Neurogenic Orthostatic Hypotension, Autonomic Failure, and Acquired and Familial Autonomic Neuropathy

Louis H. Weimer

INTRODUCTION

Autonomic disorders are generally considered to be uncommon conditions, but in fact, autonomic dysfunction is ubiquitous in neurologic disease, including highly prevalent processes such as seizures, strokes, mass lesions, infections, multiple sclerosis (MS) plaques, and others, but dysautonomia is often a secondary concern. A limited number of disorders produce severe or isolated dysautonomia or autonomic failure (AF). Because autonomic systems affect virtually all organ systems, symptoms produced are multiple and varied, often affecting functions not considered by most neurologists. Problems can arise from any site of autonomic control including the central cortical and subcortical autonomic network, brain stem, spinal cord, autonomic ganglia, or peripheral autonomic nerves. The range of pathogenic mechanisms is highly varied, including degenerative, hereditary, immune-mediated, paraneoplastic, aberrant reflex, and metabolic, among others. Suspicion of autonomic dysfunction rests with the clinician and can be missed if symptoms that can appear to be nonspecific are considered in isolation (Table 112.1). Early symptoms of the most characteristic finding, orthostatic hypotension (OH), may appear as postural fatigue, cognitive change, anxiety, or vertigo. This lack of certainty in many cases makes more objective assessment desirable in these instances (see Chapter 27). Postural hypotension (OH) is a prevalent clinical sign seen in numerous and diverse neurologic and nonneurologic conditions. Shibao et al. estimated over 80,000 U.S. OH-related hospitalizations in 2004; OH was the primary diagnosis in 35%. One consensus agreement defines OH as a fall in systolic blood pressure (SBP) of 20 or 10 mm Hg diastolic within 3 minutes of standing or similar orthostatic challenge, such as upright tilt, although some require a 30 mm Hg decline. OH, however, may be asymptomatic, especially in the elderly, and varies according to underlying conditions or confounding factors (Table 112.2). The sign is one marker of advanced AF caused by either diseases of central autonomic pathways or autonomic neuropathy. Some severe and important causes are discussed; a more comprehensive list is provided in Table 112.3. Acute and subacute processes are generally considered separately from more chronic conditions.

ACUTE AND SUBACUTE AUTONOMIC DISORDERS

Acute or subacute autonomic neuropathy (AAN) or acute pandysautonomia is an unusual but distinct entity, which primarily affects peripheral autonomic nerves. Roughly, half are preceded by a viral prodrome similar to Guillain-Barré syndrome (GBS). Patients typically develop generalized AF including OH, anhidrosis, parasympathetic failure, and gastrointestinal dysfunction, although predominantly adrenergic and cholinergic variants are seen. The illness is monophasic with acute or subacute onset over several weeks. Recovery generally occurs but is often slow and incomplete. Acute signs such as ileus may develop into lesser degrees of gastrointestinal dysmotility including bloating, early satiety, nausea, vomiting, and alternating diarrhea and constipation. Antecedent viruses include herpes simplex, mononucleosis, rubella, and nondescript febrile illnesses. Roughly 25% have a restricted cholinergic form (acute cholinergic neuropathy) characterized by dry eyes and mouth, gastrointestinal dysmotility, bladder dysfunction, hypohidrosis, unreactive pupils, fixed heart rate, and sexual dysfunction but without significant OH. Abnormalities on formal autonomic testing are prominent in the involved systems. Nerve conduction studies are typically normal or show minor sensory abnormalities. The lack of OH in cholinergic cases complicates the diagnosis.

Demonstration of high-titer antibodies to nicotinic ganglionic AChR α-3 subunits, which are similar but distinct from those at the neuromuscular junction (α-1 subunits), supports an immune-mediated basis. A paraneoplastic form, which develops in a similar time course and is indistinguishable on clinical or laboratory
grounds, may appear prior to tumor discovery, most commonly thymoma. In screening patients with autonomic disorders and controls, Vernino et al. found that 41% of patients with idiopathic autonomic neuropathy had high antibody titers; paraneoplastic neuropathy patients were frequently positive as well. Rarely, patients with chronic OH and AF have high antibody titers and respond to immunotherapy, such as intravenous immunoglobulin (IVIG) or plasma exchange. Some patients with orthostatic intolerance, discussed later, and idiopathic gastrointestinal dysmotility, but none with chronic degenerative autonomic processes, also had positive assays at lower titers. Knockout mouse models of the α-3 subunit gene, rabbits immunized against the subunit, and passive antibody transfer to other animals all induce signs of AF supporting the assertion that the antibodies are causative. Antibody titers also correlate with disease severity. Of note, low-level titers may occur in patients with other disorders or nonspecific symptoms. One-third of AAN patients recover, one-third have a partial recovery with substantial deficits, and the remainder do not improve. Gastrointestinal dysfunction and OH are usually the most debilitating manifestations. Supportive care and management of the OH and system-specific problems are the mainstays of treatment. Rare cases with AAN and myasthenia gravis have both types of AChR antibodies. Autonomic involvement is common in typical GBS, discussed in Chapter 87, especially in more severe cases, and is a prominent cause of morbidity and mortality.

