179
function may also require ICU management. Patients who Factors associated with prolonged course and limited recov-
become bedbound also require aggressive skin care, deep vein ery include old age, rapid onset of disability, severity of
thrombosis prophylaxis, pharmacologic maintenance of a symptoms, need for mechanical ventilation, and prodromal
bowel regimen, and physical therapy, as well as acute psycho- diarrheal illness.180,181
social support if needed. Acute and subacute neuropathic pain
is common and may require opioid analgesia as well as with ANESTHETIC CONSIDERATIONS
nonopioid adjuncts, such as gabapentin or pregabalin, carba- Anesthetic management in patients with Guillain-Barré syn-
mazepine, and TCAs. drome is similar to that for motor neuron degeneration and
Current evidence does not support the use of corticoste- other demyelinating conditions (Box 8-10). Succinylcholine
roids or interferon-beta in the management of GBS.172 On should be avoided because of the potential for potassium
the other hand, large multicenter RCTs have demonstrated release, and clinicians should be especially aware of the poten-
the superiority of plasmapheresis over supportive care alone. tial for increased sensitivity to nondepolarizing NMB. An
The proposed mechanism of action is removal of circulating arterial line may be useful for patients with autonomic dys-
antibodies, complement, and other immunoactive factors. function, and postoperative ventilation may be necessary
Patients treated with plasmapheresis in the first 30 days after because of reduced respiratory function. Regional anesthe-
onset (and ideally within 7 days) had earlier return of strength, sia is controversial; a limited number of case reports claim an
BOX 8-10 n GUILLAIN-BARRÉ SYNDROME (GBS): BOX 8-11 n DEGENERATIVE MOTOR NEURON DISEASES

ANESTHETIC ISSUES
Amyotrophic lateral sclerosis (ALS)
Up to one third of GBS patients will require mechanical ventilation; Progressive muscular atrophy
almost all will have severely diminished respiratory reserve. Primary lateral sclerosis
Autonomic instability, including episodic severe hypertension and Progressive bulbar (pseudobulbar) palsy
orthostatic hypotension, are common and may warrant invasive Inherited motor neuron diseases
monitoring. Autosomal recessive spinal muscle atrophy
Early plasmapheresis or intravenous immune globulin (IVIG) therapy l Type I: Werdnig-Hoffmann, acute
can improve outcomes in GBS patients. l Type II: Werdnig-Hoffmann, chronic
Patients with severe disease are vulnerable to complications l Type III: Kugelberg-Welander
of critical illness, including decubitus ulcers, venous ▪l Type IV: Adult onset
thromboembolism, and ventilator-associated pneumonia. Familial ALS
Familial ALS with dementia or Parkinson's disease (Guam)
Other
l Arthrogryposis multiplex congenita
l Progressive juvenile bulbar palsy (Fazio-Londe)
▪l Neuroaxonal dystrophy
association with onset or exacerbation of GBS,182,183 although
Associated with other degenerative disorders
uneventful use in obstetric patients has also been reported.184,185 Olivopontocerebellar atrophies
Autonomic instability may also complicate regional anes- Peroneal muscle atrophy
thesia; one case report describes a cardiac arrest in a patient Friedreich's ataxia
with autonomic instability from GBS after low subarachnoid Guillain-Barré syndrome
block.186 At least three reports of GBS onset in the immediate Balo's disease
Acute disseminated encephalomyelitis following measles,
postoperative period suggest that anesthesia or surgery may chickenpox, smallpox, mumps, rubella, or influenza
be a trigger, but supportive evidence is lacking.187-189 Although Acute and subacute necrotizing hemorrhagic encephalitis
extensive data on the use of general anesthesia for GBS patients Acute encephalopathic form (Hurst's disease)
are not available, several case reports describe successful use Subacute necrotic myelopathy
Acute brain purpura
of general anesthesia with and without NMB for emergency
exploratory laparotomy, video-assisted thoracoscopy, gastros-
tomy, abdominal aortic aneurysm repair, and coronary artery
bypass grafting.190-194 and symptoms. Characteristic UMN findings include lack of
coordination, hyperreflexia, and spasticity. Degeneration of
LMNs produces weakness, muscle atrophy, and fasciculations.
MOTOR NEURON DISEASES Asymmetric limb weakness is the most common present-
Motor neuron diseases are characterized by variable, progres- ing symptom in patients who are ultimately diagnosed with
sive, degenerative loss of motor neurons in the frontal cortex, ALS, but a minority of patients will present with bulbar symp-
the ventral horn of the spinal cord, and the lower cranial nerve toms (dysphagia or dysarthria), axial or truncal weakness, or
nuclei. Clinically, this degeneration manifests as muscle weak- respiratory insufficiency. Diagnosis is based on the presence
ness, atrophy, and corticospinal tract signs, often without sig- of UMN and LMN signs in multiple segments, supported by
nificant cognitive or sensory impairment. Pathologic changes electrophysiologic testing and not ruled out by neuroimag-
include loss of anterior horn cells in the spinal cord and lower ing or laboratory studies suggesting an alternative diagno-
brainstem, in which loss of large fibers precedes that of small sis.196,197 Although disease progression is generally relentless
fibers. Astrocytes and lipofuscin replace the absent neurons. and median survival after diagnosis is only 3 to 5 years, sig-
In addition to depletion of large motor nerve fibers, there is nificant individual variation is present in terms of distribution
loss of muscarinic, cholinergic, glycinergic, and GABA recep- and spread of symptoms. The most common cause of death in
tors, up to and including the motor cortex. Mutations involv- ALS is neuromuscular respiratory failure, often complicated
ing superoxide dismutase have been identified in some types by progressive dysphagia. Survival may be prolonged in those
of motor neuron degeneration, suggesting that free-radical patients who elect to undergo tracheostomy and gastrostomy
activity may contribute to disease progression.195 Box 8-11 cat- to facilitate long-term mechanical ventilation and total enteral
egorizes several of the most common forms of motor neuron nutrition.
disease; amyotrophic lateral sclerosis, Friedreich's ataxia, and Several related forms of motor neuron disease, which were
spinal muscular atrophy are discussed in more detail. previously understood as separate disease entities, are increas-
ingly thought to belong to a spectrum of motor neuron degen-
eration that includes ALS. Progressive muscular atrophy is a
Amyotrophic Lateral Sclerosis
condition in which LMN signs predominate. Primary lateral
Amyotrophic lateral sclerosis (ALS) is a progressive neu- sclerosis involves primarily UMN signs. Although many of
rodegenerative disease involving a combination of upper these patients will ultimately develop some LMN involvement
motor neuron (UMN) and lower motor neuron (LMN) signs as well, this variant and a related form of UMN-dominant ALS
appear to have a more benign course. Progressive bulbar palsy a process that may be evident on MRI as bilateral white-mat-
refers to UMN and LMN degeneration of the cranial nerves, ter abnormalities. The spinal cord and ventral roots atro-
which often generalizes to other anatomic segments and is phy and become sclerotic. Affected muscles demonstrate
then referred to as “bulbar-onset ALS.” Flail arm and flail leg denervation atrophy and fiber-type grouping characteris-
syndromes are ALS variants involving asymmetric progressive tic of re-enervation. At the cellular level, neurofilament and
LMN degeneration of the proximal arm or distal leg and are ubiquitin-positive inclusions are common, as are eosinophilic
also notable for a more gradual progression to other segments aggregates called bunina bodies, which contain cystatin C, a
and respiratory muscle weakness.198 protease inhibitor, and appear unique to ALS.
Pathophysiology and Incidence. Although ALS has clas- Symptom Management and Palliation. Until recently,
sically been understood as a disease confined to the motor treatment of ALS has been entirely supportive and focused
neurons, recognition of a subset of patients with ALS who on symptom management. As the disease progresses, many
also develop frontotemporal dementia, autonomic insuffi- patients will require respiratory support, initially noninva-
ciency, parkinsonism, supranuclear gaze palsies, and sensory sive but often leading to an eventual tracheotomy for full-
loss has led to the term ALS-plus. It has become increasingly time mechanical ventilation. Recent efforts to improve
clear that many patients with ALS will also have either clini- respiratory function using an implantable diaphragmatic
cal or subclinical manifestations of cognitive and executive pacemaker have shown some promise in preliminary trials
dysfunction, autonomic dysregulation (decreased bowel in ALS patients.210 With progressive dysphagia, gastrostomy
motility, hyperhidrosis, sympathetic hyperactivity), extrapy- for total enteral nutrition may also be elected. Dysarthria is
ramidal signs, and paresthesias or mild sensory loss. Autopsy common in later stages of the disease, and nonverbal forms
results suggest that the histopathologic hallmarks of ALS are of communication become increasingly important. Many
often identifiable to a lesser extent in sensory and autonomic patients will also develop dyspnea and may benefit from
pathways.199-201 chest physiotherapy, truncal support, supplemental oxygen,
Incidence of ALS in Europe and North America has been benzodiazepine therapy, and inhaled or IV opiates. Muscle
estimated at 1.5 to 2.7 per 100,000 people per year.195,202 Men spasm may be a significant source of pain and disability for
are more likely to be affected than women before age 70, at ALS patients.
which time the male/female ratio begins to equalize. Age is Quinine was previously considered the therapy of choice,
the only established risk factor for the development of ALS, but concerns over its safety profile have virtually eliminated
and incidence rises with each decade, peaking at age 74.195 its use for ALS. In its place, carbamazepine and phenytoin
Epidemiologic studies demonstrate a gradual increase over have been suggested, and baclofen, neurontin, and tizani-
time in both the incidence and the mortality of ALS, which dine have been used to treat spasticity, although there is lit-
may represent patterns of environmental exposure, or alter- tle evidence to support the use of any of these therapies.211
natively, may be a function of increased life expectancy.203–205 Sialorrhea, generally pseudohypersalivation from neuromus-
Approximately 10% of cases are thought to be familial; the cular weakness, is also common and may be treated with
rest are sporadic. Cigarette smoking, heavy-metal expo- atropine, hyoscyamine, amitriptyline, or botulinum toxin
sure, military service, agricultural labor, and other occu- injection of the salivary glands. Conversely, patients may
pational exposures have all been suggested as risk factors, also develop thickened or retained secretions, necessitating
but none of these factors has been clearly established. Three humidification, increased hydration, and chest physiother-
high-prevalence geographic clusters have been identified in apy. Finally, many patients with advanced disease will have
Guam, West New Guinea, and the Kii Peninsula of Japan, outbreaks of inappropriate crying or laughter, referred to as
but it remains unclear whether environmental exposure or the “pseudobulbar affect.” Despite limited data, amitriptyline
genetic vulnerability is responsible. Several gene mutations and fluvoxamine have been used for the treatment of pseu-
identified in familial cases of ALS, including SOD1 (super- dobulbar affect. Although the mechanism is unclear, there is
oxide dismutase), ANG, TDP-43, and FUS, have also been better evidence for the use of a combination of dextrometh
found in some patients with sporadic ALS, suggesting that orphan (a mild NMDA antagonist) and quinine, a cyto-
these may represent important susceptibility factors.206–209 chrome P450 inhibitor that may prolong the effective plasma
The precise etiology of ALS also remains obscure. Free- levels of dextromethorphan.212
radical damage, excitotoxicity, cytoskeletal abnormalities,
viral infections, mitochondrial dysfunction, and abnormal Pharmacologic Therapy. Countless pharmacologic agents
programmed cell death or RNA processing have all been have been evaluated for their potential to delay or reverse the
under suspicion. progression of ALS. To date, riluzole remains the only agent
Frontal motor neurons in the motor strip disappear in with demonstrated mortality benefit in ALS.213,214 Although
patients with ALS, followed by retrograde degeneration of its mechanism of action in ALS is unclear, riluzole is a sodium
axons in the corona radiata, internal capsule, cerebral pedun- channel blocker, has anti-NMDA activity, and is thought to
cles, pontine base, medullary pyramids, and corticospinal attenuate glutamate-induced excitotoxicity. Riluzole is gen-
tracts. Astrocytic gliosis replaces the lost motor neurons, erally well tolerated. Metabolism is through the cytochrome
P450 enzyme 1A2 and may be affected by other inhibitors or Anatomically, Friedreich's ataxia is characterized by degen-
inducers of this pathway. Notable side effects include weak- eration of long ascending and descending fibers in the pos-
ness, dizziness, and GI distress. Increases in transaminases terior columns and spinocerebellar tracts of the spinal cord
are common and can be significant. All patients should have and the sensory cells in the dorsal root ganglia. Nerve con-
liver enzymes tested frequently in the first few months of use duction studies are consistent with a primarily sensory axonal
and periodically thereafter. A number of other glutamate neuropathy, and neuropathology demonstrates degenera-
antagonists, neurotrophic factors, antioxidants, and immu- tion of myelinated sensory nerve fibers and secondary axonal
nomodulatory and antiapoptotic agents are currently under degeneration. In addition to neuropathologic changes, a car-
investigation, as are stem cell treatments and gene therapy. diomyopathy is often present, typified by cardiomyocytic
hypertrophy, lymphocytic and eosinophilic infiltrates, and
ANESTHETIC CONSIDERATIONS interstitial fibrosis and fatty degeneration.
Preoperative evaluation should include a review of the indi- Cerebellar dysarthria, optic atrophy, and swallowing dys-
vidual patient's symptomatology as well as any medications function are common in Friedreich's ataxia patients. With
used in symptom management. Patients with prominent bul- degeneration of the posterior columns of the spinal cord
bar symptoms or advanced disease are at increased risk of and dorsal roots, loss of proprioception and vibration sense
aspiration and respiratory insufficiency. Prediction of respira- occurs early in the disease course. Autonomic involvement
tory failure based on the results of pulmonary testing (various may lead to bladder dysfunction. Motor neuron degeneration
inspiratory force and vital capacity assessments) is imprecise, also leads to distal muscle atrophy and subsequently, in young
but decreased measures of inspiratory force (particularly SNIF, patients, to the development of talipes (pes) cavus and kypho-
or maximal sniff nasal inspiratory force test) and vital capacity scoliosis. Many patients will be confined to a wheelchair as
less than 50% of predicted are concerns. the disease progresses. Hypertrophic cardiomyopathy leads
Succinylcholine should be avoided because of the risk of to an increased risk of lethal arrhythmia, and most patients
exaggerated hyperkalemic response. Nondepolarizing neu- will develop electrocardiographic and echocardiographic
romuscular blockers should be used with extreme caution abnormalities.222 As many as one third of patients will develop
because of the potential for increased sensitivity to these impaired glucose tolerance or diabetes mellitus.223
drugs. Although elective intubation of patients with signifi- Treatment of Friedrich's ataxia is primarily supportive.
cant neuromuscular weakness is problematic, there is no abso- Antioxidant therapy has been advocated based on the theory
lute contraindication to any anesthetic technique for patients that it is a disease of oxidative stress. However, data support-
with ALS. In a case series of patients with ALS undergoing the use of vitamin E, coenzyme Q10, and the free-radical
ing general anesthesia for diaphragmatic stimulation, use of scavenger idebenone are limited or conflicting. Although no
short-acting analgesic and amnestic agents, in conjunction clear evidence indicates that idebenone improves neurologic
with avoidance of NMB, facilitated postoperative extubation function in patients with Friedreich's ataxia, the drug has
and was not associated with increased 30-day mortality.215 an excellent safety profile, and some data support its use in
Successful use of total IV general anesthesia without NMB patients with cardiomyopathy.224 Iron chelation, primarily
has also been described.216 Others have reported success using with the agent deferiprone, has also been studied, but the risk
local or regional techniques, including peripheral nerve block of agranulocytosis and the typically normal or low serum iron
and neuraxial anesthesia.217,218 levels in patients with Friedreich's ataxia are limitations to this
approach.225 Gene therapy and targeted modulation of DNA
transcription (e.g., using histone deacetylase inhibitors) are
Friedreich's Ataxia
promising future therapies.226
Friedreich's ataxia is a progressive, autosomal recessive genetic
syndrome characterized by ataxia, sensory and motor neu- ANESTHETIC CONSIDERATIONS
ropathy, cardiomyopathy, and diabetes mellitus. The disease Friedreich's ataxia patients with bulbar symptoms are at risk
has been linked to loss-of-function mutations of the frataxin for aspiration and postoperative respiratory compromise, and
gene, generally involving inheritance of an expanded trinucle- patients with severe scoliosis may have restrictive lung dis-
otide repeat (GAA), which is further subject to age-dependent ease or impaired respiratory reserve. As in other motor neu-
somatic expansion.219 Although its precise function is unclear, ron diseases, succinylcholine should be avoided, and patients
frataxin is a mitochondrial protein overexpressed in patients may exhibit increased sensitivity to nondeploarizing neuro-
with Friedreich's ataxia, and mutant frataxin may lead to muscular blockers. There are no contraindications to any spe-
excess mitochondrial iron storage and thus to injury from oxi- cific anesthesia technique, including regional anesthesia. An
dative stress.220 Incidence of Friedreich's ataxia in Caucasians IV technique for general anesthesia and endotracheal intu-
has been estimated at 1:50,000, and this syndrome accounts bation using alfentanil and propofol has been used without
for approximately half of all familial ataxias.221 Onset generally complication.227 Safe use of nondepolarizing NMB with care-
occurs before age 25, and typical presentation includes vary- ful train-of-four measurement has also been described.228,229
ing degrees of ataxia in all four limbs, diminished or absent Neuromonitoring for spine, cardiac, or vascular surgery
lower extremity reflexes, and pyramidal signs. may be complicated, because these patients generally have
abnormal somatosensory evoked potentials. As noted previ- ANESTHETIC CONSIDERATIONS

