3424 PART 13 Neurologic Disorders

FIGURE 439-1 Sagittal magnetic resonance imaging (MRI) of the brain of a 60-yearold man with gait ataxia and dysarthria due to spinocerebellar ataxia type 1 (SCA1),

illustrating cerebellar atrophy (arrows). (Reproduced with permission from RN

Rosenberg, P Khemani, in RN Rosenberg, JM Pascual [eds]: Rosenberg’s Molecular

and Genetic Basis of Neurological and Psychiatric Disease, 5th ed. London, Elsevier,

2015.)

has become the gold standard for diagnosis and classification. CAG

encodes glutamine, and these expanded CAG triplet repeat expansions result in expanded polyglutamine proteins, termed ataxins, that

produce a toxic gain of function with autosomal dominant inheritance. Although the phenotype is variable for any given disease gene,

a pattern of neuronal loss with gliosis is produced that is relatively

unique for each ataxia. Immunohistochemical and biochemical studies

have shown cytoplasmic (SCA2), neuronal (SCA1, MJD, SCA7), and

nucleolar (SCA7) accumulation of the specific mutant polyglutaminecontaining ataxin proteins. Expanded polyglutamine ataxins with more

than ~40 glutamines are potentially toxic to neurons for a variety of

reasons including: high levels of gene expression for the mutant polyglutamine ataxin in affected neurons; conformational change of the

aggregated protein to a β-pleated structure; abnormal transport of the

ataxin into the nucleus (SCA1, MJD, SCA7); binding to other polyglutamine proteins, including the TATA-binding transcription protein

and the CREB-binding protein, impairing their functions; altering the

efficiency of the ubiquitin-proteasome system of protein turnover; and

inducing neuronal apoptosis. An earlier age of onset (anticipation) and

more aggressive disease in subsequent generations are due to further

expansion of the CAG triplet repeat and increased polyglutamine number in the mutant ataxin. The most common disorders are discussed

below.

■ SCA1

SCA1 was previously referred to as olivopontocerebellar atrophy, but

genomic data have shown that that entity represents several different

genotypes with overlapping clinical features.

Symptoms and Signs SCA1 is characterized by the development

in early- or middle-adult life of progressive cerebellar ataxia of the

trunk and limbs, impairment of equilibrium and gait, slowness of

voluntary movements, scanning speech, nystagmoid eye movements,

and oscillatory tremor of the head and trunk. Dysarthria, dysphagia,

and oculomotor and facial palsies may also occur. Extrapyramidal

symptoms include rigidity, an immobile face, and parkinsonian tremor.

The reflexes are usually normal, but knee and ankle jerks may be lost,

and extensor plantar responses may occur. Dementia may be noted

but is usually mild. Impairment of sphincter function is common, with

urinary and sometimes fecal incontinence. Cerebellar and brainstem

atrophy are evident on MRI (Fig. 439-1).

Marked shrinkage of the ventral half of the pons, disappearance of

the olivary eminence on the ventral surface of the medulla, and atrophy

of the cerebellum are evident on gross postmortem inspection of the

brain. Variable loss of Purkinje cells, reduced numbers of cells in the

molecular and granular layer, demyelination of the middle cerebellar

peduncle and the cerebellar hemispheres, and severe loss of cells in

the pontine nuclei and olives are found on histologic examination.

Degenerative changes in the striatum, especially the putamen, and loss

of the pigmented cells of the substantia nigra may be found in cases

with extrapyramidal features. More widespread degeneration in the

central nervous system (CNS), including involvement of the posterior

columns and the spinocerebellar fibers, is often present.

■ GENETIC CONSIDERATIONS

SCA1 encodes a gene product, called ataxin-1 that regulates transcriptional repression with various nuclear factors. As a protein

that can bind RNA, ataxin 1 may also regulate gene transcription

posttranslationally. The mutant allele has 40 CAG repeats located

within the coding region, whereas alleles from unaffected individuals

have ≤36 repeats. A few patients with 38–40 CAG repeats have been

described. There is a direct correlation between a larger number of

repeats and a younger age of onset for SCA1. Juvenile patients have

higher numbers of repeats, and anticipation is present in subsequent

generations. Transgenic mice carrying SCA1 developed ataxia and

Purkinje cell pathology. Leucine-rich acidic nuclear protein localization, but not aggregation, of ataxin-1 appears to be required for cell

death initiated by the mutant protein.

■ SCA2

Symptoms and Signs Another clinical phenotype, SCA2, has been

described in patients from Cuba and India. Cuban patients probably

are descendants of a common ancestor, and the population may be the

largest homogeneous group of patients with ataxia described. The age

of onset ranges from 2 to 65 years, and there is considerable clinical

variability within families. Although neuropathologic and clinical findings are compatible with a diagnosis of SCA1, including slow saccadic

eye movements, ataxia, dysarthria, parkinsonian rigidity, optic disc

pallor, mild spasticity, and retinal degeneration, SCA2 is a unique form

of cerebellar degenerative disease.

■ GENETIC CONSIDERATIONS

The gene in SCA2 families also contains CAG repeat expansions

coding for a polyglutamine-containing protein, ataxin-2. Normal

alleles contain 15–32 repeats; mutant alleles have 35–77 repeats.

Ataxin-2 has recently been shown to assemble with polyribosomes.

Ataxin-2 is also an important risk factor for sporadic amyotrophic lateral sclerosis (ALS).

■ MACHADO-JOSEPH DISEASE/SCA3

MJD was first described among the Portuguese and their descendants

in New England and California. Subsequently, MJD has been found

in families from Portugal, Australia, Brazil, Canada, China, England,

France, India, Israel, Italy, Japan, Spain, Taiwan, and the United States.

In most populations, it is the most common autosomal dominant

ataxia.

Symptoms and Signs MJD has been classified into three clinical

types. In type I MJD (ALS-parkinsonism-dystonia type), neurologic

deficits appear in the first two decades and involve weakness and spasticity of extremities, especially the legs, often with dystonia of the face,

neck, trunk, and extremities. Patellar and ankle clonus are common, as

are extensor plantar responses. The gait is slow and stiff, with a slightly

broadened base and lurching from side to side; this gait results from

spasticity, not true ataxia. There is no truncal titubation. Pharyngeal

weakness and spasticity cause difficulty with speech and swallowing.

Of note is the prominence of horizontal and vertical nystagmus, loss of

fast saccadic eye movements, hypermetric and hypometric saccades,

and impairment of upward vertical gaze. Facial fasciculations, facial

myokymia, lingual fasciculations without atrophy, ophthalmoparesis,

and ocular prominence are common early manifestations.

3425Ataxic Disorders CHAPTER 439

In type II MJD (ataxic type), true cerebellar deficits of dysarthria

and gait and extremity ataxia begin in the second to fourth decades

along with corticospinal and extrapyramidal deficits of spasticity,

rigidity, and dystonia. Type II is the most common form of MJD.

Ophthalmoparesis, upward vertical gaze deficits, and facial and lingual

fasciculations are also present. Type II MJD can be distinguished from

the clinically similar disorders SCA1 and SCA2.

Type III MJD (ataxic-amyotrophic type) presents in the fifth to

seventh decades with a pancerebellar disorder that includes dysarthria

and gait and extremity ataxia. Distal sensory loss involving pain, touch,

vibration, and position senses and distal atrophy are prominent, indicating the presence of peripheral neuropathy. The deep tendon reflexes

are depressed to absent, and there are no corticospinal or extrapyramidal findings.

The mean age of onset of symptoms in MJD is 25 years. Neurologic

deficits invariably progress and lead to death from debilitation within

15 years of onset, especially in patients with types I and II disease.

Usually, patients retain full intellectual function.

The major pathologic findings are variable loss of neurons and glial

replacement in the corpus striatum and severe loss of neurons in the

pars compacta of the substantia nigra. A moderate loss of neurons

occurs in the dentate nucleus of the cerebellum and in the red nucleus.

Purkinje cell loss and granule cell loss occur in the cerebellar cortex.

Cell loss also occurs in the dentate nucleus and in the cranial nerve

motor nuclei. Sparing of the inferior olives distinguishes MJD from

other dominantly inherited ataxias.

■ GENETIC CONSIDERATIONS

The gene for MJD maps to 14q24.3-q32. Unstable CAG repeat

expansions are present in the MJD gene coding for a polyglutaminecontaining protein named ataxin-3, or MJD-ataxin. An earlier age

of onset is associated with longer repeats. Alleles from normal individuals have between 12 and 37 CAG repeats, whereas MJD alleles have

60–84 CAG repeats. Polyglutamine-containing aggregates of ataxin-3

(MJD-ataxin) have been described in neuronal nuclei undergoing degeneration. MJD-ataxin codes for a ubiquitin protease, which is inactive due

to expanded polyglutamines. Proteosome function is impaired, resulting

in altered clearance of proteins and cerebellar neuronal loss.

■ SCA6

Genomic screening for CAG repeats in other families with autosomal

dominant ataxia and vibratory and proprioceptive sensory loss have

yielded another locus. Of interest is that different mutations in the

same gene for the α1A voltage-dependent calcium channel subunit

(CACNLIA4; also referred to as the CACNA1A gene) at 19p13 result in

different clinical disorders. CAG repeat expansions (21–27 in patients;

4–16 triplets in normal individuals) result in late-onset progressive

ataxia with cerebellar degeneration. Missense mutations in this gene

result in familial hemiplegic migraine. Nonsense mutations resulting

in termination of protein synthesis of the gene product yield hereditary

paroxysmal cerebellar ataxia or EA. Some patients with familial hemiplegic migraine develop progressive ataxia and also have cerebellar

atrophy.