TABLE 112.1 Auttonomiic Reviiew off Sympttoms

Secretomotor: dry eyes and mouth, often required natural tears or frequent sips of water. Excessive saliva can also occur.

Orthostatic: dizziness, weakness, fatigue, cognitive changes, visual disturbance, vertigo, anxiety, palpitations, pallor, nausea, syncope

Postprandial: bloating, fullness, nausea, dizziness, sweating, orthostatic hypotension

GI: constipation, nocturnal or intermittent diarrhea

Genitourinary (GU): urinary retention, difficulty with initiation, incomplete emptying, incontinence

Sexual: erectile failure, ejaculatory dysfunction, retrograde ejaculation into bladder

Visual: blurred vision, sensitivity to light/glare, reduced night vision

Sudomotor: reduced loss of sweating ability (distally in polyneuropathies); excessive, paroxysmal, or inappropriate sweating; mixed pattern of loss and excessive areas, heat intolerance

Vasomotor: distal color changes, change in skin appearance, persistently cold extremities, Raynaud phenomenon, loss of skin wrinkling in water, heat intolerance

Other: unexplained syncope

GI, gastrointestinal

TABLE 112.2 Factors Affecting Orthostatic Hypotension

Aggravating Factors

Warm environment, hot bath

Post exercise

Prolonged motionless standing

Large meals (carbohydrate load)

Early morning

Valsalva maneuver, isometric exercise

Volume depletion

Rising after prolonged bed rest

Rapid postural change

Space flight

Alcohol

Medications

Beneficial maneuvers

Squatting, leg crossing

Abdominal and leg compression

Nighttime slight upright tilt

Isotonic exercise

PARANEOPLASTIC AUTONOMIC NEUROPATHY

Subacute autonomic neuropathy or predominantly enteric neuropathy is also seen in isolation or with somatic sensory neuropathy and other underlying antibodies, especially type 1 antineuronal nuclear antibodies (ANNA-1, anti-Hu) usually in patients with small cell lung cancer. Paraneoplastic neuropathy is also associated with other paraneoplastic antibodies including Purkinje cell cytoplasmic antibody type 2 (PCA-2) and collapsing response mediator protein-5 (CRMP-5). Botulism (cholinergic), acute intermittent porphyria, and toxic neuropathy are other diagnostic considerations. A rare chronic form associated with high titers to ganglionic antibodies is known that can mimic degenerative AF. Autonomic manifestations are also common in patients with Lambert-Eaton myasthenic syndrome, especially cholinergic complaints and manifestations (see Chapter 89).

ORTHOSTATIC INTOLERANCE

Exaggerated orthostatic tachycardia may be evident in some cases without significant cardiac denervation. This led to the proposal that some patients with the common syndrome of idiopathic orthostatic intolerance without OH (postural orthostatic tachycardia syndrome), also known as orthostatic intolerance, may have an attenuated form of acute autonomic neuropathy. Orthostatic intolerance symptoms include postural lightheadedness, fatigue, cognitive changes, and presyncope despite minimal changes in blood pressure (BP). Potential mechanisms are multiple, including excessive venous pooling, idiopathic hypovolemia, adrenergic hypersensitivity, and altered cerebrovascular autoregulation. Some may have an attenuated form of AAN supported by abnormalities of sudomotor and other autonomic systems in one-third of cases and an overrepresentation of antecedent viral infection in these patients. The common physiologic thread is presumed bouts of cerebral hypoperfusion, despite a seemingly adequate systemic BP. This syndrome is the most common cause of consultation in most autonomic centers. The condition is much more common in women, roughly 5:1 and commonly initially develops between ages 15 and 25 years, often after an acute illness, such as a viral syndrome. An association with joint hypermobility and presumed or documented Ehlers-Danlos syndrome type III is increasingly recognized. Patients with grade I Chiari malformations also typically have multiple autonomic symptoms, including orthostatic intolerance. Roughly, 40% of patients have additional vasovagal syncopal episodes. The condition must be distinguished from depression, vestibular disorders, chronic fatigue, fibromyalgia, and panic disorders but many overlap cases exist; many patients have coincident chronic and not postural fatigue, insomnia, and chronic pain. Uncommon symptomatic causes must be considered, such as adrenal insufficiency, pheochromocytoma, and Sjögren syndrome. The syndrome often leads to secondary deconditioning, which complicates recovery. An indistinguishable hereditary form resulting from a mutation in a norepinephrine transporter gene is known but is exceedingly rare. Similar symptoms can be seen in patients with predominantly painful small fiber neuropathy due to additional involvement of distal autonomic nerves. Treatment must be individualized based on the most prominent symptoms but is generally based on improving standing BP, increasing blood volume, minimizing anemia, and increasing activity levels. Beta blockade is helpful in patients with bothersome palpitations and hyperadrenergic forms but is counterproductive in other subtypes.

