Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes

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.

• References

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.

• References

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.

• References

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]}

• References

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.

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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.

• References

History

Features of autonomic disturbance in any of these conditions may include orthostasis, nausea, constipation, urinary retention or incontinence, nocturia, impotence, heat intolerance, and dry mucous membranes. Less commonly, patients experience periods of apnea or inspiratory stridor. Postural orthostatic tachycardia syndrome (POTS) results in prominent excessive adrenergic symptoms, especially tachycardia.

• 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 (PAF)

  • PAF is by definition not associated with CNS symptoms. Careful questioning is required to exclude symptoms of CNS dysfunction, such as gait disturbance or spasticity. Patients should also be questioned in detail about sensory loss or neuropathic pain, which may suggest autoimmune autonomic neuropathy (AAN).
  • In older literature, the terms PAF and idiopathic orthostatic hypotension were sometimes used interchangeably. Orthostatic hypotension is the most common complaint in this group of patients.
  • Abnormalities of urination, salivation, sweating, and defecation can occur, though these are less common in PAF than in AAN.

   

  

   
• Autoimmune autonomic neuropathy

  • Patients with apparent PAF should be questioned carefully regarding dry mouth or dry eyes.
  • Such sicca symptoms may be associated with ganglionic AChR autoantibodies.
  • Mild sensory disturbances may be present and overshadowed by autonomic dysfunction.

   

  

   
• Multiple system atrophy

  • MSA is a chronic, progressive disorder with mixed features of chronic autonomic dysfunction, parkinsonism, and ataxia.^[9]
  • Autonomic dysfunction is a common finding in MSA and in the absence of pathological findings essential to the diagnosis.
  • A subset of patients with PAF may eventually develop MSA, but no clinical or diagnostic markers identify this group at the outset.
  • Depending on their clinical features, patients with MSA may be categorized as parkinsonian (MSAp) or cerebellar (MSAc) variants, depending on the most prominent symptoms and findings on physical examination.

   

  

   
• Postural orthostatic tachycardia syndrome

  • POTS is a relatively benign disorder that is often self-limiting.
  • Patients may complain of dizziness, blurry vision, weakness, lightheadedness, and fatigue upon standing. Palpitations, tremulousness, and anxiety can also be seen.
  • Other associated symptoms include neurocognitive or sleep disorders, exercise intolerance, hyperpnea, dyspnea, nausea, abdominal pain, and sweating.

   

  

   

• References

Physical

See the list below:

• Pure autonomic failure

  • Cardiovascular manifestations include orthostatic hypotension with an inappropriate lack of compensatory increase in heart rate with standing. Orthostatic hypotension is defined as a decrease of at least 20 mm Hg in systolic blood pressure or at least 10 mm Hg in diastolic blood pressure within 3 minutes of standing.
  • Gastroparesis is common and is associated with nausea or constipation. The abdomen may be distended, and patients may have discomfort on palpation. An acute abdomen is unusual. Diarrhea may also occur, with or without fecal incontinence.
  • Urinary retention is seen frequently and may cause bladder distention. A distended bladder can be detected on examination by percussion or palpation. Bladder emptying may be incomplete with post-void residuals of 100 mL or more.
  • Decreased sweating manifests as heat or exercise intolerance. Patients may have noticeably warm and/or dry skin.
  • The eyes may be affected. Careful ophthalmologic examination may reveal ptosis, anisocoria, Horner syndrome, or tonic pupils
  • Failure of either erection or ejaculation is a common physical manifestation in males. Female sexual dysfunction has not been well studied in these disorders.

   

  

   
• 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. However, additional neurologic features may be present.

  • Pyramidal or cerebellar abnormalities including weakness, ataxia, incoordination, and eye-movement abnormalities may precede the autonomic features by as long as 2 years.
  • Patients with the MSA parkinsonian variant have variable parkinsonian findings, including rigidity, bradykinesia, tremor, and truncal instability, that do not respond to levodopa.
  • Patients with the MSA cerebellar variant have evidence of cerebellar dysfunction that manifests as 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.