ously, patients with Friedreich's ataxia are also at significantly Patients with SMA are at variably increased risk for perioper-
increased risk for cardiomyopathy and congestive heart fail- ative respiratory compromise. Patients who are not mechan-
ure, as well as lethal arrhythmia, and should be evaluated for ically ventilated preoperatively may require or may benefit
cardiac disease before surgery. from noninvasive positive-pressure ventilation in the postop-
erative period. Degeneration of the anterior horn cells leads to
decreased choline acetyltransferase (part of acetylcholine syn-
Spinal Muscular Atrophy
thesis pathway) and may produce increased sensitivity to non-
Spinal muscular atrophy (SMA) refers to a group of degener- depolarizing NMB. Succinylcholine should be avoided because
ative disorders of the anterior horn cells and lower brainstem of its potential to cause an exaggerated hyperkalemic response
motor nuclei, resulting in diffuse proximal muscle weakness. and myotonia-like contractions. Narcotics should be titrated
SMA type I, or Werdnig-Hoffman disease, typically presents in carefully because of potential postoperative respiratory hypop-
the neonatal period and is characterized by severe, symmetric nea. Neuraxial and regional anesthesia have been used success-
flaccid paralysis and generally results in death from respira- fully in SMA patients,237–240 but blocks affecting the accessory
tory failure during the first year of life. SMA type II (interme- muscles of respiration or the diaphragm may not be well toler-
diate form) and type III (Kugelberg-Welander disease) present ated. TIVA has been used successfully, as has dexmedetomidine
slightly later (3 months to 2 years), have more variable degrees of for semiawake fiberoptic intubation.240–242 In a retrospective
weakness, and progress more slowly.230 SMA type IV is a slowly case review in pediatric patients with SMA, successful anes-
progressive, adult-onset variant with a more benign course. thetics included balanced general anesthesia with inhalational
Spinal muscle atrophy is inherited in an autosomal reces- agents, TIVA approaches, and regional techniques.243
sive pattern, although sporadic cases account for a small
minority. Most forms are caused by mutations or deletions of
NEUROECTODERMAL DISORDERS
the survival motor neuron 1 (SMN-1) gene on chromosome
5q. A clinically heterogeneous group of non-5q SMA disor- Neuroectodermal disorders belong to a group of con-
ders have also been described, but these are rare. The vari- genital malformations affecting structures of ectoder-
ability in onset and progression of disease in all forms of SMA mal origin and are characterized by coexistent skin and
is thought to depend partly on the ability of a related protein, nervous system lesions. Neurofibromatosis type I (von
referred to as SMN-2, to carry out the functions of SMN-1. Recklinghausen's disease) and type II, von Hippel–Lindau
SMN is believed to be involved in mRNA synthesis in motor disease (VHLD), tuberous sclerosis, and Sturge-Weber
neurons and may inhibit apoptosis.231,232 syndrome are of particular interest to anesthesiologists
Treatment of patients with SMA is supportive, prevent- because of the multiple anesthetic challenges that these
ing aspiration and providing supplemental nutrition, chest patients may present. Table 8-5 provides patterns of inher-
physiotherapy, and respiratory support. Valproate increases itance, genetic characteristics, and encoded proteins asso-
expression of SMN type II in vitro and may improve strength ciated with identified genetic mutations.
in patients with SMA type III or IV.233,234 Although promising Neurofibromatoses, VHLD, and tuberous sclerosis are also
in preclinical studies, phenylbutyrate showed no benefit in an often called phakomatoses on the basis of the patchy oph-
RCT.235 In a mouse model, gene therapy using a viral vector to thalmologic manifestations observed in these disorders.
augment spinal cord SMN expression has shown promise.236 Significant progress in understanding pathogenesis reveals that
TABLE 8-5 n Neuroectodermal Disorders: Genetic Characteristics and Mutations
Disorder Pattern of Inheritance Genetic Mapping and Protein Product
Neurofibromatosis type I Autosomal dominant trait, familial transmission NF1 gene on chromosome 17, truncated
(von Recklinghausen's disease) in 50%, the rest are spontaneous mutations. (nonfunctional) neurofibromin
Neurofibromatosis type II Complete penetrance, variable expression NF2 tumor suppressor gene on chromosome 22,
truncated merlin; other genes may be involved
von Hippel–Lindau disease Autosomal dominant trait with variable high VHL gene on chromosome 3, VHL protein; other
penetrance genes may be involved
Tuberous sclerosis Autosomal dominant trait, one-third are familial TSC1 gene on chromosome 9 and TSC2 on
transmission, the rest are spontaneous chromosome 16, encoding for hamartin and
mutations or mosaicism. tuberin, respectively
Complete penetrance, variable expression
Sturge-Weber syndrome Not inherited Unknown
phakomatosis is characterized by loss of function of various tumors. The neurofibromatoses are divided into type I, or
tumor suppressor genes, which in turn leads to the development NF1, also known by its eponym as von Recklinghausen's dis-
of benign or malignant tumors in many tissues.244 Although the ease, and type II, or NF2. The former is much more common
inheritance patterns and pathogenesis of Sturge-Weber syn- and accounts for 90% of all neurofibromatoses. These two
drome are unknown, it is usually discussed together with phako- types have different causes, and their clinical manifestations
matoses because of the similarity of the clinical manifestations and diagnostic criteria differ significantly (Table 8-6). Other
and the distribution of lesions observed in these disorders.245 All rare forms of neurofibromatosis have been reviewed.246
these neuroectodermal disorders are chronic conditions, with While evaluating a patient diagnosed with neurofibroma-
increasing pathology over the patient's lifetime. tosis for surgery and anesthesia, it is important to make a dis-
tinction between NF1 and NF2. Unlike patients with NF1,
in which associated pathology may involve all systems in the
Neurofibromatoses
body, relevant clinical manifestations of NF2 are largely lim-
Neurofibromatoses are genetic disorders of the nervous ited to intracranial pathology.247 Importantly, although NF2
system primarily affecting the development and growth
is much less prevalent in the general population (1:210,000)
of neural tissues and causing subsequent growth of neural than NF1 (1:5000), most of the patients with NF2 will require
TABLE 8-6 n Comparison of Neurofibromatosis Types 1 and 2 (NF1 vs. NF2)
NF1 NF2
Neural tissue tumors Neurofibromas (major feature) of the skin, Vestibular (often called acoustic neuromas)
peripheral nerves and along nerve roots; or other cranial nerve schwannomas (main
plexiform neurofibromas (can become feature); spinal schwannomas, astrocytomas,
malignant), astrocytomas (not malignant), optic meningiomas, and ependymomas
nerve gliomas
Cutaneous manifestations Café au lait spots (usually the first symptom of Rare
NF1), cutaneous neurofibromas
Ocular manifestations Pigmented iris hamartomas or Lisch nodules None
Central nervous system Epilepsy, hydrocephalus, and mild mental Intracerebral calcifications
(besides tumors) retardation more frequent than in general
population
Cardiovascular involvement Essential hypertension, renovascular None

