eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes

Jeffrey Tam Sing, MD, Consulting Physician, Neurology of the Rockies, Parker, Colorado
Bjorn E Oskarsson, MD, Assistant Professor, Department of Neurology, University of California Davis; Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center

Updated: Nov 18, 2009

Introduction

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 are 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.

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

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.
  • 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.

Physical

• 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, dysdiadokinesia, 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 are diagnostic.

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.
  • 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.

Differential Diagnoses

Other Problems to Be Considered

Transthyretin-related amyloidosis
Diseases of tetrapyrrole metabolism - Refsum disease, hepatic porphyrias

Workup

Laboratory Studies

• 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.^1,2 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.

Imaging Studies

• 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.³
• No imaging abnormalities are expected in pure autonomic failure, autoimmune autonomic neuropathy, or postural orthostatic tachycardia syndrome.

Other Tests

• 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.

Procedures

• 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.⁴ In patients with either acute or chronic demyelinating neuropathies, the subgroups with autonomic symptoms have lower intraepidermal nerve-fiber densities.

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.

Treatment

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.⁶
  • 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.^7,8
  • 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.⁹
  • Other pharmacologic treatment options are directed toward symptomatic relief only (See Medication).⁵

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.

Medication

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

Mineralocorticoids

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

Fludrocortisone (Florinef)

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

Dosing

Adult

0.1-0.2 mg PO qd

Pediatric

Not established

Interactions

Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Supine hypertension may limit use; may cause adrenal insufficiency if withdrawn too rapidly; increased dose may be required in times of physiologic stress

Alpha-adrenergic agonists

These agents improve the hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. They also increase peripheral resistance by causing vasoconstriction. Increased cardiac output and increased peripheral resistance lead to increased blood pressure.

Midodrine (ProAmatine)

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.

Dosing

Adult

2.5-10 mg PO tid

Pediatric

Not established

Interactions

Drugs that stimulate alpha-adrenergic agonists may enhance or potentiate pressor effects; cardiac glycosides may enhance or precipitate bradycardia; psychopharmacologic agents or beta-blockers may enhance or precipitate AV block or arrhythmia

Contraindications

Documented hypersensitivity; acute renal disease; severe organic heart disease; pheochromocytoma; urinary retention; persistent and excessive supine hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in diabetes or visual complications; discontinue drug and reevaluate if any signs or symptoms suggesting bradycardia occur

Beta-adrenergic blocking agents

These agents limit heart rate and reduce blood pressure.

Propranolol (Inderal)

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

Dosing

Adult

10-60 mg PO qd

Pediatric

Not established

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol

Contraindications

Documented hypersensitivity; history of bronchospasm; congestive heart failure; bradycardia; cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may hide signs of acute hypoglycemia and hyperthyroidism, Raynaud phenomenon, hypotension, decreased libido, impotence, lethargy, depression, and decreased HDL; caution in Wolff-Parkinson-White syndrome and renal or hepatic dysfunction

Vasopressors

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

Desmopressin (DDAVP, Stimate)

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

Dosing

Adult

0.1-0.4 mL of 100-mcg/mL solution intranasally qd or divided bid/tid

Pediatric

Not established

Interactions

Demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects

Contraindications

Documented hypersensitivity; platelet-type von Willebrand disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Avoid overhydration; may exacerbate hyponatremia

Erythropoietins

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.

Epoetin alfa (Epogen, Procrit)

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.

Dosing

Adult

50 U/kg IV/SC, initially once or twice weekly

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sufficient bodily iron stores are needed for EPO to increase hematocrit; may predispose patients to seizures, usually due to uncontrolled hypertension; caution in porphyria, hypertension, or history of seizures

Gastroprokinetic agents

These agents promote motility of the GI tract.

Metoclopramide (Reglan)

Dopamine agonist helpful in relieving GI paresis.

Dosing

Adult

5-15 mg PO qid given 30 min ac and hs

Pediatric

Not established

Interactions

May antagonize effects of metoclopramide; opiate analgesics may increase toxicity in CNS; may slow absorption of drugs from stomach but increase rate of absorption of drugs from small bowel

Contraindications

Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in history of mental illness, Parkinson disease, or hypertension

Anticholinesterase inhibitors

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

Pyridostigmine bromide (Mestinon)

Stimulates muscarinic AChR, increasing salivation and gastric motility.