■ SCA7

This disorder is distinguished from all other SCAs by the presence

of retinal pigmentary degeneration. The visual abnormalities first

appear as blue-yellow color blindness and proceed to frank visual

loss with macular degeneration. In almost all other respects, SCA7

resembles several other SCAs in which ataxia is accompanied by various noncerebellar findings, including ophthalmoparesis and extensor

plantar responses. The genetic defect is an expanded CAG repeat in

the SCA7 gene at 3p14-p21.1. The expanded repeat size in SCA7 is

highly variable. Consistent with this, the severity of clinical findings

varies from essentially asymptomatic to mild late-onset symptoms to

severe, aggressive disease in childhood with rapid progression. Marked

anticipation has been recorded, especially with paternal transmission.

The disease protein, ataxin-7, forms aggregates in nuclei of affected

neurons, as has also been described for SCA1 and SCA3/MJD. Ataxin 7

is a subunit of GCN5, a histone acetyltransferase-containing complex.

■ SCA8

This form of ataxia is caused by a CTG repeat expansion in an untranslated region of a gene on chromosome 13q21. There is marked maternal bias in transmission, perhaps reflecting contractions of the repeat

during spermatogenesis. The mutation is not fully penetrant. Symptoms include slowly progressive dysarthria and gait ataxia beginning at

~40 years of age with a range between 20 and 65 years. Other features

include nystagmus, leg spasticity, and reduced vibratory sensation.

Severely affected individuals are nonambulatory by the fourth to sixth

decades. MRI shows cerebellar atrophy. The mechanism of disease may

involve a dominant “toxic” effect occurring at the RNA level, as occurs

in myotonic dystrophy.

■ DENTATORUBROPALLIDOLUYSIAN ATROPHY

DRPLA has a variable presentation that may include progressive ataxia,

choreoathetosis, dystonia, seizures, myoclonus, and dementia. DRPLA

is due to unstable CAG triplet repeats in the open reading frame of a

gene named atrophin located on chromosome 12p12-ter. Larger expansions are found in patients with earlier onset. The number of repeats

is 49 in patients with DRPLA and ≤26 in normal individuals. Anticipation occurs in successive generations, with earlier onset of disease

in association with an increasing CAG repeat number in children who

inherit the disease from their father. One well-characterized family in

North Carolina has a phenotypic variant known as the Haw River syndrome, now recognized to be due to the DRPLA mutation.

■ EPISODIC ATAXIA

EA types 1 and 2 are two rare dominantly inherited disorders that

have been mapped to chromosomes 12p (a potassium channel gene,

KCNA1, Phe249Leu mutation) for type 1 and 19p for type 2. Patients

with EA-1 have brief episodes of ataxia with myokymia and nystagmus

that last only minutes. Startle, sudden change in posture, and exercise

can induce episodes. Acetazolamide or anticonvulsants may be therapeutic. Patients with EA-2 have episodes of ataxia with nystagmus that

can last for hours or days. Stress, exercise, or excessive fatigue may be

precipitants. Acetazolamide may be therapeutic and can reverse the relative intracellular alkalosis detected by magnetic resonance spectroscopy. Stop codon, nonsense mutations causing EA-2 have been found

in the CACNA1A gene, encoding the α1A voltage-dependent calcium

channel subunit (see “SCA6,” above).

■ AUTOSOMAL RECESSIVE ATAXIAS

Friedreich’s Ataxia This is the most common form of inherited

ataxia, comprising one-half of all hereditary ataxias. It can occur in a

classic form or in association with a genetically determined vitamin E

deficiency syndrome; the two forms are clinically indistinguishable.

SYMPTOMS AND SIGNS Friedreich’s ataxia presents before 25 years of

age with progressive staggering gait, frequent falling, and titubation.

The lower extremities are more severely involved than the upper ones.

Dysarthria occasionally is the presenting symptom; rarely, progressive

scoliosis, foot deformity, nystagmus, or cardiopathy is the initial sign.

The neurologic examination reveals nystagmus, loss of fast saccadic

eye movements, truncal titubation, dysarthria, dysmetria, and ataxia of

trunk and limb movements. Extensor plantar responses (with normal

tone in trunk and extremities), absence of deep tendon reflexes, and

weakness (greater distally than proximally) are usually found. Loss of

vibratory and proprioceptive sensation occurs. The median age of death

is 35 years. Women have a significantly better prognosis than men.

Cardiac involvement occurs in 90% of patients. Cardiomegaly, symmetric hypertrophy, murmurs, and conduction defects are reported.

Moderate mental retardation or psychiatric syndromes are present

in a small percentage of patients. A high incidence (20%) of diabetes

mellitus is found and is associated with insulin resistance and pancreatic β-cell dysfunction. Musculoskeletal deformities are common and

3426 PART 13 Neurologic Disorders

FIGURE 439-2 Sagittal magnetic resonance imaging (MRI) of the brain and spinal

cord of a patient with Friedreich’s ataxia, demonstrating spinal cord atrophy.

(Reproduced with permission from RN Rosenberg, P Khemani, in RN Rosenberg,

JM Pascual [eds]: Rosenberg’s Molecular and Genetic Basis of Neurological and

Psychiatric Disease, 5th ed. London, Elsevier, 2015.)

include pes cavus, pes equinovarus, and scoliosis. MRI of the spinal

cord shows atrophy (Fig. 439-2).

The primary sites of pathology are the spinal cord, dorsal root

ganglion cells, and the peripheral nerves. Slight atrophy of the cerebellum and cerebral gyri may occur. Sclerosis and degeneration occur

predominantly in the spinocerebellar tracts, lateral corticospinal tracts,

and posterior columns. Degeneration of the glossopharyngeal, vagus,

hypoglossal, and deep cerebellar nuclei is described. The cerebral cortex is histologically normal except for loss of Betz cells in the precentral

gyri. The peripheral nerves are extensively involved, with a loss of large

myelinated fibers. Cardiac pathology consists of myocytic hypertrophy

and fibrosis, focal vascular fibromuscular dysplasia with subintimal

or medial deposition of periodic acid-Schiff (PAS)-positive material,

myocytopathy with unusual pleomorphic nuclei, and focal degeneration of nerves and cardiac ganglia.

■ GENETIC CONSIDERATIONS

The classic form of Friedreich’s ataxia has been mapped to 9q13-

q21.1, and the mutant gene, frataxin, contains expanded GAA

triplet repeats in the first intron. There is homozygosity for

expanded GAA repeats in >95% of patients. Normal persons have 7–22

GAA repeats, and patients have 200–900 GAA repeats. A more varied

clinical syndrome has been described in compound heterozygotes who

have one copy of the GAA expansion and the other copy a point mutation in the frataxin gene. When the point mutation is located in the

region of the gene that encodes the amino-terminal half of frataxin, the

phenotype is milder, often consisting of a spastic gait, retained or exaggerated reflexes, no dysarthria, and mild or absent ataxia.

Patients with Friedreich’s ataxia have undetectable or extremely low

levels of frataxin mRNA, as compared with carriers and unrelated individuals; thus, disease appears to be caused by a loss of expression of the

frataxin protein. Frataxin is a mitochondrial protein involved in iron

homeostasis. Mitochondrial iron accumulation due to loss of the iron

transporter coded by the mutant frataxin gene results in a deficiency in

iron/sulfur clusters containing mitochondrial enzymes, decreased ATP

production, and accumulation of iron in the heart. Excess oxidized iron

results in turn in the oxidation of cellular components and irreversible

cell injury.

Two forms of hereditary ataxia associated with abnormalities in the

interactions of vitamin E (α-tocopherol) with very-low-density lipoprotein (VLDL) have been delineated. These are abetalipoproteinemia

(Bassen-Kornzweig syndrome) and ataxia with vitamin E deficiency

(AVED). Abetalipoproteinemia is caused by mutations in the gene

coding for the larger subunit of the microsomal triglyceride transfer

protein (MTP). Defects in MTP result in impairment of formation and

secretion of VLDL in liver. This defect results in a deficiency of delivery

of vitamin E to tissues, including the central and peripheral nervous

system, as VLDL is the transport molecule for vitamin E and other

fat-soluble substitutes. AVED is due to mutations in the gene for α-tocopherol transfer protein (α-TTP). These patients have an impaired

ability to bind vitamin E into the VLDL produced and secreted by the

liver, resulting in a deficiency of vitamin E in peripheral tissues. Hence,

either absence of VLDL (abetalipoproteinemia) or impaired binding of

vitamin E to VLDL (AVED) causes an ataxic syndrome. Once again,

a genotype classification has proved to be essential in sorting out the

various forms of the Friedreich’s disease syndrome, which may be clinically indistinguishable.

Ataxia Telangiectasia • SYMPTOMS AND SIGNS Patients with

ataxia telangiectasia (AT) present in the first decade of life with progressive telangiectatic lesions associated with deficits in cerebellar

function and nystagmus. The neurologic manifestations correspond

to those in Friedreich’s disease, which should be included in the differential diagnosis. Truncal and limb ataxia, dysarthria, extensor plantar

responses, myoclonic jerks, areflexia, and distal sensory deficits may

develop. There is a high incidence of recurrent pulmonary infections

and neoplasms of the lymphatic and reticuloendothelial system in

patients with AT. Thymic hypoplasia with cellular and humoral (IgA

and IgG2) immunodeficiencies, premature aging, and endocrine

disorders such as type 1 diabetes mellitus are described. There is an

increased incidence of lymphomas, Hodgkin’s disease, acute T-cell

leukemias, and breast cancer.