• References

Laboratory Studies

See the list below:

• The patient's clinical history directs the evaluation of orthostatic hypotension and autonomic failure.

  • An acute onset of autonomic symptoms without other neurologic problems or with features such as, subtle weakness, or numbness, should prompt an evaluation for acute inflammatory demyelinating polyneuropathy (AIDP). Elevated cerebrospinal fluid (CSF) protein levels without notable cellularity may be seen (albuminocytologic dissociation) but may take several days to develop.
  • A subacute onset without other neurologic or systemic findings may indicate autoimmune autonomic neuropathy (AAN). Ganglionic AChR antibody titers can be measured.^{[2, 3]} These antibodies are different from the antibodies against nicotinic muscle AChRs seen in myasthenia gravis.
  • A chronic onset should trigger a search for other neurologic abnormalities. In particular, evaluation for Parkinson's disease and MSA is essential. A few patients with classic idiopathic Parkinson's disease have autonomic failure early in the course of the illness. No specific laboratory test is useful for confirming this diagnosis.

   

  

   
• 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.

  • Increased sympathetic activity may be caused by amphetamines, cocaine, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and beta-adrenergic agonists.
  • Decreased sympathetic activity may be seen with centrally active agents, such as clonidine, methyldopa, reserpine, or barbiturates. Peripherally acting agents (eg, alpha- or beta-adrenergic antagonists) may cause a similar picture.
  • Increased parasympathetic activity can be seen in the setting of cholinergic agonists, such as bethanechol or pilocarpine. Anticholinesterase inhibitors, such pyridostigmine or organophosphate pesticides may create a similar clinical picture.
  • Decreased parasympathetic activity may be seen in the setting of antidepressants, phenothiazines, anticholinergic agents, and botulinum toxicity.

   

  

   
• A positive family history with onset in the first decades of life may suggest a hereditary sensory and autonomic neuropathy (HSAN).
• Tests for other systemic disorders causing secondary pandysautonomia may be ordered according to clues from the history.

  • Glycosylated hemoglobin or glucose tolerance test may be indicated to test for diabetes.
  • Anti-Hu antibody titers may be needed if the patient has associated sensory neuropathy or cognitive changes.
  • Anti-calcium channel antibody titers for Lambert-Eaton myasthenic syndrome (LEMS), a presynaptic disorder of neuromuscular transmission, are sometimes associated with acute or subacute autonomic symptoms. About one half of patients have an associated neoplasm. As many as 80% of these may be small cell lung cancer. Patients may give a history of smoking or recent weight loss.
  • In cases of suspected poisoning by food or wound contamination, screen stool for botulinum by culture and detection of toxin. Botulism is another presynaptic disorder of neuromuscular transmission that may be associated with autonomic symptoms. However, a negative result does not exclude the possibility of botulism. Consultation with the Centers for Disease Control and Prevention may be a prerequisite of ordering the test because of heightened bioterrorism surveillance.
  • Serum and urine protein electrophoresis may be ordered to evaluate myeloma with amyloidosis, or genetic testing to evaluate for familial amyloidosis.
  • Rapid plasma reagent (RPR) or Venereal Disease Research Laboratory test (VDRL) may be needed to test for syphilis.
  • HIV testing may be indicated.
  • Autoimmune screening helps to evaluate for collagen-vascular disease. This testing may include antinuclear antibody levels, erythrocyte sedimentation rate, and other autoimmune tests (eg, rheumatoid factor, SS-A and SS-B antibodies), as the clinical syndrome dictates.
  • Assessment of the urinary porphyrins and erythrocyte porphobilinogen deaminase levels are indicated if the clinical history suggests the possibility of porphyria.

   

  

   

• References

Imaging Studies

See the list below:

• Brain MRI may be useful, 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 the other conditions of primary autonomic dysfunction.^[4]
• No imaging abnormalities are expected in pure autonomic failure, autoimmune autonomic neuropathy, or postural orthostatic tachycardia syndrome.