Dosing

Adult

60-960 mg/d PO in divided doses; individualize to patient

Pediatric

7 mg/kg/d PO in divided doses

Interactions

Increases effects of depolarizing neuromuscular blockers; increases edrophonium toxicity

Contraindications

Documented hypersensitivity, peritonitis, mechanical obstruction of GI or GU tract

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Overdose may cause cholinergic crisis, which may be fatal; use cautiously in patients with bronchial asthma and those receiving a cardiac glycoside; adverse effects stem from dose-related, excessive muscarinic AChR effects

Bulk agents

Used for the chronic treatment of constipation.

Psyllium (Metamucil, Fiberall)

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

Dosing

Adult

15-60 g/d PO with at least 8 glasses of water

Pediatric

7.5-15 g/d PO with at least 4 glasses water

Interactions

May reduce bioavailability of medications if taken within 30-60 min of fiber supplements because of adsorption to fiber; may decrease absorption of salicylates, nitrofurantoin, tetracyclines, and diuretics

Contraindications

Documented hypersensitivity; fecal impaction, intestinal obstruction, or undiagnosed abdominal pain

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with poor mobility, intestinal adhesions, ulcers, or bowel stenosis

Antispasmodic agents

These agents may be helpful for urinary symptoms.

Oxybutynin (Ditropan)

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.

Dosing

Adult

5 mg PO bid/tid; not to exceed 5 mg qid

Pediatric

<5 years: Not established
>5 years: 5 mg PO bid/tid

Interactions

CNS effects increase with concurrent CNS depressants

Contraindications

Documented hypersensitivity; untreated angle-closure glaucoma or untreated narrow anterior chamber angles; GI obstruction; paralytic ileus; colitis; myasthenia gravis; unstable cardiovascular status

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in the elderly and in patients with hepatic or renal disease; may exacerbate symptoms of hyperthyroidism, coronary artery disease, tachycardia or other cardiac arrhythmias, hiatal hernia, hypertension, and prostatic hypertrophy; may contribute to decreased GI motility

Cholinergic agents

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

Bethanechol hydrochloride (Duvoid, Urecholine)

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.

Dosing

Adult

10-50 mg PO tid/qid

Pediatric

Not established

Interactions

Concurrent ganglion-blocking compounds may critically decrease BP

Contraindications

Documented hypersensitivity; peptic ulcer disease; obstructive pulmonary disease; bradycardia; vasomotor instability; hypotension; AV conduction defects; hyperthyroidism; epilepsy; mechanical GI/GU obstruction.

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Urinary retention secondary to possible urine reflux into kidneys

Phosphodiesterase inhibitors

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

Sildenafil (Viagra)

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.

Dosing

Adult

25-100 mg PO 1 h before sexual activity

Pediatric

Not established

Interactions

Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil

Contraindications

Documented hypersensitivity; concurrent or intermittent use of organic nitrates in any form

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), blue haze at the periphery of vision (3%); AEs more common in men taking 100 mg; serious AEs in severe heart disease and those taking nitrates; rates of MI 1.7 (drug) and 1.4 (placebo) per 100 man-years

Corticosteroids

These agents regulate key factors in the immune system.

Prednisone (Deltasone, Orasone, Meticorten)

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

Dosing

Adult

Not established; in 1 series, 2 patients given 60 mg/d PO for several months, with subjective improvement but no quantitative follow-up data

Pediatric

Not established

Interactions

Estrogens may decrease clearance; may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); diuretics may cause hypokalemia

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for hypokalemia if diuretics taken concurrently; long-term use may predispose patients to various problems including hyperglycemia, manifestation of latent diabetes mellitus, nonketotic hyperosmolar state, osteoporosis, avascular necrosis of hip, peptic ulcer disease, cataracts and glaucoma, steroid myopathy, cushingoid appearance, weight gain, suppression of pituitary-hypothalamic axis, growth suppression (in children); water retention may precipitate congestive heart failure and hypertension; unmasking of latent infections (eg, tuberculosis, herpes zoster) and predisposition to fungal and parasitic infection; because of suppressed pituitary-hypothalamic axis, additional steroid dosing may be necessary at times of stress (eg, systemic infections, surgery)

Immune globulins

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.

Immune globulins intravenous (IVIG, Gammagard, Gamimune)

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%).