(renal artery stenosis) hypertension,
pheochromocytoma-related hypertension,
vascular neurofibromatosis, aortic and cerebral
aneurysms, obstruction of major thoracic
vessels by neurofibromas
Pulmonary involvement Fibrosing alveolitis None
Osseous involvement Many bone abnormalities, including chest None

deformities, kyphoscoliosis, sphenoid and
occipital bone dysplasia, and long-bone
deformities
Other systems Neurofibromas of gastrointestinal system, None

intestinal carcinoid tumors, association with
multiple endocrine neoplasia syndrome type III,
which includes pheochromocytoma, NF1, and
medullar thyroid carcinoma
Diagnostic criteria Cutaneous (95% of adult patients), nodular Bilateral acoustic neuromas or first-degree
(peripheral nerves) and plexiform (30%) relative with NF2 in combination with unilateral
neurofibromas, café au lait spots, Lisch nodules acoustic neuroma, meningioma, glioma, or
(95%), optic nerve glioma schwannoma
Symptoms Symptomatic picture of NF1 is immensely diverse Tinnitus and poor balance from eighth nerve
and determined by degree of involvement of tumors. Headache, facial pain, facial
various body systems. Severity of symptoms numbness, and other symptoms are related to
varies widely among patients. pressure effect of growing neural lesions.
surgical removal of cranial nerve schwannomas, an NF2 pri- Coarctation of the abdominal or thoracic aorta is another rare
mary manifestation. As a result, anesthesiologists in neurosur- cause of hypertension in NF1. Other cardiovascular pathologic
gical practice frequently see these patients, whereas in general processes associated with NF1 include vena caval obstruction
practice the likelihood of seeing patients with NF2 is very low. by mediastinal tumors, generalized vasculopathy caused by
To date, most anesthetic and medical literature concerned vascular nodular proliferation, and potential association with
with management of neurofibromatosis is limited to NF1. hypertrophic cardiomyopathy.247
Here, we cover mainly the issues related to the perioperative
management of NF1 patients. The specifics of NF2 anesthetic Pulmonary Assessment. Pulmonary function should be
management are addressed when relevant. evaluated for the presence of restrictive lung disease, which
can be caused by kyphoscoliosis, intrapulmonary neurofi-
PREOPERATIVE EVALUATION bromas, and progressive pulmonary fibrosis associated with
The severity of clinical manifestations of NF1 varies greatly NF1.247 Patients are questioned for the presence of cough or
between patients and usually increases over the patient's life- dyspnea. Chest radiography and ABG analysis are ordered if
time. NF1 might involve multiple organ systems, thus present- pulmonary involvement is suspected, to help evaluate the need
ing a formidable challenge to an anesthesiologist. Familiarity for postoperative ventilation and ICU admission.
with the clinical manifestations of NF1 and a systematic
approach to preoperative assessment of these patients are Central Nervous System Assessment. CNS tumors are
essential to successful anesthetic management.247 major manifestations of both NF1 and NF2. Therefore, all
patients must be evaluated for undiagnosed CNS tumors and
Airway Assessment. Thorough assessment of the airway increased intracranial pressure (ICP). The clinician cannot
is important in NF1 patients. Neurofibromas associated with rely on absence of intracranial or intraspinal tumors on earlier
NF1 can affect any segment of the airway. Intraoral lesions examinations, because new, asymptomatic tumors in different
have been reported in up to 5% of patients with NF1, involv- locations can appear over time. Also, new neurologic symp-
ing the tongue and the laryngeal and pharyngeal structures, toms should not be ascribed to the pre-existing CNS lesions,
leading to obstruction and dyspnea.247 Plexiform and major and the possibility of new pathology should be explored.
subcutaneous neurofibromas are often found in the cervical Additionally, these patients should be assessed for the pres-
region and parapharyngeal spaces. Large lesions can cause ence of epilepsy and questioned for the nature of their seizures
significant airway distortion and obstruction. Unanticipated and type of anticonvulsant therapy. The possibility of cere-
sudden airway obstruction after induction of general anesthe- bral aneurysms or intracranial internal carotid artery steno-
sia has been reported requiring emergency tracheostomy.248,249 sis should be investigated if the patient is symptomatic.254 The
Large neurofibromas originating in the posterior mediasti- brainstem structures can also be affected by neurofibroma or
num, retroperitoneal space, or cervical paraspinal areas can gliomas, which can lead to central hypoventilation, requiring
lead to progressive compression of the distal airway.250,251 ventilation support with prolonged weaning after surgery.255
Additionally, involvement of the recurrent laryngeal nerve Mild mental retardation may be present in these patients, and
can result in unilateral vocal cord paralysis.252 Cranial nerve the degree of the patient's cooperation should be evaluated.
involvement from the large intracranial tumors found in neu-
rofibromatosis can lead to impairment and loss of effective gag Other Systems. Patients with NF1 may have carcinoid
reflex and swallowing mechanisms,247 which can leave the air- tumors, especially in the duodenum,247 and present with car-
way unprotected after extubation in these patients. cinoid syndrome and significant risk of perioperative morbid-
Additionally, some NF1 patients can have macrocephaly, ity and mortality. Symptoms of carcinoid syndrome include
mandibular abnormalities, and undiagnosed cervical spine flushing, bronchoconstriction, diarrhea, and right-sided heart
instability, further complicating airway management. Patients lesions. Perioperative management of patients with carcinoid
with neurofibromas involving the cervical spine should be syndrome has been reviewed.256 The association of NF1, carci-
evaluated for cervical instability, including radiography, neck noid tumor, and pheochromocytoma would make the correct
CT, or MRI as needed. diagnosis especially difficult.257
In pregnancy, NF1 presents an increased risk of severe
Cardiovascular Assessment. All NF1 patients should be hypertension, potentially rapid growth of CNS lesions, and
screened for hypertension, which is common and caused by intracranial hypertension. Patients should be assessed for the
renal artery stenosis, catecholamine-secreting nodular plexi- presence of an intraspinal tumor before deciding to employ
form neurofibroma, or pheochromocytoma (found in up to neuraxial anesthesia. The association of pregnancy, NF1, and
1% of patients).253 In patients with hypertension that is parox- pheochromocytoma carries very high risks.247
ysmal or resistant to routine treatment, it is essential to exclude
pheochromocytoma, which is associated with high intraopera- ANESTHETIC CONSIDERATIONS
tive morbidity and may lead to death if not detected preop- Anesthetic experience in patients with neurofibromatosis is
eratively.247 All patients with NF1 should be questioned for limited to few case reports. The anesthetic challenges in these
the presence of brief headaches, anxiety attacks, palpitations, patients are many, and anesthetic management should be
and night sweats, which are common for pheochromocytoma. based on the existing pathology and its severity (Box 8-12).
The severity of the cardiovascular or cerebrovascular