• References

Other Tests

See the list below:

• In addition to supine and standing blood pressure and pulse measurements, additional cardiovascular evaluation (eg, ECG, cardiac telemetry) may be indicated to identify tachycardia, bradycardia, or other dysrhythmias.

  • Assessment of heart rate variability with deep breathing or Valsalva maneuver can further define the extent of cardiac involvement.
  • If the patient is unable to stand, 45° head-up tilt testing can be performed.
  • Patients with POTS have an exaggerated increase in heart rate on tilt table testing, defined as an increase of greater than 30 bpm or an increase to greater than 120 bpm within 10 minutes of tilt.

   

  

   
• Nerve conduction studies (NCS) and electromyography (EMG) are important to document any coexisting neuropathy or disorder of neuromuscular transmission.
• Additional autonomic testing, such as sympathetic skin response, is available in some electrodiagnostic laboratories. Skin vasomotor responses and sweat testing are 2 highly specialized autonomic tests that can be performed in a few autonomic laboratories. Skin vasomotor responses may help distinguish PAF from MSA. Sweat testing, either with acetylcholine iontophoresis or thermoregulatory testing, may be helpful even if the patient does not complain specifically of sweating abnormalities.
• GI motility can be evaluated in a number of ways, including an upper or lower GI series, cine videofluoroscopy, endoscopy, and gastric-emptying studies.
• Bladder ultrasound and postvoiding residual volumes should be assessed in patients with urinary symptoms. Urodynamic studies and intravenous urography also may help to define the cause of urinary retention or incontinence.
• Male impotence can be evaluated by using penile plethysmography and response to intracavernosal papaverine.
• Measurement of levels of plasma noradrenalin with the patient supine may help distinguish central from peripheral autonomic failure. MSA patients, who have centrally mediated autonomic failure, have normal supine levels of noradrenalin.

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Procedures

See the list below:

• Because of the frequency of autonomic dysfunction in AIDP, acute onset of autonomic abnormalities must prompt consideration of AIDP in the differential diagnosis.

  • A lumbar puncture is indicated for CSF studies.
  • Patients with AIDP typically develop elevated protein levels but no elevation of the cell counts (ie, albuminocytologic dissociation).
  • Highly cellular CSF suggests alternate diagnoses, such as infection or inflammation.

   

  

   
• Sural nerve biopsy may be indicated if the clinical presentation suggests amyloidosis or if an unexplained axonal neuropathy is present on NCS or EMG testing.

  • If the clinical suspicion for amyloidosis is high, biopsy of the abdominal fat pad or a rectal biopsy should be performed to look for amyloid deposits. Patients with amyloid neuropathy, may have patchy deposition of the abnormal proteins in nerve, but sural nerve biopsy may still be helpful, especially if the findings on fat pad and rectal biopsy are normal.
  • Nerve biopsy is unnecessary if NCS reveals clear evidence of focal demyelination, or if the course of disease and clinical findings are otherwise consistent with AAN.

   

  

   
• Skin biopsy has been studied in the evaluation of small fiber neuropathy as well as demyelinating neuropathies with autonomic symptoms.^[10] In patients with either acute or chronic demyelinating neuropathies, the subgroups with autonomic symptoms have lower intraepidermal nerve-fiber densities.

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Histologic Findings

Biopsy of the CNS is never part of the routine evaluation for these disorders (see Procedures). However, brain autopsy specimens in MSA show distinct glial cytoplasmic inclusions composed of 20- to 30-nm multilayered tubular filaments that are argyrophilic. The inclusions are found in the basal ganglia, the supplementary and primary motor cortex, the reticular formation, and the pontocerebellar system.

Alpha-synuclein is present in the glial inclusions and appears to play an important role in MSA. The autonomic failure in MSA likely results from cell loss in the dorsal motor nucleus of vagus nerve, locus coeruleus, and the catecholaminergic neurons of the ventrolateral medulla. Cell loss in the pontomedullary reticular formation, parasympathetic preganglionic nuclei of the spinal cord, and sympathetic intermediolateral column of the spinal cord are also important.