The most striking neuropathologic changes include loss of Purkinje,

granule, and basket cells in the cerebellar cortex as well as of neurons

in the deep cerebellar nuclei. The inferior olives of the medulla may

also have neuronal loss. There is a loss of anterior horn neurons in the

spinal cord and of dorsal root ganglion cells associated with posterior

column spinal cord demyelination. A poorly developed or absent thymus gland is the most consistent defect of the lymphoid system.

■ GENETIC CONSIDERATIONS

The gene for AT (the ATM gene) at 11q22-23 encodes a protein that

is similar to several yeast and mammalian phosphatidylinositol-3′

kinases involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. Defective DNA repair in AT fibroblasts

exposed to ultraviolet light has been demonstrated. The discovery

of ATM permits early diagnosis and identification of heterozygotes

who are at risk for cancer (e.g., breast cancer). Elevated serum alphafetoprotein and immunoglobulin deficiency are noted.

■ MITOCHONDRIAL ATAXIAS

Spinocerebellar syndromes have been identified with mutations in

mitochondrial DNA (mtDNA). Thirty pathogenic mtDNA point mutations and 60 different types of mtDNA deletions are known, several of

which cause or are associated with ataxia (Chap. 449).

TREATMENT

Ataxic Disorders

The most important goal in management of patients with ataxia is

to identify treatable disease entities. Mass lesions must be recognized promptly and treated appropriately. Autoimmune paraneoplastic disorders can often be identified by the clinical patterns of

disease that they produce, measurement of specific autoantibodies,

and uncovering the primary cancer; these disorders are often

refractory to therapy, but some patients improve following removal

of the tumor or immunotherapy (Chap. 94). Ataxia with antigliadin

antibodies and gluten-sensitive enteropathy may improve with a

gluten-free diet. Malabsorption syndromes leading to vitamin E

deficiency may lead to ataxia. The vitamin E deficiency form of

Friedreich’s ataxia must be considered, and serum vitamin E levels

measured. Vitamin E therapy is indicated for these rare patients.

Vitamin B1

 and B12 levels in serum should be measured, and the

3427 Disorders of the Autonomic Nervous System CHAPTER 440

The autonomic nervous system (ANS) innervates the entire neuraxis

and influences all organ systems. It regulates blood pressure (BP);

heart rate; sleep; and glandular, pupillary, bladder, and bowel function.

It maintains organ homeostasis and operates automatically; its full

importance becomes recognized only when ANS function is compromised, resulting in dysautonomia. Dysautonomia can result from a

primary disorder of the central or peripheral nervous system, or from

a nonneurogenic cause. Not infrequently more than one contributor

may be present, for example the additive effects of a medication in a

patient with diabetes mellitus, cardiovascular insufficiency, or normal

aging may be responsible. It is helpful to characterize dysautonomia

by its time course (acute, subacute, or chronic; progressive or static),

severity, and whether manifestations are continuous or intermittent.

Hypothalamic disorders that cause disturbances in homeostasis are

discussed in Chaps. 18 and 378.

ANATOMIC ORGANIZATION

The activity of the ANS is regulated by central neurons responsive

to diverse afferent inputs. After central integration of afferent information, autonomic outflow is adjusted to permit the functioning of

the major organ systems in accordance with the needs of the whole

organism. Connections between the cerebral cortex and the autonomic

centers in the brainstem coordinate autonomic outflow with higher

mental functions.

The preganglionic neurons of the parasympathetic nervous system

leave the central nervous system (CNS) in the third, seventh, ninth,

and tenth cranial nerves as well as the second and third sacral nerves,

whereas the preganglionic neurons of the sympathetic nervous system

exit the spinal cord between the first thoracic and the second lumbar

segments (Fig. 440-1). The autonomic preganglionic fibers are thinly

myelinated. The postganglionic neurons, located in ganglia outside the

CNS, give rise to the postganglionic unmyelinated autonomic nerves

that innervate organs and tissues throughout the body. Responses to

sympathetic and parasympathetic stimulation are frequently antagonistic (Table 440-1), reflecting highly coordinated interactions within

the CNS; the resultant changes in parasympathetic and sympathetic

activity provide more precise control of autonomic responses than

could be achieved by the modulation of a single system. In general, the

“fight or flight” response is a consequence of increased sympathetic

activity while the “rest and digest” reflects increased parasympathetic

activity.

Acetylcholine (ACh) is the preganglionic neurotransmitter for both

the sympathetic and parasympathetic divisions of the ANS as well as the

postganglionic neurotransmitter of the parasympathetic neurons; the

preganglionic receptors are nicotinic, and the postganglionic are muscarinic in type. Norepinephrine (NE) is the neurotransmitter of the

postganglionic sympathetic neurons, except for cholinergic neurons

innervating the eccrine sweat glands.

The gastrointestinal (GI) tract has long been described as part of

the sympathetic and parasympathetic nervous systems. However, it has

many unique characteristics such that it is now considered separately

as the enteric nervous system. Parasympathetic control of the GI system is through the craniospinal nerves (vagus and S2-S4 nerves) while

sympathetic efferent control is through the thoracolumbar region. The

enteric nervous system itself is made up of a series of ganglia that form

a network of plexuses with several hundred million cells (the equivalent of the number of cells in the spinal cord). Meissner’s (submucosal)

plexus, Auerbach’s (myenteric), Cajal’s (deep muscular), mucosal,

440 Disorders of the

Autonomic Nervous System

Richard J. Barohn, John W. Engstrom

vitamins administered to patients having deficient levels. Hypothyroidism is easily treated. The cerebrospinal fluid should be tested

for a syphilitic infection in patients with progressive ataxia and

other features of tabes dorsalis. Similarly, antibody titers for Lyme

disease and Legionella should be measured and appropriate antibiotic therapy should be instituted in antibody-positive patients.

Aminoacidopathies, leukodystrophies, urea-cycle abnormalities,

and mitochondrial encephalomyopathies may produce ataxia, and

some dietary or metabolic therapies are available for these disorders. The deleterious effects of phenytoin and alcohol on the cerebellum are well known, and these exposures should be avoided in

patients with ataxia of any cause.

There is no proven therapy for any of the autosomal dominant

ataxias (SCA1 to SCA43). There is preliminary evidence that idebenone, a free-radical scavenger, can improve myocardial hypertrophy in patients with classic Friedreich’s ataxia; there is no current

evidence, however, that it improves neurologic function. A small

preliminary study in a mixed population of patients with different

inherited ataxias raised the possibility that the glutamate antagonist

riluzole may offer modest benefit. Iron chelators and antioxidant

drugs are potentially harmful in Friedreich’s patients because they

may increase heart muscle injury. Acetazolamide can reduce the

duration of symptoms of EA. At present, identification of an at-risk

person’s genotype, together with appropriate family and genetic

counseling, can reduce the incidence of these cerebellar syndromes

in future generations (Chap. 467).

■ GENETIC DIAGNOSTIC LABORATORIES

1. Baylor College of Medicine; Houston, Texas, 1-713-798-6522

http://www.bcm.edu/genetics/index.cfm?pmid=21387

2. GeneDx

http://www.genedx.com

3. Transgenomic, 1-877-274-9432

http://www.transgenomic.com/labs/neurology

■ GLOBAL FEATURES

Ataxias with autosomal dominant, autosomal recessive, X-linked,

or mitochondrial forms of inheritance are present on a worldwide

basis. Machado-Joseph disease (SCA3) (autosomal dominant) and

Friedreich’s ataxia (autosomal recessive) are the most common types

in most populations. Genetic markers are now commercially available

to precisely identify the genetic mutation for correct diagnosis and

also for family planning. Early detection of asymptomatic preclinical

disease can reduce or eliminate the inherited form of ataxia in some

families on a global, worldwide basis.

■ FURTHER READING

Anheim M et al: The autosomal recessive cerebellar ataxias. N Engl J

Med 16:636, 2012.

Jacobi H et al: Long-term disease progression in spinocerebellar

ataxia types 1, 2, 3, and 6: A longitudinal cohort study. Lancet Neurol

14:1101, 2015.

Martin D, Hayden M: Role of repeats in protein clearance. Nature

545:33, 2017.

Paulson HL et al: Polyglutamine spinocerebellar ataxias—from genes

to potential therapy. Nat Rev Neurosci 18:613; 2017.

Romano S et al: Riluzole in patients with hereditary cerebellar ataxia:

A randomised, double-blind, placebo-controlled trial. Lancet Neurol

14:985, 2015.

3428 PART 13 Neurologic Disorders

T1

III Ciliary

ganglion Eye

Lacrimal gland

Submandibular

and sublingual

salivary glands

Parotid gland

Heart

Lungs

Stomach

Small

intestine

Suprarenal

gland

Kidney

Colon

Rectum

Urinary

bladder

Pelvic splanchnic

nerve

Inf.

mes.

g.

Renal g.

Sup.

mes.

g.

Celiac g.

Otic g.