BOX 8-12 n NEUROECTODERMAL DISORDERS: pathology will dictate the extent of hemodynamic monitoring.
ANESTHETIC ISSUES
An intra-arterial catheter is advised in all patients with severe
Neurofibromatosis (NF1 and NF2) hypertension and associated cerebrovascular pathology to
Anesthetic challenges relate to the severity of symptoms, which vary ensure appropriate cerebral perfusion pressure. Use of central
greatly between patients, from insignificant to life threatening, but
venous and pulmonary artery catheters should be reserved for
increase with age.
Intracranial tumors are frequently present, and patients with
patients with active pheochromocytoma, carcinoid syndrome,
neurofibromatosis must be evaluated for possible intracranial and cardiac lesions with advanced cardiac disease.
hypertension. Neuraxial anesthesia should not be performed in patients
Airway involvement is common and takes different forms. Thorough with increased ICP or intraspinal lesions. The presence of sig-
examination of the entire length of the airway is mandatory to
nificant kyphoscoliosis might also complicate conduction of
avoid unanticipated, life-threatening complications. Consider
special airway techniques.
neuraxial anesthesia.263 If it is perceived that neuraxial anes-
Cardiovascular pathology is common, extremely diverse, and thesia is preferable because of the high risk of general anesthe-
progresses with age. Preoperative optimization may be required. sia, spinal cord neurofibromas and intracranial hypertension
Thorough evaluation of hypertension is mandatory to exclude need to be ruled out using CT or MRI.264,265
associated pheochromocytoma.
Although there have been many reports of altered response
Pulmonary, endocrine, and renal pathology is less common but can
have serious anesthetic implications and should be included in the
to nondepolarizing muscular blockers and succinylcholine, the
evaluation. results of a large retrospective study indicate that the response
No specific anesthetic techniques or agents are contraindicated in to various muscular blockers is unchanged in patients with
NF1 or NF2 patients. neurofibromatoses.247,266 However, NMB should be monitored,
von Hippel–Lindau Disease (VHLD) especially in NF1 patients with renal impairment or those
Anesthetic challenges are mainly determined by the type of surgery. receiving anticonvulsant therapy. Succinylcholine should be
Independent of type of surgery, all patients with VHLD must be avoided in the presence of neurologic deficits. There are no
evaluated for concurrent pathology.
contraindications to any specific anesthetic agents. Potent
Presence of spinal or cerebellar lesions (hemangioblastomas) is a
relative contraindication for the use of neuroaxial anesthesia and inhalational agents and N2O should be used with caution in
should be considered even in asymptomatic patients. patients with large intracranial tumors and increased ICP.
Tuberous Sclerosis (TS)
Positioning of NF1 patients may be complicated by gross
Patients typically display various degrees of mental retardation and deformities of the chest, spine, or the neck. Potential cervi-
poor cooperation. cal instability should be considered when positioning these
Seizure disorder is one of the main manifestations of TS. Effects patients.259 The combination of chest deformities and intra-
of anticonvulsant therapy on anesthetic agents, especially
thoracic neurofibromas can lead to severe hemodynamic com-
neuromuscular blockers, need to be considered.
Airway management should consider high probability for intra-airway
promise caused by the sternal compression of the heart in the
lesions, including significant obstruction and potential for bleeding; prone position.267
adequate preparations must be made. Careful planning for extubation is warranted in patients
Intrapulmonary, cardiac, and renal lesions are frequent findings with a difficult airway. Postoperative respiratory support
in patients with TS. Functional evaluation of these systems
and slow weaning may be necessary in patients with restric-
preoperatively is advisable with such involvement.
No specific anesthetic techniques or agents are contraindicated in
tive lung disease of hypoventilation syndromes because of the
TS patients. brainstem involvement.
von Hippel–Lindau Disease

Awake fiberoptic intubation is the preferred approach in
patients with airway lesions, although even elective awake von Hippel–Lindau disease is an autosomal dominant neo-
fiberoptic intubation can fail when gross anatomic distor- plastic syndrome of variable expression. VHLD is charac-
tion is present.258,259 In pediatric or mentally impaired patients, terized by the development of various benign or malignant
an asleep fiberoptic intubation in a spontaneously breath- tumors and cystic lesions in many organ systems.268 Whereas
ing patient should be considered. Sevoflurane induction fol- hemangioblastomas of the retina and the CNS are the most
lowed by fiberoptic intubation in spontaneously breathing typical lesions found in VHLD patients, lesions of many other
patients has been successfully employed.260 Alternatively, dex- visceral organs are also frequently found (Table 8-7). The clin-
medetomidine has been successfully used for awake fiberop- ical presentation of VHLD is highly variable and progressive.
tic intubation in a patient with cervical lesions compressing Various tumors can affect multiple organs at the same time.
the spinal cord.259 In all NF1 patients with complicated air- Penetrance of VHLD increases with age, reaching 90% by age
way, advanced planning as outlined in the American Society 60.269 In the past, the majority of patients with VHDL died of
of Anesthesiologists (ASA) guidelines for the difficult air- complications of the renal cell carcinoma and CNS hemangio-
way management is advised.261 A difficult airway cart and blastoma. With improvements in the treatment and diagnosis
possibly equipment for emergency tracheostomy should be of VHDL, including serial screening and a multidisciplinary
immediately available, depending on the severity of airway approach to management of these patients, their life expec-
distortion.262 tancy has significantly improved.268 Over their lifetime, the
TABLE 8-7 n Von Hippel–Lindau Disease: Distribution of Lesions
Lesion Frequency in Patients Mean Age at Onset Clinical Symptoms
CENTRAL NERVOUS SYSTEM (CNS)

Retinal hemangioblastoma 25%-60% 25 yr Glaucoma, vision loss, blindness
CNS Hemangioblastomas
Cerebellum 44%-72% 33 yr Headache, nausea, ataxia, motor and
Brainstem 10%-25% 32 yr sensory deficits, hearing loss; pain
Spinal cord 13%-50% 33 yr syndromes
Lumbosacral nerve roots <1% Unknown
Supratentorial <1% Unknown
Other CNS Lesions

Endolymphatic sac tumors (petrous 11% 22 yr Hearing loss, tinnitus, vertigo, facial
bone papillary adenoma) paresis
Syringomyelia 80% (in patients with CNS

lesions)
VISCERAL
Renal cell carcinoma or cysts 25%-60% 39 yr Hematuria, flank pain
Pheochromocytoma 10%-20% 30 yr Often asymptomatic, with sudden

