Practice Essentials

Primary syndromes of generalized autonomic failure include the following:

• Idiopathic orthostatic hypotension and other forms of pure autonomic failure (PAF)
• Autoimmune autonomic neuropathy (AAN)
• Multiple system atrophy (MSA)

Unlike the above disorders, which each affect sympathetic and parasympathetic function, the autonomic condition postural orthostatic tachycardia syndrome (POTS) affects only sympathetic function.

Signs and symptoms

Symptoms of decreased sympathetic function may include the following:

• Orthostatic hypotension
• Decreased sweating
• Ejaculatory dysfunction
• Ptosis associated with Horner syndrome

Symptoms of decreased parasympathetic function may include the following:

• Constipation
• Nausea
• Urinary retention
• Erectile dysfunction

Pure autonomic failure

More specifically, symptoms of PAF include the following:

• Orthostatic hypotension: With an inappropriate lack of compensatory increase in heart rate with standing
• Gastroparesis: Associated with nausea or constipation
• Urinary retention: May cause bladder distention
• Decreased sweating: Manifesting as heat or exercise intolerance
• Ophthalmologic manifestations: Including ptosis, anisocoria, Horner syndrome, and tonic pupils
• Failure of either erection or ejaculation

Autoimmune autonomic neuropathy

The overall physical findings are similar to those observed in PAF. Patients may have additional findings of sensory abnormalities, pain, or loss of deep tendon reflexes.

Multiple system atrophy

Autonomic manifestations are similar to those observed in AAN and PAF. The following neurologic features may also be present:

• Pyramidal or cerebellar abnormalities: Weakness, ataxia, incoordination, and eye-movement abnormalities may precede the autonomic features by as long as 2 years
• Variable parkinsonian findings: Found in MSA parkinsonian variant; are unresponsive to levodopa; include rigidity, bradykinesia, tremor, and truncal instability
• Evidence of cerebellar dysfunction: Found in MSA cerebellar variant; includes ataxia, dysmetria, dysdiadochokinesia, and incoordination; eye-movement abnormalities are frequently present

Postural orthostatic tachycardia syndrome

A greater than 30-bpm increase in heart rate on standing, without a clinically significant decrease in blood pressure, is diagnostic.

See Clinical Presentation for more detail.

Diagnosis

Lab studies

• Evaluation for acute inflammatory demyelinating polyneuropathy (AIDP): Prompted by an acute onset of autonomic symptoms without other neurologic problems or with features such as subtle weakness or numbness
• Measurement of ganglionic AChR antibody: A subacute onset without other neurologic or systemic findings may indicate AAN ^{[2, 3]}
• Evaluation for Parkinson's disease and MSA: Should be performed in patients with a chronic onset

Drug or toxin exposure may cause generalized or organ-specific acute autonomic dysfunction. The predominant abnormality (ie, increased or decreased sympathetic or parasympathetic activity) should be identified. The patient's medications should be reviewed carefully.

Tests for systemic disorders causing secondary pandysautonomia, including the following, may be ordered according to clues from the patient’s history:

• Glycosylated hemoglobin or glucose tolerance test: To test for diabetes
• Anti-Hu antibody titers: If the patient has associated sensory neuropathy or cognitive changes.
• Anti-calcium channel antibody titers: For Lambert-Eaton myasthenic syndrome (LEMS)
• Stool screen for botulinum by culture and detection of toxin: In cases of suspected poisoning by food or wound contamination
• Serum and urine protein electrophoresis: To evaluate myeloma with amyloidosis
• Genetic testing: To evaluate for familial amyloidosis
• Rapid plasma reagent (RPR) or Venereal Disease Research Laboratory test (VDRL): To test for syphilis
• Human immunodeficiency virus (HIV) testing
• Autoimmune screening: To evaluate for collagen-vascular disease; may include antinuclear antibody levels, erythrocyte sedimentation rate, and other autoimmune tests (eg, rheumatoid factor, SS-A and SS-B antibodies)
• Assessment of the urinary porphyrins and erythrocyte porphobilinogen deaminase levels: If the clinical history suggests the possibility of porphyria

Imaging studies

Brain magnetic resonance imaging (MRI): Particularly in cases of centrally mediated dysautonomia

In MSA, brainstem or cerebellar atrophy may be seen, with T2 hyperintensity of the pons (the hot-crossed bun sign); these findings differentiate MSA from other types of primary autonomic dysfunction.^[4]

See Workup for more detail.