CHRONIC NEUROGENIC ORTHOSTATIC HYPOTENSION AND AUTONOMIC NEUROPATHY

PARKINSONIAN SYNDROMES AND PURE AUTONOMIC FAILURE

Marked AF in patients with multiple system atrophy (MSA), especially the former Shy-Drager syndrome, is frequent. Other autonomic
symptoms often predate OH, including impotence, decreased sweating, and urinary incontinence. MSA is a group of disorders with overlapping neuropathology and may have autonomic, parkinsonian, or cerebellar symptoms at onset or later, as discussed in Chapter 84. Other common manifestations include sleep apnea, incontinence, impotence, dystonia, inspiratory stridor, hoarseness, lack of rest tremor, and ineffective or transient L-dopa response. Virtually all MSA patients eventually show autonomic signs or symptoms, regardless of initial manifestations. Demonstration of argyrophilic glial cytoplasmic inclusions (GCIs) in oligodendroglia is a characteristic but not a pathognomonic MSA hallmark. GCIs are prominent in sites of central autonomic control and correlate better with clinical findings than do areas of neuronal loss. Consensus diagnostic criteria first published in 1996 were simplified and refined in 2008. Increased risk of MSA has been found in families and some sporadic cases from various mutations in the gene COQ2, which is essential for the biosynthesis of coenzyme Q10. Median survival from symptom onset is approximately 10 years based on the most recent natural history studies; parkinsonism at onset and incomplete bladder emptying were the most predictive factors for faster progression.

TABLE 112.3 Sellectted Disorders of Autonomy Function

Isolated Degenerative Autonomic

Pure autonomic failure (PAF), “Bradbury-Eggleston syndrome”

Multisystem Degenerative Disorders

MSA

Parkinson disease with autonomic failure

Central

Brain tumors (posterior fossa, third ventricle, hypothalamus), syringobulbia, MS, tetanus, Wernicke-Korsakoff syndrome, fatal familial insomnia

Spinal Cord

MS, syringomyelia, transverse myelitis, trauma, mass lesion

Peripheral

Immune mediated

Guillain-Barré syndrome (see Chapter 87), acute and subacute autonomic neuropathy, acute cholinergic neuropathy, Sjögren disease, SLE, rheumatoid arthritis, Holmes-Adie syndrome, Ross syndrome, Harlequin syndrome, acute anhidrosis

Metabolic

Diabetes, vitamin B₁₂ and thiamine deficiency, uremia

Paraneoplastic

Paraneoplastic autonomic neuropathy and paraneoplastic syndromes with autonomic neuropathy (ANNA-1, α3-AchR ganglionic, CRMP-5, PCA-2 antibodies), enteric neuropathy, Lambert-Eaton myasthenic syndrome (cholinergic)

Infectious

Chagas disease (cholinergic), syphilis, leprosy, HIV, Lyme disease, diphtheri

Hereditary

Familial amyloidosis, hereditary sensory and autonomic neuropathies (see Chapter 88), dopamine β-hydroxylase deficiency, porphyria, Fabry disease, norepinephrine transporter deficiency, fragile X premutation-associated tremor/ataxia syndrome, CANVAS syndrome, Hirschsprung megacolon, Ehlers-Danlos type III, myopathy, external ophthalmoplegia, neuropathy, gastrointestinal encephalopathy (MNGIE), Machado-Joseph disease, prion-induced diarrhea, and autonomic neuropathy

Toxins and Medications

Botulism, vincristine, cisplatin, taxoids, amiodarone, pyriminil (Vacor), hexacarbon, carbon disulfide, heavy metals, podophyllin, alcohol

Drug and Medication Effects

Anticholinergics: tricyclic antidepressants, atropine, oxybutynin

β-Adrenergic blockers: propranolol and others

α2-Agonists: clonidine, prazosin, α-methyl dopa, terazosin, doxazosin

α1-Antagonists: phentolamine, phenoxybenzamine, guanabenz

Ganglionic blockers: guanethidine, hexamethonium, mecamylamine

Others: hydralazine, nitrates, diuretics, calcium channel blockers, ACE inhibitors, antihistamines, antipsychotics, Sinemet, narcotics, sildenafil, tadalafil

Reduced orthostatic tolerance

Neurocardiogenic syncope, POTS, mitral valve prolapse syndrome, prolonged bed rest or weightlessness, Chiari malformation

Others

Acquired amyloidosis, chronic idiopathic autonomic neuropathies, small-fiber neuropathy, idiopathic hyperhidrosis, idiopathic anhidrosis, Horner syndrome

MSA, multiple system atrophy; MS, multiple sclerosis; SLE, systemic lupus erythematosus; CRMP-5, collapsing response mediator protein-5; PCA-2, Purkinje cell cytoplasmic antibody type 2; CANVAS, cerebellar ataxia, neuropathy, vestibular areflexia syndrome; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; ACE, angiotensin-converting enzyme; POTS, postural orthostatic tachycardia syndrome.

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