Other limited data on PAF demonstrate additional nerve cell loss and Lewy bodies, which stain for ubiquitin in the paravertebral sympathetic ganglia. Whether these patients had a form fruste of MSA is unclear.

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Medical Care

The treatment of autoimmune autonomic neuropathy (AAN) is based on anecdotal evidence. No data from large, controlled trials are available owing to the rarity of the disorder. The treatment of chronic pure autonomic failure syndromes is symptomatic only. Postural orthostatic tachycardia syndrome can be treated by using 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]

• Discontinue antihypertensive medications and other medications known to lower blood pressure, if feasible.
• Increase fluid and salt intake.
• 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 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 prevent overheating.
• Large meals may exacerbate hypotension and should be avoided.
• Perform positional changes, such as standing up, slowly and gradually.
• Elevate the head of the bed and avoid prolonged recumbency.

Immunomodulatory therapy has been used successfully to shorten the duration of symptoms and improve overall prognosis in acute and chronic pandysautonomia.^[11]

• Cases in which clinical improvement began within a few days of intravenous immunoglobulin (IVIg) administration (2 g/kg body weight over 2-5 d), along with normalization of autonomic test parameters, have been reported.^{[12, 13]}
• Presumably, IVIg has an immunomodulatory action, but the exact mechanism of its effect in this disorder is unclear.
• In 1 series, 2 patients with acute pandysautonomia were treated with prednisone 60 mg/d for several months and reported subjective improvement. No quantitative follow-up data were obtained.
• In a series of 3 patients with autoimmune autonomic ganglionopathy, patients treated with prednisone, mycophenolate mofetil, and plasmapheresis reported improvement when plasmapheresis or IVIg alone was not effective.^[14]
• Other pharmacologic treatment options are directed toward symptomatic relief only (See Medication).^[5]

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Activity

Symptoms limit activity. Precautions for falling should be taken in patients who have orthostatic hypotension. In those with decreased sweating, vigorous exercise should be limited, and patients should be advised to have spray bottles of water or wet sponges available during hot weather or during physical activity.

• References

Medication Summary

Several medications are available to help manage symptoms of autonomic dysfunction. The most commonly used are listed below.

• References

Fludrocortisone (Florinef)

• Dosing, Interactions, etc.

Clinical Context:  Used to increase standing blood pressure. Acts to increase sodium retention and expand plasma volume.

• References

Class Summary

These agents play a role in hemodynamics and can be used to control orthostatic hypotension.

• References

Midodrine (ProAmatine)

• Dosing, Interactions, etc.

Clinical Context:  Alpha-adrenergic agonist used in orthostatic hypotension to increase standing blood pressure. Acts at level of resistance vessels and is useful for peripherally mediated hypotension.

• References

Droxidopa (Northera)

• Dosing, Interactions, etc.

Clinical Context:  Droxidopa is a norepinephrine precursor that is metabolized to norepinephrine by dopa-decarboxylase. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction. It is indicated for symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

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Class Summary

These agents improve the hemodynamic status by increasing blood pressure. Midodrine forms the active metabolite desglymidodrine, which is an alpha1-agonist. Desglymidodrine exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Droxidopa increases blood pressure by conversion to norepinephrine, but has no clinically significant effect on standing or supine heart rates in patients with autonomic failure.

• References

Propranolol (Inderal)

• Dosing, Interactions, etc.

Clinical Context:  Nonselective beta-blocker that is lipophilic (penetrates CNS).

• References

Class Summary

These agents limit heart rate and reduce blood pressure.

• References

Desmopressin (DDAVP, Stimate)

• Dosing, Interactions, etc.

Clinical Context:  Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys. Helpful for symptoms of nocturia.

• References

Class Summary

These agents augment both coronary and cerebral blood flow that occurs during the low flow state associated idiopathic hypotension.

• References

Epoetin alfa (Epogen, Procrit)

• Dosing, Interactions, etc.

Clinical Context:  Stimulates RBC production in bone marrow. Increases sensitivity to pressor effects of angiotensin II, intravascular volume, cytosolic free calcium in vascular smooth muscle, and plasma endothelin level. Enhances renal tubular reabsorption.