Management

Treatment strategies for autonomic disorders include the following:

• AAN: Treatment is based on anecdotal evidence
• Chronic PAF syndromes: Treatment is symptomatic only
• POTS: Can be treated with low doses of beta blockers, as patients are normally sensitive to their adverse effects

Nonpharmacologic measures are useful for all patients with autonomic dysfunction.^[5] They include the following:

• Antihypertensive medications and other medications known to lower blood pressure should be discontinued, if feasible
• Fluid and salt intake should be increased
• Equipment aids may be helpful; these include tight support stockings, abdominal binders, or antigravity suits for symptomatic hypotension and bladder catheterization for urinary retention
• Dietary fiber and enemas may help to improve bowel motility and decrease straining during defecation
• Patients with decreased sweating should limit their physical activity, particularly in hot weather; sponging with water during activity may help to prevent overheating
• Large meals may exacerbate hypotension and should be avoided
• Positional changes, such as standing up, should be performed slowly and gradually
• The head of the bed should be elevated, and prolonged recumbency should be avoided

See Treatment and Medication for more detail.

Next

Background

Autonomic failure has many causes and manifestations.

It may result from a primary disturbance of autonomic regulation or more commonly as a secondary effect of another systemic disorder (eg, diabetes, amyloidosis). This article focuses on primary syndromes of generalized autonomic failure and includes a discussion of pure autonomic failure and idiopathic orthostatic hypotension, autoimmune autonomic neuropathy (AAN), and multiple system atrophy (MSA). The selective sympathetic disturbance of postural orthostatic tachycardia syndrome (POTS) is also discussed briefly.

On clinical examination, the syndromes sometimes may be difficult to differentiate, particularly in the early stages of disease. This has led to some confusion over the nomenclature of these disorders. The terminology continues to evolve and become more precise as a result of our improving understanding of the different pathophysiologic mechanisms leading to autonomic dysfunction.

The term pure autonomic failure (PAF) was coined by Roger Bannister. It encompasses disorders of autonomic function that do not affect the central nervous system (CNS). The term is more descriptive of a clinical presentation than of a single pathologic process. Idiopathic orthostatic hypotension, sometimes also referred to as Bradbury-Eggleston syndrome, falls into this general category. Although patients with PAF may share many common clinical features, especially orthostatic hypotension, it is now evident that the underlying disease processes are heterogeneous. Many patients who present with PAF may actually have an immunologically mediated autonomic neuropathy, whereas others may go on to develop MSA or other diseases that fall outside the PAF definition.

Autoimmune autonomic neuropathy (also known as autoimmune autonomic ganglionopathy, acute panautonomic neuropathy, or acute pandysautonomia) has been increasingly recognized as an important cause of autonomic failure. It typically presents as a subacute or chronic condition. Antibodies to ganglionic acetylcholine receptors (AChR) are present in about two thirds of all subacute cases and in one third of chronic cases. AAN may also present as acute pandysautonomia and may be part of the spectrum of immunologically mediated neuropathies such as acute inflammatory demyelinating polyneuropathy (AIDP, or Guillain-Barré syndrome) and chronic inflammatory demyelinating neuropathy. Mild somatic sensory and motor disturbances are sometimes seen in autonomic neuropathies.

MSA is a progressive, adult-onset disorder characterized by a combination of autonomic dysfunction, parkinsonism, and ataxia. Numerous accounts of the disorder were recorded throughout the 20th century under different labels such as olivopontocerebellar atrophy, striatonigral degeneration, or Shy-Drager syndrome. MSA with prominent autonomic abnormalities is still sometimes referred to as Shy-Drager syndrome. The disparate clinical presentations were not widely recognized as being histopathologically related until 1989. Today the dominant clinical features provide the basis for further classification of MSA into parkinsonian, and cerebellar variants.

POTS is a common, relatively benign disturbance of the sympathetic nervous system that primarily affects young women. POTS either develops slowly in adolescence, or abruptly after a febrile illness or other immunological challenge. This latter presentation may be due to an autoimmune mechanism. POTS is characterized by excessive adrenergic symptoms when the patient stands up. Syncope may occur but is unusual. A greater than 30-bpm increase in heart rate on standing, without substantial blood pressure reduction, is diagnostic. The causes of POTS are likely heterogeneous.