hypertensive crisis
Pancreatic tumor or cysts 35%-70% 36 yr Abdominal pain, jaundice
Epididymal cystadenoma 25%-60% Unknown
Broad ligament cystadenoma Unknown Unknown
majority of patients with VHLD require surgical treatment swallowing mechanisms have been reported after removal of
under general anesthesia for the CNS hemangioblastomas, brainstem hemangioblastomas.272 Postoperative respiratory
sometimes preceded by embolization, pheochromocytomas, support and careful planning for extubation are warranted.
and renal cell carcinoma. The experience of anesthetic management of patients with
Several serious anesthetic concerns in patients with VHLD VHLD is limited to a few case reports in the literature.273-283
need to be considered during preoperative evaluation. These The choice of anesthesia and monitoring in these patients is
patients need to be evaluated for the presence of pheochromo- dictated by type of surgery and extent of existing pathology
cytomas, CNS lesions, and renal function impairment caused (see Box 8-12). For example, the anesthetic management for a
by renal cell carcinoma. patient undergoing posterior fossa decompression in the sitting
Pheochromocytomas in VHLD can be multiple, bilateral, position for the excision of intramedullary hemangioblastoma
and in some patients the only manifestation of the disease, differs from that for nephrectomy for renal cell carcinoma. There
with 5% of the tumors being malignant. Although pheo- is no contraindication to use of any specific anesthetic agents. The
chromocytomas are found only in 10% to 20% of VHLD use of an intra-arterial catheter is indicated for craniotomy and
patients, the recent preoperative screening for hidden pheo- pheochromocytoma removal. Use of a central venous or pulmo-
chromocytomas is essential because of the high potential nary artery catheter is warranted for the removal of pheochro-
for perioperative hypertensive crisis and potential mor- mocytoma. Neuraxial anesthesia has been successfully used for
tality associated with undiagnosed pheochromocytoma, cesarean section or delivery in patients with VHLD.273,275,279,281,282
especially in pregnancy.270 Anesthesia for a patient with However, risks related to use of neuraxial anesthesia in patients
pheochromocytoma has been reviewed271 and is also covered with an asymptomatic spinal cord or cerebellar hemangioblas-
in Chapter 13. Definitive diagnosis is based on demonstrat- toma should be carefully considered.284
ing excessive production of catecholamines, by measuring
urine and blood levels of catecholamines and urinary meta-
Tuberous Sclerosis
nephrines, and supported by CT and MRI.269
Patients with VHLD should be evaluated for the pres- Tuberous sclerosis (TS) complex is inherited as an autosomal
ence, distribution, and size of the CNS lesions. Symptoms dominant trait with a prevalence of 1 in 50,000 to 300,000 pop-
of increased ICP or local mass effect can be present in these ulation. TS is a multisystem disorder primarily characterized
patients (see Table 8-7). The postoperative central hypoven- by cutaneous and neurologic involvement. However, cardiac,
tilation syndrome and bulbar palsy with impairment of pulmonary, and renal involvement have also been reported.244
The clinical picture of TS is determined by the organs involved postoperative ventilation and ICU admission. Renal function
and the extent of that involvement. However, the most fre- should be assessed and associated hypertension ruled out.
quent clinical presentation of TS is generalized or partial
seizures, which typically start in early childhood. The sever- ANESTHETIC CONSIDERATIONS
ity and onset of the seizure disorder correlate with degree of The experience of anesthetic management of patients with TS
developmental problems.189 is limited to a number of case reports and retrospective series
The characteristic skin lesions are usually the first evidence reported in the literature285-290 (see Box 8-12). No specific
of TS, with the most common being hypopigmented macula in anesthetic agents are contraindicated in TS, and the choice of
different shapes (90%), adenoma sebaceum (50%), “shagreen” anesthetic is determined by the magnitude of the surgical pro-
patches, café au lait spots, fibromas, and angiomas. The CNS cedure and the severity of TS. Airway management might be
pathology consists of subependymal nodules or giant cell astro- complicated in patients with airway lesions, and alternatives
cytomas (90%) and hamartomatous regions in the cortex called to direct laryngoscopy should be considered. Careful planning
tubers, which give the name to the disorder and are believed to be for extubation in these patients is warranted and is based on
the cause of seizures (80%-100%) and mental retardation (50%). the size of the airway masses and extent of pulmonary involve-
Developmental delays and behavioral problems are found in 45% ment. Anticonvulsant therapy should be optimized before
to 70% of patients with TS. Cardiac rhabdomyomas are present surgery and continued throughout the perioperative period.
in up to 50% of infants with TS and often regress with age.285 Anesthetic management is tailored to prevent exacerbation of
A high incidence of congenital heart disease in patients with TS seizures. NMB should be monitored with a nerve stimulator.
has been reported.285 Cardiac abnormalities secondary to TS can Patients receiving chronic anticonvulsive therapy may have
lead to obstruction of flow, congestive heart failure, arrhythmias, higher requirements for nondepolarizing muscle relaxants.291
conduction delays, and pre-excitation. Renal lesions composed Regional anesthesia is not contraindicated in TS patients and
of primary renal cysts and angiomyolipomas are found in half of has been safely employed.287
all patients with TS. Renal angiomyolipomas are associated with
early-onset severe hypertension and may result in renal hemor-
Sturge-Weber Syndrome
rhage. Pulmonary cysts and lymphangiomyomatosis have been
reported. Pleural thickening can lead to recurrent spontaneous Sturge-Weber syndrome (SWS) is a rare congenital (not heri-
pneumothorax. Upper airway fibromas and papillomas involv- table) vascular disorder of unknown etiology.245 Its hallmark
ing the tongue, the palate, and sometimes the larynx or pharynx manifestations are a facial angioma (port-wine stain) and a
have been reported in TS patients. leptomeningeal angioma. The facial angioma, besides present-
No specific treatment exists for most TS manifestations, ing a serious aesthetic problem for the patient, can also involve
except standard medical anticonvulsant therapy. Based on the eye structures, leading to glaucoma. In cases of increased
clinical series, many patients with TS require general anesthe- intraocular pressure refractory to medication, surgical inter-
sia for diagnostic or surgical procedures in their childhood.285 vention is recommended. The leptomeningeal angioma is asso-
Most of these patients have surgery for intractable seizures ciated with progressive neurologic symptoms, such as seizures
caused by tuberous lesions. (80%), hemiparesis, mental retardation (50%-66%), behavioral
problems, visual field defects, and hydrocephalus. Seizures are
PREOPERATIVE EVALUATION treated with anticonvulsant therapy but may be refractory in
Preoperative evaluation of patients with TS should be directed more than 50% of patients, in whom hemispherectomy or lim-
toward determination of the extent of neurologic, cardiovas- ited surgical excision of epileptogenic tissue has been performed
cular, pulmonary/airway, and renal involvement. Data on the successfully. Differential diagnosis of SWS is not problematic
nature of seizure disorder, anticonvulsant medications and their because clinical features do not overlap with other disorders.
effectiveness, degree of mental retardation, and behavioral prob- Prognosis for SWS patients is determined largely by the severity
lems should be collected. Patient cooperation is also assessed. of seizures and size of leptomeningeal angioma. However, the
Increased ICP caused by intracranial lesions should be excluded. disease is typically not fatal. There is no specific treatment for
Cardiovascular assessment includes an ECG and is per- SWS, although the cutaneous, ocular, and neurologic manifes-
formed in all patients to exclude arrhythmias, conduction tations are managed medically or surgically with mixed success.
defects, or pre-excitation, which are often found in patients Most of the patients with SWS requiring a surgical pro-
with rhabdomyomas. If heart involvement is suspected, echo- cedure will need it for the surgical treatment of facial or
cardiography and chest radiography are performed to rule out ocular angioma or removal of intracranial leptomeningeal
congenital heart disease and congestive heart failure caused angioma causing seizures that are refractory to medical ther-
by rhabdomyomas or TS pulmonary involvement. The upper apy. Preoperative evaluation of patients with SWS should be
airway should be evaluated for the presence of TS nodular directed toward determination of the extent of neurologic
tumors. A history of spontaneous pneumothorax is noted, pathology and associated symptoms. Patients should be evalu-
because it can recur and is associated with high mortality. ated for signs of increased ICP and hydrocephalus. If the surgi-
Chest radiography and ABG analysis are ordered if pulmo- cal procedure is not for the treatment of seizures, optimization
nary involvement is suspected, to help evaluate the need for of anticonvulsant therapy should be considered.
Minimal evidence in the literature supports any particu- of brainstem and cerebellar development. However, the current
lar anesthetic approach to these patients. Two case reports lack of understanding of etiology and pathogenesis in most of
describing anesthetic management of patients with SWS pro- these conditions precludes a complete classification that would
vide no information regarding adverse reactions to particular be accepted in all the different fields of medicine involved with
anesthetic regimens.292,293 Adverse outcomes related to use of the management of posterior fossa disorders.294
general anesthesia are also not reported in the surgical litera- This discussion details CM-I and CM-II, which constitute the
ture on management of patients with Sturge-Weber syndrome. vast majority of all posterior fossa anomalies in the general pop-
ulation. The rest (or at least some) of these disorders and their
characteristic features are presented in Table 8-8. In the past the
POSTERIOR FOSSA ANOMALIES AND term Arnold-Chiari malformation was often used as a combined
ARNOLD-CHIARI MALFORMATIONS term for different types of posterior fossa abnormalities or used
The “Arnold-Chiari malformation” (Chiari malformation type II) interchangeably with Chiari types I and II. To avoid this seman-
is the traditional eponym used in the anesthesia literature to tic confusion, we use the Chiari I and II malformation definition,
denote a group of congenital posterior fossa anomalies. This which is most often used in the modern literature.
group of disorders includes many other disorders besides Chiari
malformation type I (CM-I) and type II (CM-II), and the list
Chiari I Malformation
grows every year (Table 8-8). The semantic confusion in the litera-
ture regarding precise definition and classification of this group of Chiari malformation type I is anatomically defined as an
disorders can be explained by rapid progress in the neuroimaging extension of the cerebellar tonsils below the foramen mag-
characterization of existing pathology and in the understanding num. It is not associated with caudal displacement of the
TABLE 8-8 n Posterior Fossa Anomalies, Including Chiari Malformations
Malformation Pathophysiology Clinical Features Associated Pathology
Chiari type I malformation Cerebellar tonsils displaced Usually presents in late teens or Syringomyelia, syringobulbia,
into cervical spinal canal, adult years scoliosis, skeletal anomalies
small posterior fossa Wide variety of neurologic
symptoms caused by upper
cervical canal compression
Chiari type II malformation Cerebellar vermis and Presents at birth or early infancy Myelomeningocele and
brainstem displaced into Lower brainstem and cranial other lumbosacral neural
cervical spinal canal nerve dysfunction tube closure defects,
Could be medical emergency hydrocephalus, syringomyelia
Chiari type III malformation Cerebellum displaced into large Respiratory and swallowing Corpus callosum agenesis,
(very uncommon) occipital encephalocele disorders, cranial nerve deficits, tentorium dysplasia,
dystonias (often fatal) midbrain deformities
Dandy-Walker malformation Cystlike dilation of fourth Very heterogeneous in Corpus callossum agenesis,
ventricle, enlarged posterior presentation, depending on brainstem anomalies,
fossa, hypoplasia and associated pathology hydrocephalus
anterior rotation of cerebellar Ataxia, brainstem dysfunction,
vermis mental retardation (varies),
hydrocephalus
Jourbet's syndrome Cerebellar vermis aplasia Motor hypotonia, ataxia, Occipital meningocele,
(extremely rare) behavioral delay scoliosis, hydrocephalus,
hepatic fibrosis
Cerebellar disruptions Cerebellar tissue loss Motor deficits, mental retardation,

(rare) often early death
Pontocerebellar Pontine hypoplasia, cerebellar Severe developmental disorders,

hypoplasias hypoplasia seizures, often early death
(rare)
Rhombencephalo-synapsis Fusion of cerebellar Variable presentation Hydrocephalus,

(extremely rare) hemispheres, vermis Mental retardation, epilepsy, ventriculomegaly
agenesis, fusion of dentate and spasticity are common.
nuclei and superior
cerebellar peduncles
TABLE 8-9 n Chiari Malformation Type 1: Associated TABLE 8-10 n Chiari Malformation Type 1: Signs and
Abnormalities Symptoms
Abnormality Features Signs/Symptoms Features
SKELETAL CAUSED BY COMPRESSION AT CRANIOCERVICAL JUNCTION