• References

Class Summary

Anemia may occur due to low blood levels of endogenous erythropoietin, which can result from a lack of sympathetic innervation. Erythropoietins may also increase blood pressure through other mechanisms.

• References

Metoclopramide (Reglan)

• Dosing, Interactions, etc.

Clinical Context:  Dopamine agonist helpful in relieving GI paresis.

• References

Class Summary

These agents promote motility of the GI tract.

• References

Pyridostigmine bromide (Mestinon)

• Dosing, Interactions, etc.

Clinical Context:  Stimulates muscarinic AChR, increasing salivation and gastric motility.

• References

Class Summary

These agents inhibit acetylcholinesterase (AChE), raising the concentration of ACh at cholinergic synapses and increasing the chance of activating the AChR.

• References

Psyllium (Metamucil, Fiberall)

• Dosing, Interactions, etc.

Clinical Context:  Must be taken with water or may cause obstruction. Increase dose gradually. Inform patient that effect not immediate.

• References

Class Summary

Used for the chronic treatment of constipation.

• References

Oxybutynin (Ditropan)

• Dosing, Interactions, etc.

Clinical Context:  Useful for urinary urgency. Inhibits action of ACh on smooth muscle and direct antispasmodic effect on smooth muscle, which increases bladder capacity and decreases uninhibited contractions.

• References

Class Summary

These agents may be helpful for urinary symptoms.

• References

Bethanechol hydrochloride (Duvoid, Urecholine)

• Dosing, Interactions, etc.

Clinical Context:  For selective stimulation of the bladder to produce contraction to initiate micturition and empty bladder. Most useful in bladder hypotonia. Rarely used because of GI stimulation and difficulty in timing effect.

• References

Class Summary

These agents stimulate cholinergic receptors in the smooth muscle of the urinary bladder for stimulation of bladder emptying.

• References

Sildenafil (Viagra)

• Dosing, Interactions, etc.

Clinical Context:  Selective PDE5 inhibitor that inactivates cGMP, attenuating vasodilatory effect of NO. Effective in mild-to-moderate erectile dysfunction. Patient should take on an empty stomach about 1 h before sexual activity. Sexual stimulation necessary to activate response. Increased sensitivity for erections may last 24 h.

• References

Class Summary

These oral agents act peripherally to induce smooth muscle relaxation of the corpora cavernosa.

• References

Prednisone (Deltasone, Orasone, Meticorten)

• Dosing, Interactions, etc.

Clinical Context:  Shorten duration of symptoms and improves overall prognosis in acute pandysautonomia.

• References

Class Summary

These agents regulate key factors in the immune system.

• References

Immune globulins intravenous (IVIG, Gammagard, Gamimune)

• Dosing, Interactions, etc.

Clinical Context:  Shortens duration of symptoms and improves overall prognosis in acute pandysautonomia. Clinical improvements have been reported within few days of administration, with normalization of autonomic parameters.

Neutralize circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).

• References

Class Summary

These agents are used to improve clinical and immunologic aspects of the disease. May decrease autoantibody production, and increase solubilization and removal of immune complexes.

• References

Further Inpatient Care

See the list below:

• Physical therapy is useful for gait training. Patients also should be instructed in safety precautions.
• Patients should be monitored closely for drug efficacy and adverse effects. Doses should be adjusted accordingly.

• References

Prognosis

See the list below:

• The prognosis for autoimmune autonomic neuropathy (AAN) is poor without treatment, and many patients have residual autonomic symptoms. With IVIg therapy, a few patients who are treated early in the disease course can have excellent recovery of function. However, additional patients must be treated to confirm the initial favorable findings.
• Patients with pure autonomic failure have symptoms that remain confined to the autonomic nervous system. These patients generally improve little over time, and their symptoms may worsen. Some may later develop multiple system atrophy or Parkinson's disease.
• The prognosis for patients with multiple system atrophy is poor overall. Neurologic function declines gradually over time. The autonomic symptoms often become debilitating. Survival is typically 6-9 years from the time of diagnosis.

• References