Sex organs

VII

IX

X

T2

T3

T4

T5

T6

T7

T8

T9

T10

T11

T12

L1

L2

S2

S3

S4

Parasympathetic nerves

Preganglionic fibers

Postganglionic fibers

Sympathetic nerves

Preganglionic fibers

Postganglionic fibers

FIGURE 440-1 Schematic representation of the autonomic nervous system. (Adapted with permission from R Snell: Clinical Neuroanatomy, 7th ed. Philadelphia: Wolters

Kluwer Health/Lippincott Williams & Wilkins, 2009.)

3429 Disorders of the Autonomic Nervous System CHAPTER 440

TABLE 440-1 Effects of Sympathetic and Parasympathetic Systems on

Various Effector Organs

SYMPATHETIC PARASYMPATHETIC

Pupil Pupillodilation (alpha) Pupilloconstriction

Accommodation Decreased Increased

Heart Positive chronotropic effect

(beta)

Positive inotropic effect

(beta)

Negative chronotropic

effect

Negative inotropic effect

Arteries Vasoconstriction (alpha)

Vasodilation (beta)

Vasodilation

Veins Vasoconstriction (alpha)

Vasoconstriction (beta)

Tracheobronchial

tree

Bronchodilation (beta) Bronchoconstriction

Increased bronchial gland

secretions

Gastrointestinal

tract

Decreased motility (beta)

Contraction of sphincters

(alpha)

Increased motility

Relaxation of sphincter

Bladder Detrusor relaxation (beta)

Contraction of sphincter

(alpha)

Detrusor contraction

Relaxation of sphincter

Salivary glands Scant, thick, viscid saliva

(alpha)

Copious, thin, watery saliva

Skin Piloerection (cutis anserina) No piloerection

Sweat glands Increased secretion

(cholinergic)

Decreased secretion

Genitalia Ejaculation Ejaculation/Erection

Adrenal medulla Catecholamine release

Glycogen Glycogenolysis (alpha and

beta)

Lipolysis (alpha and beta)

Glycogen synthesis

Source: Reproduced with permission from WW Campbell: The autonomic nervous

system, in DeJong’s The Neurologic Examination, 8th ed. Wolters Kluwer, 2020.

and submucosal plexuses comprise the majority of nerves within the

enteric nervous system. Numerous neurotransmitters have now been

identified within the enteric nervous system, with many neurons containing both primary and co-transmitter neurotransmitters.

CLINICAL EVALUATION

■ CLASSIFICATION

Disorders of the ANS may result from pathology of either the CNS

or the peripheral nervous system (PNS) (Table 440-2). Signs and

symptoms may result from interruption of the afferent limb, CNS processing centers, or efferent limb of reflex arcs controlling autonomic

responses. For example, a lesion of the medulla produced by a posterior

fossa tumor can impair BP responses to postural changes and result

in orthostatic hypotension (OH). OH can also be caused by lesions of

the afferent limb of the baroreflex arc (e.g., radiation or congenital disease), spinal cord, or peripheral vasomotor nerve fibers (e.g., diabetic

and other neuropathies). Lesions of the efferent limb cause the most

consistent and severe OH. The site of reflex interruption is usually

established by the clinical context in which the dysautonomia arises,

combined with judicious use of ANS testing and neuroimaging studies. The presence or absence of CNS signs, association with sensory or

motor polyneuropathy, medical illnesses, medication use, and family

history are important considerations. Some syndromes do not fit easily

into any classification scheme.

■ SYMPTOMS OF AUTONOMIC DYSFUNCTION

Clinical manifestations can result from loss of function, overactivity, or

dysregulation of autonomic circuits. Disorders of autonomic function

should be considered in patients with unexplained OH, syncope, sleep

dysfunction, altered sweating (hyperhidrosis or hypohidrosis), impotence, constipation, or other GI symptoms (bloating, nausea, vomiting

of old food, diarrhea), or bladder disorders (urinary frequency, hesitancy, or incontinence). Symptoms may be widespread or regional

in distribution. An autonomic history focuses on systemic functions

(orthostatic symptoms, BP, heart rate, sleep, fever, hypothermia,

sweating) and involvement of individual organ systems (pupils, bowel,

bladder, sexual function). Specific symptoms of orthostatic intolerance

are diverse (Table 440-3).

Early autonomic symptoms may be overlooked. Impotence,

although not specific for autonomic failure, often heralds autonomic

failure in men and may precede other symptoms by years (Chap.

397). A decrease in the frequency of spontaneous early-morning erections may occur months before loss of nocturnal penile tumescence

and development of total impotence. Bladder dysfunction may appear

early in men and women, particularly in those with a CNS etiology.

Cold feet may indicate increased peripheral vasomotor constriction,

although this symptom is a very common complaint among healthy

individuals as well. Brain and spinal cord disease above the level of the

lumbar spine results first in urinary frequency and small bladder volumes and eventually in urinary incontinence (upper motor neuron or

spastic bladder). By contrast, PNS disease of autonomic nerve fibers

results in large bladder volumes, urinary frequency, and overflow

incontinence (lower motor neuron or flaccid bladder). Measurements of bladder volume (postvoid residual), or urodynamic studies,

are useful tests for distinguishing between upper and lower motor

neuron bladder dysfunction in the early stages of dysautonomia. GI

autonomic dysfunction typically presents as progressively severe constipation. Diarrhea may develop (typically in diabetes mellitus) due

to many reasons including rapid transit of contents, uncoordinated

small-bowel motor activity, an osmotic basis from bacterial overgrowth associated with small-bowel stasis, or anorectal dysfunction

with diminished sphincter control and increased intestinal secretion.

Impaired glandular secretory function may cause difficulty with food

intake due to decreased salivation or eye irritation due to decreased

lacrimation. Loss of sweat function (anhidrosis), a critical element

of thermoregulation, may result in hyperthermia. Patients with a

length-dependent neuropathy may present with distal anhidrosis but

the primary symptom may be proximal hyperhidrosis that occurs

to maintain thermoregulation (Chap. 18). Lack of sweating after a

hot bath, during exercise, or on a hot day can suggest sudomotor

failure.

OH (also called postural hypotension) is perhaps the most common

and disabling feature of autonomic dysfunction. There are numerous

causes of OH (e.g., medications, anemia, dehydration, or volume

depletion), but when the OH is specifically due to dysfunction of

the ANS it is referred to as neurogenic OH. The prevalence of OH

is relatively high, especially when OH associated with aging and

diabetes mellitus is included (Table 440-4). OH can cause a variety

of symptoms, including dimming or loss of vision, light-headedness,

diaphoresis, diminished hearing, pallor, weakness, and shortness

of breath. Syncope results when the drop in BP impairs cerebral

perfusion. Other manifestations of impaired baroreflexes are supine

hypertension, a heart rate that is fixed regardless of posture, postprandial hypotension, and an excessively high nocturnal BP. Many

patients with OH have a preexisting diagnosis of hypertension or have

concomitant supine hypertension, reflecting the great importance of

baroreflexes in maintaining postural and supine normotension. The

appearance of OH in patients receiving antihypertensive treatment

may indicate overtreatment or the onset of an autonomic disorder.

The most common causes of OH are not neurologic in origin (Table

440-5); these must be distinguished from the neurogenic causes. The

mortality rates of nonneurogenic OH are similar to that of the general

population while neurogenic OH carries a three- to sevenfold higher

mortality rate. Neurocardiogenic and cardiac causes of syncope are

considered in Chap. 21.

3430 PART 13 Neurologic Disorders

TABLE 440-4 Prevalence of Orthostatic Hypotension in

Different Situations

DISORDER PREVALENCE

Aging 14–20%

Diabetic neuropathy 10%

Other autonomic neuropathies >60%

Multiple-system atrophy >90%

Pure autonomic failure >95%

TABLE 440-3 Symptoms of Orthostatic Intolerance

Light-headedness (dizziness) 88%

Weakness or tiredness 72%

Cognitive difficulty (thinking/

concentrating)

47%

Blurred vision 47%

Tremulousness 38%

Vertigo 37%

Pallor 31%

Anxiety 29%

Palpitations 26%

Clammy feeling 19%

Nausea 18%

Source: Reproduced with permission from PA Low et al: Prospective evaluation of

clinical characteristics of orthostatic hypotension. Mayo Clinic Proceedings 70:617,

1995.