Basilar impression Decreased overall cervical spine Occipital/posterior cervical Associated with Valsalva
Atlanto-occipital fusion mobility combined with c-spine pain maneuvers
Klippel-Feil syndrome instability
Atlantoaxial assimilation Increased risk of neurologic injury Weakness Typically caused by distortion
from minor trauma Sensory deficits of medulla
Hyperreflexia
Scoliosis Common finding in patients with Babinski response
syringomyelia
Vocal cord paralysis, Typically caused by involvement
CENTRAL NERVOUS SYSTEM hoarseness, dysarthria of lower cranial nerves
Syringomyelia Usually maximal in cervical spinal cord Dysphagia, recurrent
aspirations
Sleep apnea
Sinus bradycardia, syncope
medulla or supratentorial abnormalities. The etiology of Ataxia Symptoms of the rare
CM-I is not well established. The small size of the poste- Nystagmus cerebellar syndrome
rior fossa causing the cerebellar displacement is the most
CAUSED BY SYRINGOMYELIA
likely explanation. Downward tonsillar displacement is not
Upper limb weakness with Usually starts distally at hand
associated with any actual malformations of the cerebellum atrophy and spreads proximally
or midbrain structures found in most other posterior fossa
anomalies. CM-I is associated with various skeletal and CNS Suspended sensory loss Pain and temperature
loss; touch and position
abnormalities (Table 8-9). The diagnosis of CM-I in other-
preserved
wise asymptomatic patients is made progressively more often
during the investigation of these abnormalities with neuroim- Progressive scoliosis
aging techniques.295 Lower motor neuron
The signs and symptoms of CM-I can be divided into paralysis
those caused by the compression of dural or neural struc-
ture by the displaced cerebellar tonsils and those related to
the progressive development of syringomyelia (Table 8-10).
The patients with CM-I usually become symptomatic in their differs. The patients scheduled for craniectomy already pres-
late teens. However, some may first display symptoms at a ent with some degree of neurologic involvement, which indi-
more advanced age, even in the presence of the syringomy- cates significant compression of the neural elements in the
elia.296 The differential diagnosis in CM-I with syringomyelia craniocervical junction. Most pregnant patients diagnosed
is complex because of the wide range of neurologic symp- with CM-I are either asymptomatic or have already under-
toms and signs. Many neurologic diseases of the spinal cord gone surgical correction.297
and cerebellum (e.g., MS, SMA, ALS, spinocerebellar atax- Neurologic assessment is directed toward evaluation of signs
ias, mononeuropathy multiplex, cervical disc degenerative of brainstem compression or cranial nerve involvement: vocal
disease) have a similar clinical picture. However, CNS and cord dysfunction, ventilation disorders, and swallowing control.
skeletal imaging studies resolve most of these difficulties. A It is important to determine whether any neurologic symptoms
paucity of imaging findings in the patient with a florid clini- are exacerbated with laughing, coughing, or exertion or during
cal neurologic picture might make it difficult to differenti- flexion-extension of the neck. Symptoms of increased ICP are
ate CM-I from hematomyelia, astrocytoma, or ependymoma sought. Appropriate imaging studies should be performed in
of the spinal cord; Leigh's disease; or necrotizing myelopathy. all patients with suspected CM-I. The presence of syringomy-
elia is determined even in patients without a clinical picture of
PREOPERATIVE EVALUATION myelopathy, especially in parturients, in whom neuroaxial anes-
Patients with CM-I require anesthesia that falls under two thesia is considered. The presence and location of motor deficit
categories: (1) suboccipital craniectomy with or without cervi- are noted to avoid overdosing nondepolarizing muscle relaxants
cal laminectomy for the decompression of neural structures by monitoring NMB on denervated muscles.
trapped in the foramen magnum (occasionally, decompres- Autonomic function should be evaluated in patients with
sion or shunting of coexisting syrinx is required) and (2) significant brainstem involvement. Subclinical autonomic
anesthesia for labor and delivery and cesarean section in par- dysfunction, a well-recognized condition in CM-I, can result
turients. Generally, both categories pose similar anesthetic in unstable hemodynamics, lack of compensatory responses
risk, although the preoperative neurologic status typically to hypotension, hypoxia, and hypocarbia intraoperatively.298,299
Chiari II Malformation, Myelomeningocele,

The absence of heart rate beat-to-beat variability and lack of
and Hydrocephalus
cardiac responses to postural maneuvers are good predictors
of autonomic dysfunction. Chiari malformation type II is distinct from CM-I in its pre-
Cervical spine assessment is directed toward evaluation sentation, anatomy, prognosis, and outcomes. One striking
of possible associated cervical spine abnormalities listed in feature is that CM-II is present in practically every child born
Table 8-8. Limited range of motion could result from cervi- with meningomyelocele (MMC). Conversely, CM-II is diag-
cal spine fusion combined with hypermobility between fused nosed only in children with MMC.315 Additionally, hydro-
segments. Therefore, lateral and anteroposterior flexion- cephalus is found or will develop in more than 80% of children
extension cervical spine radiographs are recommended. born with MMC and CM-II and often presents as a medi-
cal emergency requiring urgent shunt placement. Therefore,
ANESTHETIC CONSIDERATIONS these conditions and their implications for anesthesia care are
General Anesthesia for Neurosurgical Procedures. A num- discussed together.
ber of case reports in the literature detail anesthetic manage- Although the etiology of CM-II is not well understood,
ment of these patients for suboccipital decompression.299-303 McLone and Knepper316 propose a likely explanation. Both
There is no evidence that any particular anesthetic agents are open neural tube defect and incomplete spinal occlusion lead
contraindicated for these patients. Although in one case the to CSF leakage from the fetal spinal canal and ventricular
patient developed asystole after dural incision and draining of system. The lack of ventricular CSF distention precludes the
CSF, the patient promptly responded to atropine and ephed- full development of the normal-size posterior fossa, which in
rine administration without sequelae.303 turn leads to the caudal displacement of the rapidly develop-
During induction of anesthesia and positioning, flexion- ing cerebellum into the spinal canal along with the brainstem.
extension of the neck should be limited to prevent further Anatomically, CM-II is characterized by the caudal displace-
compression of the neural structures. Fiberoptic bron- ment of the cerebellar vermis (not the cerebellar tonsils, as
choscopic intubation, awake or asleep, is recommended in in CM-I) below the foramen magnum. The vermis could
patients with skeletal cervical spine abnormalities and unsta- reach as far down as the upper thoracic spinal canal as the
ble cervical spine.304 Careful planning for extubation, and child ages. Other neuroanatomic anomalies typically found
possibly postoperative respiratory support with slow wean- in CM-II include small, upward-rotated cerebellum; caudal
ing, is indicated in patients with pronounced brainstem displacement of the medulla (and sometimes the pons) into
compression and cranial nerve involvement because of the the spinal canal; small posterior fossa; multiple ventricular
increased risk of postoperative ventilatory failure299 or com- anomalies; and small fourth ventricle and aqueduct. The fora-
promised upper airway reflexes.305-307 Use of invasive mon- men magnum is often enlarged. Also, hypoplasia or aplasia
itoring is usually limited to the arterial line for measuring of cranial nerve nuclei is often present (20%). Other associ-
BP and ABG analysis in the postoperative period, if needed. ated abnormalities of MMC and CM-II include neurogenic
Although often performed in the sitting position and associ- bladder, neurogenic bowel, multiple orthopedic deformities,
ated with high risk of venous air embolism in the past, sub- and lower extremity fractures. These latter conditions often
occipital decompression is routinely performed in the prone require repeated corrective surgical procedures under general
position at present; thus there is no need for right atrial cath- anesthesia.
eter placement. It is important to understand that the first indication of pos-
sible CM-II in the newborn is the presence of MMC, which will
Anesthesia for Labor and Delivery. There are a number require urgent repair. However, these neonates must be eval-
of case reports308-314 and retrospective series297 on anesthetic uated for the signs and symptoms of CM-II. Asymptomatic
management in pregnant patients with posterior fossa anoma- CM-II is the most common cause of death in children with
lies. In patients without elevated ICP or significant neurologic MMC younger than 2 years. Close to one third of patients with
symptomatology at delivery, it seems safe to employ epidural, MMC will develop symptoms of brainstem compression, and
spinal, or general anesthesia with inhalational agents, whether one third of them will die315 before age 5 years. Therefore, all
for vaginal or cesarean birth. In patients with increased ICP symptomatic CM-II patients should be aggressively evalu-
and neurologic deficits associated with syringomyelia, the ated for hydrocephalus and considered for CSF shunt place-
risks and benefits for any form of anesthesia should be care- ment. Symptomatic CM-II in children younger than 2 years
fully weighed, bearing in mind that dural puncture may result typically has a different presentation than in older children
in the sudden neurologic deterioration caused by further cere- (Table 8-11).
bellar herniation.313,314 For labor, a combination of cervical and
pudendal blocks, supplemented by parenteral opioids, may PREOPERATIVE EVALUTION
be the safest approach.297 For cesarean delivery, general endo- Most children with CM-II undergo MMC repair procedure in
tracheal anesthesia directed toward preventing ICP increase the first hours of their life. The principles of anesthetic manage-
should be considered. Other considerations for decompressive ment for MMC repair can be found in most pediatric anesthesia
suboccipital craniotomy discussed in the next section are also texts. All other procedures typically required by these patients
valid in these patients. during their lifetime can be divided into three categories: (1)
TABLE 8-11 n Chiari Malformation Type II: Clinical Presentation in Early and Late Childhood
Group Presentation Signs/Symptoms Implications
Younger children Increasing hydrocephalus Inspiratory stridor caused by abduction of Often emergency presentation, life
(≤2 yr) Brainstem dysfunction vocal cords with paralysis/paresis threatening
Cranial nerve dysfunction Apneic episodes, including cyanotic expiratory Shunt placement is lifesaving
(10th, 9th) apnea of central origin (although not in all infants).
Swallowing difficulties, chronic aspirations,
weak gag reflex, dysphagia, malnutrition
Older children Cervical myelopathy Weakness and spasticity of upper extremities, Slowly progressing, rarely life
Syringomyelia occipital headache, craniocervical pain, threatening
ataxia, sensory loss, scoliosis Decompressive surgery is often
performed after normal CSF
shunt function is confirmed.
CSF, Cerebrospinal fluid.
emergency decompressive surgery or CSF shunt placement in Succinylcholine should be avoided in patients with motor
stridorous infants, (2) elective decompressive procedure (e.g., deficits, which are typically present in these patients after
cervical laminectomy), or (3) corrective surgical procedures for MMC repairs or as a result of cervical myelopathy. NMB
associated pathology (e.g., bladder surgery, orthopedic proce- should be monitored on the limbs not affected by motor defi-
dures) in patients without obvious symptoms of CM-II. cits to avoid overdosing.
Intraoperative considerations for orthopedic, urologic, and
Emergency Procedures. These patients should be evaluated
other corrective procedures in asymptomatic patients are sim-
for the signs of vocal cord dysfunction and breathing disor-
ilar to those in patients with CM-I.
ders. Patients with these symptoms may develop respiratory
depression, such as apneic spells and vocal cord paralysis, even
if the ICP is well controlled.305,317 Patients should be monitored KLIPPEL-FEIL SYNDROME AND
postoperatively in the ICU for the signs of apnea and the com- OTHER CERVICAL SPINE DISORDERS
promised airway. Careful planning for extubation is recom- OF CHILDHOOD
mended. Volemic status should be evaluated in patients with
Anesthetic care of patients with cervical spine disorders result-
unrepaired MMC, with potentially significant loss of CSF.
ing from congenital or developmental alterations in childhood
Elective Procedures. The most important step in the sur- represent a unique and complex challenge. Increased suscep-
gical and anesthetic preoperative evaluation of these patients tibility to cervical spine injury and subsequent neurologic def-
is to rule out nonfunctioning shunt or latent hydrocephalus. icit, often combined with anatomically difficult airway, are
Otherwise, the considerations are similar to those described common for this diverse group of disorders of different eti-
in patients with CM-I. ology. Understanding of the anatomic and pathophysiologic
features of these disorders, thorough preoperative evaluation,
ANESTHETIC CONSIDERATIONS and appropriate early management are essential in preven-
Anesthetic management in the literature on CM II is limited tion of neurologic injury and other anesthetic complications
to two case reports and a series. There are no clear contra- in these patients.319,320 Klippel-Feil syndrome is a member of
indications to any particular anesthetic agents. Positioning of this group and is often mentioned in the anesthetic literature.
the patient may be a challenge, especially in those cases when It also presents one of the most formidable anesthetic chal-
shunt placement is performed simultaneously with MMC lenges. For simplicity of presentation, other disorders in this
repair. Extremes of the neck flexion or extension should be section are discussed in conjunction with the discussion of the
avoided to prevent further compression of neural structures preoperative evaluation and anesthetic management of this
in the upper cervical canal. Inhalational mask induction, even syndrome.
in the asymptomatic child, can be complicated by apneic spells Klippel-Feil syndrome is a rare congenital anomaly of the
and laryngospasm.318 cervical spine (1 in 42,000 births) typically characterized by
In the past, when suboccipital decompressive craniectomy fusion of two or more cervical vertebrae. It is unclear whether
and duraplasty were performed, an increased risk of inadver- Klippel-Feil syndrome is a discrete entity with common
tent hemorrhage from the occipital or transverse sinuses had genetic etiology or a phenotypic presentation of a heteroge-
to be considered in these patients. This life-threatening com- neous group of congenital spinal deformities.321 The classic
plication was associated with venous air embolism and carried triad of short neck, low posterior hairline, and limitations of
very high mortality. This surgery is rarely recommended at cervical motion are found in less than half of patients with this
present. However, invasive hemodynamic monitoring is indi- condition. Other common associated findings include con-
cated for decompressive cervical laminectomy. genital scoliosis (50% of patients), renal abnormalities (33%),
Sprengel's deformity (congenital elevation of scapula), hear- Cervical MRI is indicated to assess the degree of neuro-
ing impairment, posterior fossa dermoid cysts, and congeni- logic involvement, such as cord compression and myelopa-
tal heart disease (most often ventricular septal defect). Overall thy. Other perioperative considerations should include the
decreased neck mobility is the most common physical find- following:
ing and is often combined with hypermobility between fused
Congenital heart defects and cardiac conduction abnormalities.
vertebral segments, which puts these patients at high risk for
Preoperative ECG and echocardiography are indicated.
either spontaneous neurologic injury or that resulting from
Assessment of pulmonary function, which could be severely
minor trauma.322
compromised in patients with chest deformities and
Many neurologic symptoms caused by cranial nerve abnor-
advanced scoliosis. Consider chest radiography and pul-
malities, cervical radiculopathy, or myelopathy are typically
monary function tests.
found in the second or third decade of life. Most neurologic
Renal function. Patients with Klippel-Feil syndrome should be
manifestations are secondary to chronic compression of the
evaluated for kidney anomalies and renal failure.
cervical spinal cord, pons, medulla, and stretching of the cra-
nial nerves. Sudden neck movement or minor falls can cause
basilar artery insufficiency and syncope. Tetraplegia has been ANESTHETIC CONSIDERATIONS
reported as a result of minor trauma in these patients.322 Anesthetic experience in Klippel-Feil syndrome patients is
Klippel-Feil syndrome is often classified into three types, limited to a number of case reports.304,320,324-328 The main anes-
depending on the location of the fused cervical vertebrae. The thetic challenge in these patients is airway management and
presentation of clinical and anatomic features of this syndrome positioning (Box 8-13). Awake fiberoptic intubation is the
varies widely, ranging from mild deformity to severe disability. preferred approach whenever possible.304,324,328 However, most
Cervical spine abnormalities similar to those observed in pediatric and mentally impaired (Down syndrome) patients
Klippel-Feil syndrome are frequently seen in other uncommon are not suitable candidates, and asleep fiberoptic intuba-
disorders listed in Table 8-12.319 Cervical instability, increased tion in a spontaneously breathing patient should be consid-
risk of severe neurologic injury from minor trauma, and diffi- ered. Direct laryngoscopy is likely to be difficult because of
cult airway are common features in all these conditions. A full multiple facial, neck, and chest deformities. However, when
description of these disorders and relevant anesthetic issues direct laryngoscopy is chosen, a neutral neck axis needs to be
are addressed in subsequent sections of this chapter or other maintained to avoid neurologic sequelae. The laryngeal mask
chapters. airway can be used to ventilate these patients, although intu-
bation via laryngeal mask may be technically difficult.30
PREOPERATIVE EVALUATION Positioning of patients with Klippel-Feil syndrome may be
Preoperative assessment in patients with cervical spine dis- difficult because of multiple head, neck, and thoracic defor-
orders should primarily be directed at the evaluation of mities. Great care must be taken to avoid any cervical ten-
degree of cervical instability present, pre-existing neurologic sion or sudden neck movements while positioning these
impairment, and airway evaluation. A previous uneventful patients. It is important to understand that the risk of neu-
anesthetic history is a poor predictor of difficult airway or rologic injury in these patients is not limited to laryngoscopy
neurologic complications in patients with Klippel-Feil syn- and intubation and may develop thereafter.320,324,329 Regional
drome, because cervical fusion becomes progressively worse anesthesia has been successfully performed in Klippel-Feil
with time.323 Therefore, lateral and anteroposterior flexion- patients326,327 and might be preferable if indicated, to avoid
extension cervical spine radiographs are recommended. potential neurologic and respiratory complications related to
TABLE 8-12 n Cervical Spine Disorders
Disorder Cervical Spine Abnormalities Symptoms
Down syndrome Occipitocervical or atlantoaxial instability Muscle weakness, gait abnormality, neck pain
Achondroplasia Foramen magnum stenosis, lumbar spine Severe sleep apnea and sudden death in
stenosis early childhood
Cervical instability is uncommon.
Spondyloepiphyseal dysplasia Odontoid hypoplasia and/or os odontoideum Persistent hypotonia; motor developmental
with atlantoaxial instability delay
Mucopolysaccharidoses Odontoid hypoplasia with atlantoaxial Severe neurologic compromise secondary to