Pathophysiology

Dysfunction of central or peripheral nervous system pathways may cause autonomic dysfunction. A precise balance of sympathetic and parasympathetic inputs modulates the function of most major organ systems. Primary disorders of autonomic function almost never exclusively affect either sympathetic or parasympathetic function. POTS is an exception, involving only sympathetic function.

The hypothalamus, midbrain, brainstem, and intermediolateral cell columns in the spinal cord are the major regions in the CNS that are important in regulating autonomic activity. Sympathetic outputs arise in brain and brainstem centers, descend into the spinal cord, and synapse with neurons in the intermediolateral cell mass in the thoracic and upper lumbar segments. Axons originating in the spinal cord synapse with cells in paravertebral ganglia, which, in turn, provide sympathetic output to remote target organs. Parasympathetic outflow originates from the cranial and sacral segments. These axons synapse in ganglia located near their target organs.

Both sympathetic and parasympathetic preganglionic synapses use acetylcholine (ACh) as the major neurotransmitter; postganglionic parasympathetic synapses and sympathetic sweat synapses also use acetylcholine. Other postganglionic sympathetic synapses use noradrenaline.

Symptoms frequently result from a disturbance of the relative contributions of sympathetic and parasympathetic activity. Depending on the organ system, the major input may be sympathetic or parasympathetic. For example, in the cardiovascular system, absence of sympathetic input may be especially problematic, contributing to orthostatic hypotension.

Etiology

The principal forms of autonomic failure are pure autonomic failure (PAF), autoimmune autonomic neuropathy (AAN), multiple system atrophy (MSA), and postural orthostatic tachycardia syndrome (POTS). These have differing causes.

Pure autonomic failure

Patients who are initially identified as having PAF may have underlying pathology consistent with MSA or Parkinson's disease, or they may be found to have AAN after extensive testing. Involvement of the intermediolateral cell column with the loss of small sympathetic neurons has been observed in some patients.

Autoimmune autonomic neuropathy

The cause of AAN is presumed to be autoimmune. Autoantibodies against ganglionic AChRs are seen in one- to two-thirds of patients with this condition.^[6] A preceding infection or other antecedent illness is noted in about 60% of cases. In rare cases, patients have a coexisting thymus tumor.

Multiple system atrophy

In MSA with autonomic involvement, changes in the intermediolateral cell column also may be seen; in addition, widespread abnormalities are apparent in the brain. Histopathologically, alpha-synuclein immunostaining demonstrates glial cytoplasmic inclusions. Associated clinical findings are related to the constellation of affected areas. Neuronal loss may be noted in the basal ganglia, pons, cerebellum, substantia nigra, locus ceruleus, nucleus of Edinger-Westphal, hypothalamus, thalamus, and vestibular complex.

Postural orthostatic tachycardia syndrome

A norepinephrine transporter deficiency has been identified in 1 family. Polymorphisms in genes encoding the beta-2 adrenoreceptor and nitric oxide synthetase may play a role. Beta-receptor supersensitivity, reduced vagal function, brainstem dysfunction, and deficient cerebral blood flow autoregulation are other proposed mechanisms. Some patients have restricted autonomic neuropathy.

Vitamin B12 is involved in catecholamine metabolism, and Oner and colleagues have suggested that vitamin B12 deficiency in adolescents may cause sympathetic baroreceptor dysfunction. In their study of 125 adolescent patients who had suffered a short-term loss of consciousness and had been diagnosed with vasovagal syncope, 47.2% of patients had low vitamin B12 levels, compared with 18% of a group of 50 control subjects, and vitamin B12 levels were significantly lower in those patients diagnosed with POTS than in the other patients.^{[7, 8]}

Frequency

United States

All of these syndromes are relatively uncommon. The prevalence of MSA is 1.9-4.9 cases per 100,000 population, as reported in several series. No accurate data on the frequency of AAN, PAF, or POTS are available.

Mortality/Morbidity

Autonomic dysfunction may cause clinically significant functional impairment. POTS is usually a benign, sometimes self-limiting condition, though rare patients have severe limitation in their activities.

Severe autonomic dysfunction may directly cause death. More often, chronic disability increases the patient's susceptibility to other potentially fatal complications, such as infection.

Race

No reliable data regarding race are available.

Sex

AAN and MSA have no clear sex predilection. In the literature about PAF, men were affected more often than women. POTS affects women 5 times more often than men.

Age

The diseases discussed here are primarily disorders of adulthood, with the exception of POTS, which primarily affects adolescents and young adults.

Clinical Presentation