TABLE 440-2 Classification of Clinical Autonomic Disorders

I. Autonomic Disorders with Brain Involvement

A. Associated with multisystem degeneration

1. Multisystem degeneration: autonomic failure clinically prominent

a. Multiple-system atrophy (MSA)

b. Parkinson’s disease with autonomic failure

c. Diffuse Lewy body disease with autonomic failure

2. Multisystem degeneration: autonomic failure clinically not usually

prominent

a. Parkinson’s disease without autonomic failure

b. Other extrapyramidal disorders (inherited spinocerebellar

atrophies, progressive supranuclear palsy, corticobasal

degeneration, Machado-Joseph disease, fragile X syndrome

[FXTAS])

B. Unassociated with multisystem degeneration (focal CNS disorders)

1. Disorders mainly due to cerebral cortex involvement

a. Frontal cortex lesions causing urinary/bowel incontinence

b. Focal seizures (temporal lobe or anterior cingulate)

c. Cerebral infarction of the insula

2. Disorders of the limbic and paralimbic circuits

a. Shapiro’s syndrome (agenesis of corpus callosum, hyperhidrosis,

hypothermia)

b. Autonomic seizures

c. Limbic encephalitis

3. Disorders of the hypothalamus

a. Thiamine deficiency (Wernicke-Korsakoff syndrome)

b. Diencephalic syndrome

c. Neuroleptic malignant syndrome

d. Serotonin syndrome

e. Fatal familial insomnia

f. Antidiuretic hormone (ADH) syndromes (diabetes insipidus, inappropriate ADH

secretion)

g. Disturbances of temperature regulation (hyperthermia, hypothermia)

h. Disturbances of sexual function

i. Disturbances of appetite

j. Disturbances of BP/HR and gastric function

k. Horner’s syndrome

4. Disorders of the brainstem and cerebellum

a. Posterior fossa tumors

b. Syringobulbia and Arnold-Chiari malformation

c. Disorders of BP control (hypertension, hypotension)

d. Cardiac arrhythmias

e. Central sleep apnea

f. Baroreflex failure

g. Horner’s syndrome

h. Vertebrobasilar and lateral medullary (Wallenberg’s) syndromes

i. Brainstem encephalitis

II. Autonomic Disorders with Spinal Cord Involvement

A. Traumatic quadriplegia

B. Syringomyelia

C. Subacute combined degeneration

D. Multiple sclerosis and neuromyelitis optica

E. Amyotrophic lateral sclerosis

F. Tetanus

G. Stiff-person syndrome

H. Spinal cord tumors

III. Autonomic Neuropathies

A. Acute/subacute autonomic neuropathies

a. Subacute autoimmune autonomic ganglionopathy (AAG)

b. Subacute paraneoplastic autonomic neuropathy

c. Guillain-Barré syndrome

d. Botulism

e. Porphyria

f. Drug-induced autonomic neuropathies—stimulants, drug

withdrawal, vasoconstrictor, vasodilators, beta-receptor antagonists,

beta-agonists

g. Toxin-induced autonomic neuropathies

h. Subacute cholinergic neuropathy

B. Chronic peripheral autonomic neuropathies

1. Distal small fiber neuropathy—cryptogenic sensory polyneuropathy (CSPN)

2. Combined sympathetic and parasympathetic failure

a. Amyloid

b. Diabetic autonomic neuropathy

c. AAG (paraneoplastic and idiopathic)

d. Sensory neuronopathy with autonomic failure

e. Familial dysautonomia (Riley-Day syndrome)

f. Diabetic, uremic, or nutritional deficiency

g. Geriatric dysautonomia (age >80 years)

h. Hereditary sensory and autonomic neuropathy

i. HIV-related autonomic neuropathy

3. Disorders of orthostatic intolerance: reflex syncope; POTS; prolonged bed rest;

space flight; chronic fatigue

Abbreviations: BP, blood pressure; CNS, central nervous system; HR, heart rate; POTS, postural orthostatic tachycardia syndrome.

3431 Disorders of the Autonomic Nervous System CHAPTER 440

TABLE 440-5 Nonneurogenic Causes of Orthostatic Hypotension

Cardiac Pump Failure

• Myocardial infarction

• Myocarditis

• Constrictive pericarditis

• Aortic stenosis

• Tachyarrhythmias

• Bradyarrhythmias

• Venous obstruction

Reduced Intravascular Volume

• Straining or heavy lifting, urination, defecation

• Dehydration

• Diarrhea, emesis

• Hemorrhage

• Burns

• Salt-losing nephropathy

• Adrenal insufficiency

• Diabetes insipidus

Metabolic

• Adrenocortical insufficiency

• Hypoaldosteronism

• Pheochromocytoma

• Severe potassium depletion

Venous Pooling

• Alcohol

• Postprandial dilation of splanchnic vessel beds

• Vigorous exercise with dilation of skeletal vessel beds

• Heat: hot environment, hot showers and baths, fever

• Prolonged recumbency or standing

• Sepsis

Medications

• Antihypertensives

• Diuretics

• Vasodilators: nitrates, hydralazine

• Alpha- and beta-blocking agents

• Central nervous system sedatives: barbiturates, opiates

• Tricyclic antidepressants

• Phenothiazines

TABLE 440-6 Some Drugs That Affect Autonomic Function

SYMPTOM DRUG CLASS SPECIFIC EXAMPLES

Impotence Opioids Tylenol #3

Anabolic steroids —

Some antiarrhythmics Prazosin

Some antihypertensives Clonidine

Some diuretics Benazepril

Some SSRIs Venlafaxine

Urinary retention Opioids Fentanyl

Decongestants Brompheniramine

Diphenhydramine

Diaphoresis Some antihypertensives Amlodipine

Some SSRIs Citalopram

Opioids Morphine

Abbreviations: CCBs, calcium channel blockers; HCTZ, hydrochlorothiazide; SSRIs,

selective serotonin reuptake inhibitors.

APPROACH TO THE PATIENT

Orthostatic Hypotension and Other ANS Disorders

The first step in the evaluation of symptomatic OH is the exclusion

of treatable causes. The history should include a review of medications that may affect the ANS (Table 440-6). The main classes

of drugs that may cause OH are diuretics, antihypertensive agents

(preload reducers, vasodilators, negative inotropic or chronotropic

agents), antidepressants (tricyclic antidepressants and SSRIs), ethanol, opioids, insulin, dopamine agonists, and barbiturates. However,

the precipitation of OH by medications may also be the first sign

of an underlying autonomic disorder. The history may reveal an

underlying cause for symptoms (e.g., diabetes, Parkinson’s disease)

or specific underlying mechanisms (e.g., cardiac pump failure,

reduced intravascular volume). The relationship of symptoms to

meals (splanchnic pooling), standing on awakening in the morning

(intravascular volume depletion), ambient warming (vasodilatation),

or exercise (muscle arteriolar vasodilatation) should be sought.

Standing time to first symptom and to presyncope (Chap. 21) should

be followed for management.

Physical examination includes measurement of supine and

standing pulse and BP. OH is defined as a sustained drop in systolic

(≥20 mmHg) or diastolic (≥10 mmHg) BP after 3 min of standing.

In nonneurogenic causes of OH (such as hypovolemia), the BP

drop is accompanied by a compensatory increase in heart rate of

>15 beats/min. In neurogenic OH, the pulse fails to rise despite the

drop in blood pressure. A clue that the patient has neurogenic OH

is the aggravation or precipitation of OH by autonomic stressors

(a meal, hot bath, or exercise). Neurologic examination should

include mental status (neurodegenerative disorders such as Lewy

body dementia can be accompanied by significant dysautonomia),

cranial nerves (abnormal pupils with Horner’s or Adie’s syndrome),

motor tone (parkinsonian syndromes), and motor strength and

sensation (polyneuropathies). In patients without a clear diagnosis initially, follow-up evaluations every few months or whenever

symptoms worsen may reveal the underlying cause.

AUTONOMIC TESTING

Autonomic function tests are helpful to document and localize

abnormalities when findings on history and examination are inconclusive; to detect subclinical involvement; or to follow the course of

an autonomic disorder.

Heart Rate Variation With Deep Breathing This tests the parasympathetic component of cardiovascular reflexes via the vagus nerve.

Results are influenced by multiple factors including the subject’s

position (recumbent, sitting, or standing), rate and depth of respiration (6 breaths per minute and a forced vital capacity [FVC] >1.5 L

are optimal), age, medications, weight, and degree of hypocapnia.

Interpretation of results requires comparison of test data with results

from age-matched controls collected under identical test conditions.

For example, the lower limit of normal heart rate variation with

deep breathing in persons <20 years of age is >15–20 beats/min, but

for persons aged >60 it is 5–8 beats/min. Heart rate variation with

deep breathing (respiratory sinus arrhythmia) is abolished by the

muscarinic ACh receptor antagonist atropine but is unaffected by

sympathetic postganglionic blockade (e.g., propranolol).

Valsalva Response This response (Table 440-7) assesses the

integrity of the baroreflex control of heart rate (parasympathetic) and BP (sympathetic adrenergic). Under normal conditions,

increases in BP at the carotid bulb trigger a reduction in heart rate

(increased vagal tone), and decreases in BP trigger an increase in

heart rate (reduced vagal tone). The Valsalva response is tested in

the supine position. The subject exhales against a closed glottis (or

into a manometer maintaining a constant expiratory pressure

of 40 mmHg) for 15 s while measuring changes in heart rate and

beat-to-beat BP. Without directly measuring expiratory pressure,

heart rate, and beat-to-beat blood pressure, the Valsalva maneuver

cannot be interpreted correctly. There are four phases of the BP and

heart rate response to the Valsalva maneuver. Phases I and III are

mechanical and related to changes in intrathoracic and intraabdominal pressure. In early phase II, reduced venous return results in a

3432 PART 13 Neurologic Disorders

TABLE 440-7 Normal Blood Pressure and Heart Rate Changes During the Valsalva Maneuver

PHASE MANEUVER BLOOD PRESSURE HEART RATE COMMENTS

I Forced expiration against a

partially closed glottis

Rises; aortic compression from raised

intrathoracic pressure

Decreases Mechanical

II early Continued expiration Falls; decreased venous return to the heart Increases (reflex tachycardia) Reduced vagal tone