Morquio's syndrome instability and progressive myelopathy; upper cervical spinal cord compression;
extradural soft tissue hypertrophy sudden death
Isolated odontoid anomalies: aplasia, Progressive atlantoaxial instability Symptoms of upper cervical spinal cord injury,
hypoplasia, os odontoideum sudden death
function is contraindicated. Careful planning for extubation

BOX 8-13 n CHIARI MALFORMATION TYPE 1 is warranted in patients with significantly compromised pul-
AND OTHER POSTERIOR FOSSA AND
CERVICAL SPINE DISORDERS OF monary function and after difficult intubation. No contra-
CHILDHOOD: ANESTHETIC ISSUES indications exist to any specific anesthetic drugs in patients
with Klippel-Feil syndrome.
Significant autonomic dysfunction can be present, resulting in
potential hemodynamic instability.
Airway management and intraoperative positioning are directed at MUCOPOLYSACCHARIDOSES
limiting cervical flexion-extension in patients with clinical and
imaging evidence of cervical spine compression. Inclusion of mucopolysaccharidoses in the chapter on uncom-
Patients with existing vocal cord dysfunction and compromised mon neurologic disease is debatable for a number of reasons.
ventilatory function and swallowing plan for postoperative
These are primarily metabolic disorders affecting many organs
ventilatory support.
No specific anesthetic techniques or agents are contraindicated
and systems in the body containing connective tissue, most
in patients with Klippel-Feil syndrome or other childhood spinal prominently the skeletal system and soft tissue. However, most
disorders. of these disorders either affect the nervous system directly or
For labor and delivery neuroaxial anesthesia can be performed safely, result from skeletal and joint deformities (Table 8-13). These
but should be avoided in patients with increased intracranial
neurologic deficits create the potential for triggering new,
pressure and existing neurologic deficits.
potentially catastrophic neurologic complications and often
pose a formidable anesthetic challenge in the perioperative
airway management. It can be difficult to perform, consid- care for these patients.
ering the various spine deformities associated with this con- The mucopolysaccharidoses are hereditary lysosomal stor-
dition. Succinylcholine should be avoided in the presence of age disorders caused by the deficiency of various enzymes
neurologic deficit. In patients with associated renal anoma- necessary for the metabolism of glycosaminoglycans (GAGs),
lies accompanied by renal failure, the use of nondepolarizing previously called mucopolysaccharides. Excess accumula-
muscle relaxants for which excretion is dependent on renal tion of partially degraded GAGs within cells causes cellular
TABLE 8-13 n Mucopolysaccharidosis (MPS): Types and Clinical Features
Usual Age
Type Common Name (Diagnosis) Clinical Features
PRIMARILY CNS DISEASE WITH LESS SKELETAL AND SOFT TISSUE DISEASE
MPS-III, Sanfilippo's syndrome 2-6 yr Aggressive behavior followed by progressive mental retardation and
subtypes A-D types A-D neurologic decline; milder physical features of MPS-I
PRIMARILY SKELETAL AND SOFT TISSUE DISEASE WITH RANGE OF CNS MANIFESTATIONS
MPS-I Hurler's syndrome 1-2 yr Severe cardiac and skeletal abnormalities, hydrocephalus, mental
retardation, severe coarse facies, hepatosplenomegaly, airway obstruction,
dystosis multiplex, often placid and loving; death by age 10 years
Hurler-Scheie 1-5 yr Intermediate severity of skeletal abnormalities, micrognathia, moderate

syndrome coarse facies, possible normal intelligence; death by 20s
Scheie's syndrome 3-15 yr Milder form with slow progression; aortic valve and joint disease, corneal
clouding, normal facies and mentation; life span of several decades
MPS-II Hunter's syndrome: 1-3 yr No corneal clouding; physical disease similar to MPS I; aggressive
severe behavior and developmental delay
Hunter's: mild 1-5 yr Normal or near-normal intelligence
MPS-VII Sly's syndrome Birth to 5 yr Variable intermediate physical presentation similar to MPS-I
SKELETAL DISEASE AND SOFT TISSUE STORAGE WITHOUT SIGNIFICANT CNS INVOLVEMENT
MPS-IV Morquio's syndrome 1 yr to Skeletal disease with ligament laxity and high incidence of odontoid
type A and type B late teens, dysplasia and atlantoaxial instability, short stature, possible corneal
depending opacities, normal intelligence
on severity
MPS type VI Maroteaux-Lamy 1-5 yr Severe skeletal disease as in MPS-I but without CNS disease, although
syndrome (mild to hydrocephalus and severe cervical spinal cord compression may occur
severe form) later in course; death in teens and 20s
CNS, Central nervous system.
ysfunction. The faulty metabolism results in serious struc-