II late Continued expiration Rises; reflex increase in peripheral vascular

resistance

Increases at slower rate Requires intact efferent

sympathetic response

III End of expiration Falls; increased capacitance of pulmonary

bed

Increases further Mechanical

IV Recovery Rises; persistent vasoconstriction and

increased cardiac output

Compensatory bradycardia Requires intact efferent

sympathetic response

TABLE 440-8 Neural Pathways Underlying Some Standardized

Autonomic Tests

TEST EVALUATED PROCEDURE AUTONOMIC FUNCTION

HRDB 6 deep breaths/min Cardiovagal

(parasympathetic) function

Valsalva ratio Expiratory pressure,

40 mmHg for 10–15 s

Cardiovagal

(parasympathetic) function

QSART Axon-reflex test 4 limb

sites

Postganglionic (sympathetic

cholinergic) sudomotor

function

BPBB to VM BPBB response to VM Sympathetic adrenergic

function: baroreflex

adrenergic control of vagal

and vasomotor function

HUT BPBB and heart rate

response to HUT

Sympathetic adrenergic

and cardiovagal

(parasympathetic)

responses to HUT

Abbreviations: BPBB, beat-to-beat blood pressure; HRDB, heart rate response to

deep breathing; HUT, head-up tilt; QSART, quantitative sudomotor axon reflex test;

VM, Valsalva maneuver.

fall in stroke volume and BP, counteracted by a combination of reflex

tachycardia and increased total peripheral resistance. Increased

total peripheral resistance arrests the BP drop ~5–8 s after the onset

of the maneuver. Late phase II begins with a progressive rise in

BP toward or above baseline. Venous return and cardiac output

return to normal in phase IV. Persistent peripheral arteriolar

vasoconstriction and increased cardiac adrenergic tone result in a

temporary BP overshoot and phase IV bradycardia (mediated by the

baroreceptor reflex). Abnormalities in BP during phase II recovery

or phase IV overshoot suggest sympathetic adrenergic dysfunction.

Autonomic parasympathetic function during the Valsalva

maneuver is measured using heart rate changes. The Valsalva ratio

is defined as the maximum phase II tachycardia divided by the minimum phase IV bradycardia (Table 440-8) and is predominantly a

measure of parasympathetic function.

Sudomotor Function Sweating is induced by release of ACh from

sympathetic postganglionic fibers. The quantitative sudomotor

axon reflex test (QSART) is a measure of regional autonomic

function mediated by ACh-induced sweating. A reduced or absent

response indicates a lesion of the postganglionic sudomotor axon.

For example, sweating may be reduced in the feet as a result of

distal polyneuropathy (e.g., diabetes). The thermoregulatory sweat

test (TST) is a qualitative measure of global sweat production in

response to an elevation of body temperature under controlled

conditions. An indicator powder placed on the anterior surface of

the body changes color with sweat production during temperature

elevation. The pattern of color change measures the integrity of

both the preganglionic and postganglionic sudomotor function.

A postganglionic lesion is present if both QSART and TST show

absent sweating. In a preganglionic lesion, the QSART is normal

but TST shows anhidrosis.

Orthostatic BP Recordings Beat-to-beat BP measurements determined in supine, 70° tilt, and tilt-back positions are useful to quantitate orthostatic failure of BP control. Allow a 20-min period of rest

in the supine position before assessing changes in BP during tilting.

The BP change combined with heart rate monitoring is useful for the

evaluation of patients with suspected OH or unexplained syncope.

Tilt Table Testing For Syncope The great majority of patients with

syncope do not have autonomic failure. Tilt table testing can be

used to make the diagnosis of vasovagal syncope with sensitivity,

specificity, and reproducibility. A standardized protocol is used that

specifies the tilt apparatus, tilt angle, and duration of tilt. A passive

phase for 30–40 min with a tilt angle at 60°–70° can identify reflex

syncope, psychogenic syncope, or be nondiagnostic. Pharmacologic

provocation of syncope (with intravenous, sublingual, or spray

nitroglycerin) is controversial because it increases sensitivity at the

cost of specificity. Recommendations for the performance of tilt

studies for syncope have been incorporated in consensus guidelines.

SPECIFIC SYNDROMES OF ANS

DYSFUNCTION

■ MULTIPLE-SYSTEM ATROPHY

Multiple-system atrophy (MSA) is an entity that comprises autonomic

failure (OH or a neurogenic bladder) and either parkinsonism (MSA-p)

or a cerebellar syndrome (MSA-c). MSA-p is the more common form;

the parkinsonism is atypical in that there is more symmetric motor

involvement than in Parkinson’s disease (PD; Chap. 435), tremor is

not as prominent, and there is a poor or only transient response to

levodopa. Symptomatic OH within 1 year of onset of parkinsonism is

suggestive of MSA-p. There is a very high frequency of impotence in

men. Although autonomic abnormalities are common in advanced

PD, the severity and distribution of autonomic failure are more severe

and generalized in MSA. Brain MRI is a useful diagnostic adjunct: in

MSA-p, iron deposition in the striatum may be evident as T2 hypointensity, and in MSA-c, cerebellar atrophy is present with a characteristic

T2 hyperintense signal (“hot cross bun” sign) in the pons (Fig. 440-2).

However, these MRI findings are typically present only with advanced

disease. Cardiac postganglionic adrenergic innervation, measured

by uptake of fluorodopamine on positron emission tomography, is

markedly impaired in the dysautonomia of PD but is usually normal

in MSA. Neuropathologic changes include neuronal loss and gliosis

in many CNS regions, including the brainstem, cerebellum, striatum,

and intermediolateral cell column of the thoracolumbar spinal cord.

Glial cytoplasmic inclusions that stain positively (for Lewy bodies) are

present primarily in oligodendrocytes in MSA, in contrast to neuronal

inclusions in PD. Furthermore, transfer of brain extracts from MSA

patients into susceptible mice resulted in widespread α-synuclein

aggregate formation and neurodegeneration, consistent with a prion

mechanism.

MSA is uncommon, with a prevalence estimated at 2–5 per 100,000

individuals. Onset is typically in the mid-fifties, men are slightly more

often affected than women, and most cases are sporadic. The diagnosis should be considered in adults aged >30 years who present with

3433 Disorders of the Autonomic Nervous System CHAPTER 440

OH or urinary incontinence and either parkinsonism that is poorly

responsive to dopamine replacement or a cerebellar syndrome. MSA

generally progresses relentlessly to death 7–10 years after onset, but

survival beyond 15 years has been reported. MSA-p is more prevalent

in Western countries, while MSA-c is more common in Japan. Factors

that predict a worse prognosis include early autonomic dysfunction,

rapid progression of disability, bladder dysfunction, female gender, the

MSA-p subtype, and an older age at onset. Management is symptomatic for neurogenic OH (see below), sleep disorders including laryngeal

stridor, GI, and urinary dysfunction. GI management includes frequent

small meals, soft diet, stool softeners, and bulk agents. Gastroparesis

is difficult to treat; metoclopramide stimulates gastric emptying but

worsens parkinsonism by blocking central dopamine receptors. The

peripheral dopamine (D2

 and D3

) receptor antagonist domperidone has

been used in patients with various GI conditions in many countries,

and although not available in the United States, it can be obtained

through the U.S. Food and Drug Administration’s (FDA) Expanded

Access to Investigational Drugs program.

Autonomic dysfunction is also a common feature in dementia

with Lewy bodies (Chap. 434), with the severity usually intermediate between that found in MSA and PD. In multiple sclerosis (MS;

Chap. 444), autonomic complications reflect the CNS location of MS

involvement and generally worsen with disease duration and disability, but are generally a secondary complaint and not of the severity

seen in the synucleinopathies.

■ SPINAL CORD

Spinal cord lesions from any cause can result in focal autonomic

deficits or autonomic hyperreflexia (e.g., spinal cord transection or

hemisection) affecting bowel, bladder, sexual, temperature-regulation,

or cardiovascular functions. Quadriparetic patients exhibit both supine

hypertension and OH after upward tilting. Autonomic dysreflexia

describes a dramatic increase in BP in patients with traumatic spinal

cord lesions above the T6 level, often in response to irritation of the

bladder, skin, or muscles. Cord injury below T6 allows for compensatory splanchnic vasodilation and prevents autonomic dysreflexia.

The triggers may be clinically silent because perception of painful

sensations arising from structures innervated below the level of a spinal cord lesion is often blunted or absent. A distended bladder, often

from an obstructed Foley catheter or a urinary infection, is a common

trigger of dysreflexia. Associated symptoms can include facial flushing, headache, hypertension, or piloerection. Potential complications

include intracranial vasospasm or hemorrhage, cardiac arrhythmia,

and death. Awareness of the syndrome, identifying the trigger, and

careful monitoring of BP during procedures in patients with acute or

chronic spinal cord injury are essential. In patients with supine hypertension, BP can be lowered by tilting the head upward or sitting the

patient up. Vasodilator drugs may be used to treat acute elevations in

BP. Clonidine can be used prophylactically to reduce the hypertension

resulting from bladder stimulation. Dangerous increases or decreases

in body temperature may result from an inability to sense heat or cold

exposure or control peripheral vasoconstriction or sweating below the

level of the spinal cord injury.

■ PERIPHERAL NERVE AND NEUROMUSCULAR

JUNCTION DISORDERS

Peripheral neuropathies (Chap. 446) are the most common cause of

chronic autonomic insufficiency. Polyneuropathies that affect small

myelinated and unmyelinated fibers of the sympathetic and parasympathetic nerves commonly occur in diabetes mellitus, amyloidosis,

chronic alcoholism, porphyria, idiopathic small-fiber polyneuropathy,

and Guillain-Barré syndrome. Neuromuscular junction disorders with

autonomic involvement include botulism and Lambert-Eaton syndrome (Chap. 448).