d tracheal wall distort the airway, and difficulties with intuba-
tural and functional abnormalities in a wide variety of tissues, tion can increase with age as this process continues.331 A short
particularly bone and cartilage. There are now nine muco- neck with a narrow, anterior larynx accompanied by possible
polysaccharidosis (MPS) disorders, classified as types I to IX, cervical instability or history of cervical fusion offers addi-
based on enzyme deficiency and severity of the phenotype. tional airway challenges, particularly in those with Hurler's
With the exception of Hunter's syndrome (MPS-II), which is syndrome (MPS-I). Incidence of difficult intubation and
an X-linked disorder, the mucopolysaccharidoses are inher- failed intubation is reported as 53% and 23%, respectively.332,333
ited in an autosomal recessive pattern. The cumulative inci- Tracheotomy is also technically difficult because of a large
dence is estimated at 1 in 20,000 live births. Table 8-13 outlines mandible, short neck, and retrosternal trachea, and it was
the classification system and summarizes the associated clini- impossible even postmortem in one case report.334,335
cal features. Cardiac abnormalities also result from MPS. Mitral and
Diagnosis is made by elevated GAG concentration in aortic valves thicken, causing insufficiency that may progress
urine or demonstration of enzyme deficiency in leukocytes. to cardiomyopathy.336 Deposition of GAGs in arterial walls
Treatment options include enzyme replacement, bone marrow causes systemic hypertension and coronary artery disease.
transplantation, and cord blood transplantation. These thera- Coronary lesions are diffuse and can lead to ischemia or sud-
pies are symptomatic and may alter the natural progression of den death. Coronary angiography may not predict the sever-
the disease but do not prevent eventual decline in function. ity of the diseases.330,337 Pulmonary hypertension secondary to
The MPS continues to worsen as the patient grows older, and chronic hypoxemia of pulmonary disease and airway obstruc-
most patients will die of pulmonary or cardiac complications. tion can lead to right-sided heart failure.
Pulmonary dysfunction is another frequent complica-
ANESTHETIC CONSIDERATIONS tion in MPS patients. Kyphoscoliosis causes a restrictive dis-
The anesthetic implications of MPS are extensive and relate ease with recurrent pneumonia and ventilation/perfusion
to the end-organ dysfunction and anatomic distortions expe- mismatch, resulting in chronic hypoxemia and hypercarbia.
rienced by this patient population (Box 8-14). Complications Patients with Morquio's syndrome (MPS-IV) are also prone to
with general anesthesia are common, and morbidity and mor- atlantoaxial instability and odontoid dysplasia. This can lead
tality are primarily caused by airway issues. Upper airway to central apnea from cord compression.338
abnormalities such as macroglossia, hypertrophic tonsils and Neurologic complications of MPS vary depending on the
adenoids, patulous lips, micrognathia, friable tissues, copious particular classification. Developmental delay and sleep dis-
secretions, and restrictive temporomandibular joint move- turbance are common. Vertebral subluxation can occur at any
ment can hinder adequate ventilation. Many patients have level of the spinal column and compromise the spinal cord.
obstructive breathing at baseline, with sleep apnea and need Communicating hydrocephalus frequently develops and can
for continuous positive airway pressure. Bone marrow trans- cause increased ICP. Seizures are uncommon in most of these
plant can reverse upper airway obstruction.330 Lower airway patients.
abnormalities from deposition of GAG in the epiglottis and Patients with MPS often present for surgery, usually
for ear, nose, and throat procedures and hernia repairs.
Anesthetic management should begin with a preoperative
BOX 8-14 n MUCOPOLYSACCHARIDOSES: evaluation that establishes which type of MPS is involved
ANESTHETIC ISSUES and what components of the disease are present.333 Careful
Difficult to impossible airway is the central concern in the anesthesia review of cardiac, pulmonary, and neurologic function are
care of mucopolysaccharidosis (MPS) patients. paramount, and workup may include ECG, chest radio-
Thorough preoperative airway assessment and history are crucial. graph, neck films, pulmonary function tests, and echocar-
Plan for awake fiberoptic intubation in the cooperative patient.
diogram, as indicated. Preoperative flexion-extension films
Have equipment and skilled personnel immediately available for
emergency surgical airway. to evaluate stability of the cervical spine are recommended
Evaluate for cervical spine compression and cervical instability. If in those with Morquio's syndrome.339 Detailed inspection
present, minimize the range of flexion-extension during induction of the airway, review of anesthesia records, and neck imag-
and positioning. ing can help predict airway difficulties.333 However, the air-
Many MPS patients are uncooperative, requiring special approaches
way can worsen with time and disease progression. Age and
when planning for fiberoptic intubation in spontaneously breathing
patients. level of mental retardation are also important consider-
Respiratory compromise is common; plan for extended ventilatory ations in planning an anesthetic procedure. Premedication
support in the ICU. with benzodiazepines can be helpful in the uncooperative
Valvular disease, lesions of coronary arteries, and pulmonary patient but should be avoided in those with an airway prone
hypertension are common and require cardiac evaluation. In
to obstruction. An antisialagogue should be administered
compromised patients, use of invasive hemodynamic monitoring is
warranted. to decrease secretion but used cautiously in patients with
Neuroaxial and regional anesthesia are not contraindicated in patients heart disease.
with MPS but should be avoided in those with hydrocephalus. Because most reported anesthetic complications in the MPS
patient population involve airway or positioning difficulties,
regional anesthesia may be a safer option.340-342 Regional 11. Yim SY, Lee I, Moon HW, et al: Hypertrophic neuropathy with complete
technique may prove problematic if the patient cannot lie conduction block—hereditary motor and sensory neuropathy type III,
Yonsei Med J 36:466–472, 1995.
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C H A P T E R

BENJAMIN K. SCOTT, MD n

Hereditary Peripheral Neuropathies KEY POINTS

TABLE 8-1 n Hereditary Peripheral Neuropathies*

Clinical Manifestations/Underlying Electrophysiologic

HEREDITARY PRIMARY MOTOR AND SENSORY NEUROPATHIES (HMSNs)

HEREDITARY PRIMARY SENSORY AND AUTONOMIC NEUROPATHIES (HSANs)

The preoperative evaluation and preparation of HMSNs ANESTHETIC CONSIDERATIONS

BOX 8-3 n FAMILIAL DYSAUTONOMIAS: SENSORY AND AUTONOMIC DYSFUNCTION

Sensory System Postural hypotension.

Central nervous Multiple involvements Multiple involvements Unaffected Multiple involvements

Progression Fast; median survival, Slow Slow; up to 15 years and Slow

Prognosis Poor Good Good Moderate to poor

Extrapyramidal Common Common Absent Common

Cerebellar Common Common Absent Common

Glial cytoplasmic Present Absent Absent Absent

Response to Poor Good Moderate

Dementia Uncommon Usually not severe, Uncommon Early, severe, rapidly

Multiple System Atrophy

TABLE 8-3 n Pharmacologic Therapy of Parkinson's Disease

Drug Features Side Effects Contraindications

Carbidopa Decarboxylase inhibitor that does not Rebound hypertension with

Sinemet Combination of carbidopa/levodopa

CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS

TABLE 8-3 n Pharmacologic Therapy of Parkinson's Disease—Cont'd

Drug Features Side Effects Contraindications

MONOAMINE OXIDASE B (MAO-B) INHIBITORS

nausea and vomiting, and facilitate earlier ability to resume

BOX 8-7 n MULTIPLE SCLEROSIS: CLINICAL SIGNS/

BOX 8-9 n PRINCIPAL NEUROPATHIC SYNDROMES

TABLE 8-4 n Guillain-Barré Syndrome and Its Variant Forms

Incidence/Occurrence Motor or Sensory Characteristic Signs Suspected Etiology

ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY

ACUTE MOTOR AXONAL NEUROPATHY

ACUTE MOTOR-SENSORY NEUROPATHY

BOX 8-10 n GUILLAIN-BARRÉ SYNDROME (GBS): BOX 8-11 n DEGENERATIVE MOTOR NEURON DISEASES

l Progressive juvenile bulbar palsy (Fazio-Londe)

abnormal somatosensory evoked potentials. As noted previ- ANESTHETIC CONSIDERATIONS

TABLE 8-5 n Neuroectodermal Disorders: Genetic Characteristics and Mutations

Disorder Pattern of Inheritance Genetic Mapping and Protein Product

Sturge-Weber syndrome Not inherited Unknown

TABLE 8-6 n Comparison of Neurofibromatosis Types 1 and 2 (NF1 vs. NF2)

Ocular manifestations Pigmented iris hamartomas or Lisch nodules None

Cardiovascular involvement Essential hypertension, renovascular None

Pulmonary involvement Fibrosing alveolitis None

Osseous involvement Many bone abnormalities, including chest None

Other systems Neurofibromas of gastrointestinal system, None

The severity of the cardiovascular or cerebrovascular

von Hippel–Lindau Disease

TABLE 8-7 n Von Hippel–Lindau Disease: Distribution of Lesions

Lesion Frequency in Patients Mean Age at Onset Clinical Symptoms

CENTRAL NERVOUS SYSTEM (CNS)

Other CNS Lesions

Syringomyelia 80% (in patients with CNS

Pheochromocytoma 10%-20% 30 yr Often asymptomatic, with sudden

Pancreatic tumor or cysts 35%-70% 36 yr Abdominal pain, jaundice

Epididymal cystadenoma 25%-60% Unknown

Broad ligament cystadenoma Unknown Unknown

TABLE 8-8 n Posterior Fossa Anomalies, Including Chiari Malformations

Malformation Pathophysiology Clinical Features Associated Pathology

Cerebellar disruptions Cerebellar tissue loss Motor deficits, mental retardation,

Pontocerebellar Pontine hypoplasia, cerebellar Severe developmental disorders,

Rhombencephalo-synapsis Fusion of cerebellar Variable presentation Hydrocephalus,

BOX 8-3 n FAMILIAL DYSAUTONOMIAS: SENSORY AND AUTONOMIC DYSFUNCTION

BOX 8-7 n MULTIPLE SCLEROSIS: CLINICAL SIGNS/

BOX 8-10 n GUILLAIN-BARRÉ SYNDROME (GBS): BOX 8-11 n DEGENERATIVE MOTOR NEURON DISEASES

ysfunction. The faulty metabolism results in serious struc-