Diabetes Mellitus The presence of autonomic neuropathy in

patients with diabetes increases the mortality rate 1.5- to 3-fold, even

after adjusting for other cardiovascular risk factors. Estimates of 5-year

mortality risk among these patients are 15–53%. Although many deaths

are due to secondary vascular disease, there are patients who specifically suffer cardiac arrest due to autonomic neuropathy. The autonomic

involvement is also predictive of other complications including renal

disease, stroke, and sleep apnea. Tight glycemic control with insulin

significantly reduces the long-term risk of autonomic cardiovascular

neuropathy. Diabetes mellitus is discussed in Chaps. 403–405.

Amyloidosis Autonomic neuropathy occurs in both sporadic

and familial forms of amyloidosis. The AL (immunoglobulin light

chain) type is associated with primary amyloidosis or amyloidosis

secondary to multiple myeloma. The amyloid transthyretin (TTR)

type, with transthyretin as the primary protein component, is responsible for the most common form of inherited amyloidosis. Although

patients usually present with a distal sensorimotor polyneuropathy

accompanied by autonomic insufficiency that can precede the development of the polyneuropathy or occur in isolation. The diagnosis

can be made by protein electrophoresis of blood and urine, tissue

biopsy (abdominal fat pad, rectal mucosa, or sural nerve) to search

for amyloid deposits, and genetic testing for transthyretin mutations

in familial cases. Recently two gene-modulating therapies have been

shown to be effective in hereditary amyloidosis from TTR mutations.

Death is usually due to cardiac or renal involvement. Postmortem

studies reveal amyloid deposition in many organs, including two

sites that contribute to autonomic failure: intraneural blood vessels

and autonomic ganglia. Pathologic examination reveals a loss of both

unmyelinated and myelinated nerve fibers. Amyloidosis is discussed

in Chap. 112.

Alcoholic Neuropathy Abnormalities in parasympathetic vagal

and efferent sympathetic function are usually mild in alcoholic

polyneuropathy. OH is usually due to brainstem involvement, rather

than injury to the PNS. Impotence is a major problem, but concurrent

gonadal hormone abnormalities may play a role in this symptom.

Clinical symptoms of autonomic failure generally appear only when the

stocking-glove polyneuropathy is severe, and there is usually coexisting

Wernicke’s encephalopathy (Chap. 307). Autonomic involvement may

contribute to the high mortality rates associated with alcoholism. Alcoholism is discussed in Chap. 453.

Porphyria Autonomic dysfunction is most extensively documented

in acute intermittent porphyria but can also occur with variegate porphyria and hereditary coproporphyria. Autonomic symptoms include

tachycardia, sweating, urinary retention, abdominal pain, nausea and

vomiting, insomnia, hypertension, and (less commonly) hypotension. Another prominent symptom is anxiety. Abnormal autonomic

FIGURE 440-2 Multiple-system atrophy, cerebellar type (MSA-c). Axial T2-weighted

magnetic resonance image at the level of the pons shows a characteristic

hyperintense signal, the “hot cross bun” sign (arrows). This appearance can also

be seen in some spinocerebellar atrophies, as well as other neurodegenerative

conditions affecting the brainstem.

3434 PART 13 Neurologic Disorders

function can occur both during acute attacks and during remissions.

Elevated catecholamine levels during acute attacks correlate with the

degree of tachycardia and hypertension that is present. Porphyria is

discussed in Chap. 416.

Guillain-Barré Syndrome BP fluctuations and arrhythmias from

autonomic instability can be severe. It is estimated that 2–10% of

patients with severe Guillain-Barré syndrome suffer fatal cardiovascular collapse. GI autonomic involvement, sphincter disturbances, abnormal sweating, and pupillary dysfunction can also occur. Demyelination

has been described in the vagus and glossopharyngeal nerves, the

sympathetic chain, and the white rami communicantes. Interestingly,

the degree of autonomic involvement appears to be independent of the

severity of motor or sensory neuropathy. Acute autonomic and sensory

neuropathy is a variant that spares the motor system and presents with

neurogenic OH and varying degrees of sensory loss. It is treated similarly to Guillain-Barré syndrome, but prognosis is less favorable, with

persistent severe sensory deficits and variable degrees of OH in many

patients. Guillain-Barré Syndrome is discussed in Chap. 447.

Autoimmune Autonomic Ganglionopathy (AAG) and

Seronegative Autoimmune Autonomic Neuropathy

(SAAN) These conditions present with the subacute development

of autonomic disturbances including OH, enteric neuropathy (gastroparesis, ileus, constipation/diarrhea), flaccid bladder, and cholinergic failure (e.g., loss of sweating, sicca complex, and a tonic pupil).

A chronic form of AAG resembles pure autonomic failure (PAF) (see

below). Autoantibodies against the α3 subunit of the ganglionic Ach

receptor are considered diagnostic of AAG. When these antibodies

are not detected, the cases may be labeled SAAN, but it is unclear if

these can be clearly divided into different categories. Pathology shows

preferential involvement of small unmyelinated nerve fibers, with

sparing of larger myelinated ones. Onset of the neuropathy follows

a viral infection in approximately half of cases. Up to one-third of

untreated patients experience significant functional improvement over

time. Immunotherapies that have been reported to be helpful include

plasmapheresis, intravenous immune globulin, glucocorticoids, azathioprine, rituximab, and mycophenolate mofetil. OH, gastroparesis, and

sicca symptoms can be managed symptomatically.

AAG can also occur on a paraneoplastic basis, with adenocarcinoma

or small-cell carcinoma of the lung, lymphoma, or thymoma being the

most common (Chap. 94). Cerebellar involvement or dementia may

coexist (see Tables 94-1–94-3), and the neoplasm can be occult.

Botulism Botulinum toxin binds presynaptically to cholinergic

nerve terminals and, after uptake into the cytosol, blocks ACh release.

This acute cholinergic neuropathy presents as motor paralysis and

autonomic disturbances that include blurred vision, dry mouth, nausea, unreactive or sluggishly reactive pupils, constipation, and urinary

retention (Chap. 153).

■ PURE AUTONOMIC FAILURE (PAF)

This sporadic syndrome consists of postural hypotension, impotence,

bladder dysfunction, and impaired sweating. The disorder begins in

midlife and occurs in women more often than men. The symptoms

can be disabling, but life span is unaffected. The clinical and pharmacologic characteristics suggest primary involvement of postganglionic

autonomic neurons. A severe reduction in the density of neurons

within sympathetic ganglia results in low supine plasma NE levels and

noradrenergic supersensitivity. Some patients who are initially labeled

with this diagnosis subsequently go on to develop AAG, but more often

a neurodegenerative disease supervenes, typically Lewy body dementia, PD, or MSA. In one recent series, more than one-third of patients

initially diagnosed with PAF developed a CNS synucleinopathy within

4 years, and the presence of rapid eye movement sleep behavior disorder (RBD; Chap. 31) was predictive of subsequent CNS disease. Skin

biopsies and autopsy studies demonstrate phosphorylated α-synuclein

inclusions in postganglionic sympathetic adrenergic and cholinergic

nerve fibers, distinguishing PAF from AAG and indicating that PAF is

a synucleinopathy; notably, patients with PD also have alpha synuclein

inclusions in sympathetic nerve biopsies.

■ POSTURAL ORTHOSTATIC TACHYCARDIA

SYNDROME (POTS)

This syndrome is characterized by symptomatic orthostatic intolerance without OH, accompanied by either an increase in heart rate

to >120 beats/min or an increase of 30 beats/min with standing that

subsides on sitting or lying down. Women are affected approximately

five times more often than men, and most develop the syndrome

between the ages of 15 and 50. Presyncopal symptoms (light-headedness, weakness, blurred vision) combined with symptoms of autonomic

overactivity (palpitations, tremulousness, nausea) are common. The

pathogenesis is typically multifactorial, which frequently confounds

the clinical picture. A number of potential causes have been reported,

including sympathetic denervation distally in the legs with preserved

cardiovascular function or reduced cardiac function due to deconditioning. Hypovolemia, venous pooling, impaired brainstem baroreceptor regulation, or increased sympathetic activity may also play a

role. No standardized approach to diagnosis has been established,

and therapy typically has included symptomatic relief with a focus on

cardiovascular rehabilitation, including a sustained exercise program.

Expansion of fluid volume with water, salt, and fludrocortisone can be

helpful as an initial intervention. In some patients, low-dose propranolol (20 mg) provides a modest improvement in heart rate control and

exercise capacity. If these approaches are inadequate, then midodrine,

pyridostigmine, or clonidine can be considered.

■ INHERITED DISORDERS

Eight hereditary sensory and autonomic neuropathies (HSANs) exist,

designated HSAN I–VIII. The most important autonomic variants are

HSAN I and HSAN III. HSAN I is dominantly inherited and often

presents as a distal small-fiber neuropathy (burning feet syndrome)

associated with sensory loss and foot ulcers. The most common

responsible gene, on chromosome 9q, is SPTLC1. SPTLC is a key

enzyme in the regulation of ceramide. Cells from HSAN I patients with

the mutation produce higher-than-normal levels of glucosyl ceramide,

perhaps triggering apoptosis. HSAN III (Riley-Day syndrome; familial

dysautonomia) is an autosomal recessive disorder of Ashkenazi Jewish

children and adults and is much less prevalent than HSAN I. Decreased

tearing, hyperhidrosis, reduced sensitivity to pain, areflexia, absent

fungiform papillae on the tongue, and labile BP may be present. Individuals with HSAN III have afferent, but not efferent, baroreflex failure

that causes the classic episodic abdominal crises and blood pressure

surges in response to emotional stimuli. Pathologic examination of

nerves reveals a loss of sympathetic, parasympathetic, and sensory

neurons. The defective gene, IKBKAP, prevents normal transcription

of important molecules in neural development.

■ PRIMARY FOCAL HYPERHIDROSIS

This syndrome presents with excess sweating of the palms and soles or

excess sweating of the axilla beginning in childhood or early adulthood.

The condition tends to improve with age. The disorder affects 0.6–1.0%

of the population. The etiology is unclear, but there may be a genetic

component because 25% of patients have a positive family history. The

condition can be socially embarrassing (e.g., shaking hands) or even disabling (e.g., inability to write without soiling the paper). Topical antiperspirants are occasionally helpful. More useful are potent anticholinergic

drugs such as glycopyrrolate 1–2 mg PO tid or oxybutynin 5 mg po bid.

T2 ganglionectomy or sympathectomy is successful in >90% of patients

with palmar hyperhidrosis. The advent of endoscopic transaxillary T2

sympathectomy has lowered the complication rate of the procedure.

The most common postoperative complication is compensatory hyperhidrosis, which improves spontaneously over months. Other potential

complications include recurrent hyperhidrosis (16%), Horner’s syndrome

(<2%), gustatory sweating, wound infection, hemothorax, and intercostal

neuralgia. Local injection of botulinum toxin has also been used to block

cholinergic, postganglionic sympathetic fibers to sweat glands. This

3435 Disorders of the Autonomic Nervous System CHAPTER 440

approach is effective but limited by the need for repetitive injections (the

effect usually lasts 4 months before waning).

■ ACUTE SYMPATHETIC OVERACTIVITY

SYNDROMES

An autonomic storm is an acute state of sustained sympathetic surge

that results in variable combinations of alterations in BP and heart

rate, body temperature, respiration, and sweating. Causes of autonomic storm include brain and spinal cord injury, toxins and drugs,

autonomic neuropathy, and chemodectomas (e.g., pheochromocytoma). Brain injury is the most common cause of autonomic storm

and typically follows severe head trauma and postresuscitation anoxic-ischemic brain injury. Autonomic storm can also occur with other

acute intracranial lesions such as hemorrhage, cerebral infarction,

rapidly expanding tumors, subarachnoid hemorrhage, hydrocephalus,

or (less commonly) an acute spinal cord lesion. The most consistent

setting is that of an acute intracranial catastrophe of sufficient size and

rapidity to produce a massive catecholaminergic surge. The surge can

cause seizures, neurogenic pulmonary edema, and myocardial injury.

Manifestations include fever, tachycardia, hypertension, tachypnea,

hyperhidrosis, pupillary dilatation, and flushing. Lesions of the afferent

limb of the baroreflex can result in milder recurrent autonomic storms;

these can be associated with tumors or follow neck irradiation or surgery that damages the vagus and glossopharyngeal nerves.

Drugs and toxins may also be responsible, including sympathomimetics such as phenylpropanolamine, cocaine, amphetamines, and

tricyclic antidepressants; tetanus; and, less often, botulinum toxin. The

serotonin syndrome can occur from polypharmaceutical use of drugs

that inhibit serotonin uptake and metabolism (particularly selective

serotonin reuptake inhibitors and mixed norepinephrine/serotonin

reuptake inhibitors; see Chap. 452) or an antidepressant monoamine

oxidase inhibitor can produce a dramatic autonomic syndrome with

hypertension, sweating, tachycardia, dilated pupils, and mental status

changes. Cocaine, including “crack,” can cause a hypertensive state

with flushing, hypertension, tachycardia, fever, mydriasis, anhidrosis,

and a toxic psychosis. The hyperadrenergic state associated with Guillain-Barré syndrome can produce a moderate autonomic storm. Pheochromocytoma (Chap. 387) presents with a paroxysmal or sustained

hyperadrenergic state, headache, hyperhidrosis, palpitations, anxiety,

tremulousness, and hypertension.

Neuroleptic malignant syndrome refers to a syndrome of muscle

rigidity, hyperthermia, and hypertension in patients treated with

neuroleptic agents (including lower potency and atypical antipsychotic agents, and even antiemetic drugs such as metoclopramide

and promethazine) (Chap. 436). Management of autonomic storm

includes ruling out other causes of autonomic instability, including malignant hyperthermia, porphyria, and seizures. Sepsis and

encephalitis need to be excluded with appropriate studies. An

electroencephalogram (EEG) should be done to search for seizure

activity; MRI of the brain and spine is often necessary. The patient

should be managed in an intensive care unit and the causal agent discontinued. Management with lorazepam, dantrolene, bromocriptine,

or apomorphine is based upon clinical experience and not clinical

trials. Supportive treatment may need to be maintained for several

weeks. For chronic and milder autonomic storm, propranolol and/or

clonidine can be effective.

■ MISCELLANEOUS AND CONTROVERSIAL

AUTONOMIC SYNDROMES

Other conditions associated with autonomic failure include infections,

malignancy, and poisoning (organophosphates). Disorders of the

hypothalamus can affect autonomic function and produce abnormalities in temperature control, satiety, sexual function, and circadian

rhythms (Chap. 380).

■ COMPLEX REGIONAL PAIN SYNDROMES (CRPS)

The failure to identify a primary role of the ANS in the pathogenesis

of these disorders has resulted in a change of nomenclature. The terms

CRPS types I and II are now used in place of reflex sympathetic dystrophy (RSD) and causalgia.

CRPS type I is a regional pain syndrome that often develops after

tissue injury and most commonly affects one limb. Examples of associated injury include minor shoulder or limb trauma, fractures, myocardial infarction, or stroke. Allodynia (the perception of a nonpainful

stimulus as painful), hyperpathia (an exaggerated pain response to

a painful stimulus), and spontaneous pain occur. The symptoms are

unrelated to the severity of the initial trauma and are not confined to

the distribution of a single peripheral nerve. CRPS type II is a regional

pain syndrome that develops after injury to a specific peripheral nerve,

often a major nerve trunk. Spontaneous pain initially develops within

the territory of the affected nerve but eventually may spread outside the

nerve distribution. Although CRPS type I (RSD) has been classically

divided into three clinical phases, there is little evidence that CRPS

“progresses” from one stage to another. Currently, the Budapest consensus criteria for clinical diagnosis of CRPS delete staging and require

at least three symptoms and two signs in the following four categories:

(1) sensory, (2) vasomotor, (3) sudomotor/edema, and (4) motor/

trophic. Pain (usually burning or electrical in quality) is the primary

clinical feature of CRPS. Limb pain syndromes that do not meet these

criteria are best classified as “limb pain—not otherwise specified.” In

CRPS, localized sweating (increased resting sweat output) and changes

in blood flow may produce temperature differences between affected

and unaffected limbs.

The natural history of typical CRPS may be more benign and more

variable than previously recognized. A variety of surgical and medical

treatments have been developed, with conflicting reports of efficacy.

Clinical trials suggest that early mobilization with physical therapy or a

brief course of glucocorticoids may be helpful for early CRPS type I or

II. Chronic glucocorticoid treatment is not recommended. Medications

to treat neuropathic pain can be helpful. Current treatment paradigms

are multidisciplinary with a focus on early mobilization, physical therapy, pain management, patient education, and psychological support.

TREATMENT

Autonomic Failure

Management of autonomic failure is aimed at specific treatment of

the cause and alleviation of symptoms. Of particular importance

is the removal of drugs or amelioration of underlying conditions

that cause or aggravate the autonomic symptoms, especially in the

elderly. For example, OH can be caused or aggravated by antihypertensive agents, antidepressants, levodopa or dopaminergic agonists,

ethanol, opioids, insulin, and barbiturates. A summary of drugs that

can cause impotence, urinary retention, or diaphoresis by class and

putative mechanism is shown in Table 440-6.

PATIENT EDUCATION

Only a minority of patients with OH require drug treatment. All

patients should be taught the mechanisms of postural normotension (volume status, resistance and capacitance bed, autoregulation)

and the nature of orthostatic stressors (time of day and the influence of meals, heat, standing, and exercise). Patients should learn

to recognize orthostatic symptoms early (especially subtle cognitive

symptoms, weakness, and fatigue) and to modify or avoid activities

that provoke episodes. Other measures may include keeping a BP

log and dietary education (salt/fluids). Learning physical countermaneuvers that reduce standing OH and practicing postural and

resistance training and cardiovascular reconditioning are frequently

helpful.

SYMPTOMATIC TREATMENT

Nonpharmacologic approaches are summarized in Table 440-9.

Adequate intake of salt and fluids to produce a voiding volume

of 1.5–2.5 L of urine (containing >170 meq/L of Na+) each 24 h is

essential. Sleeping with the head of the bed elevated will minimize

the effects of supine nocturnal hypertension. Prolonged recumbency should be avoided when possible. Patients are advised to

sit with legs dangling over the edge of the bed for several minutes

before attempting to stand in the morning; other postural stressors