Dosing

Adult

2 g/kg body weight IV divided over 2-5 d

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies; renal insufficiency or renal artery stenosis (may cause renal failure)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Consider checking serum IgA before IVIG and using IgA-depleted IVIG (G-Gard-SD) if indicated; IVIG may increase serum viscosity and thromboembolic events; adverse effects have included migraines; 10% increased risk of aseptic meningitis; increased risk of urticaria, pruritus, or petechiae 2-5 d after infusion (may last 1 mo); increased risk of renal tubular necrosis in older, diabetic, and volume-depleted patients and in preexisting kidney disease; can change laboratory values: elevated antiviral or antibacterial antibody titers for 1 mo; 6-fold increased ESR for 2-3 wk; apparent hyponatremia

Follow-up

Further Inpatient Care

• 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.

Prognosis

• 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.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose and treat acute inflammatory demyelinating polyneuropathy
• Failure to detect an associated malignancy at the time of presentation
• Failure to prevent fatal cardiac events

References

1. Klein CM, Vernino S, Lennon VA, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol. 2003;53:752-8. [Medline].

2. Sandroni P, Vernino S, Klein CM, et al. Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol. Jan 2004;61(1):44-8. [Medline].

3. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. Feb 1 1999;163(1):94-8. [Medline].

4. Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. Jul 2007;6(7):632-42. [Medline].

5. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. Feb 7 2008;358(6):615-24. [Medline].

6. Schroeder C, Vernino S, Birkenfeld AL, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med. Oct 13 2005;353(15):1585-90. [Medline].

7. Heafield MT, Gammage MD, Nightingale S, Williams AC. Idiopathic dysautonomia treated with intravenous gammaglobulin. Lancet. Jan 6 1996;347(8993):28-9. [Medline].

8. Quan D, Rich MM, Bird SJ. Acute idiopathic dysautonomia: electrophysiology and response to intravenous immunoglobulin. Neurology. Feb 8 2000;54(3):770-1. [Medline].

9. Gibbons C, Vernino S, Freeman R. Combined immunomodulation therapy in autoimmune autonomic ganglionopathy. Arch Neurol. Feb 2008;65(2):213-217.

10. Bannister R, Mathias CJ, Polinsky R. Autonomic failure--A comparison between UK and US experience. In: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. New York, NY: Oxford University Press; 1988:282-8.

11. Daniel SE. The neuropharmacology and neurochemistry of multiple system atrophy. In: Autonomic Failure: A Textbook of Disorders of the Autonomic Nervous System. New York, NY: Oxford University Press; 1992:564-85.

12. Hoeldtke RD, Bryner KD, Hoeldtke ME, Hobbs G. Treatment of autonomic neuropathy, postural tachycardia and orthostatic syncope with octreotide LAR. Clin Auton Res. Dec 2007;17(6):334-40. [Medline].

13. Kaufmann H. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res. Apr 1996;6(2):125-6. [Medline].

14. Mathias CJ. Disorders of the autonomic nervous system. In: Neurology in Clinical Practice. Boston, Mass: Butterworth-Heinemann; 1996:1953-81.

15. Matthews MR. Autonomic ganglia in multiple system atrophy and pure autonomic failure. In: Autonomic Failure: A Textbook of Disorders of the Autonomic Nervous System. New York, NY: Oxford University Press; 1992:593-621.

16. Quinn NP, Wenning G, Marsden CD. The Shy-Drager syndrome. What did Shy and Drager really describe?. Arch Neurol. Jul 1995;52(7):656-7. [Medline].

17. Smit AA, Vermeulen M, Koelman JH, Wieling W. Unusual recovery from acute panautonomic neuropathy after immunoglobulin therapy. Mayo Clin Proc. Apr 1997;72(4):333-5. [Medline].

18. Suarez GA, Fealey RD, Camilleri M, Low PA. Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology. Sep 1994;44(9):1675-82. [Medline].

19. van Ingelghem E, van Zandijcke M, Lammens M. Pure autonomic failure: a new case with clinical, biochemical, and necropsy data. J Neurol Neurosurg Psychiatry. Jun 1994;57(6):745-7. [Medline].

20. Vernino S, Freeman R. Peripheral Autonomic Neuropathies. Continuum Lifelong Learning Neurol. Dec 2007;13(6):89-110.

Keywords

acute idiopathic dysautonomia, multiple system atrophy, olivopontocerebellar atrophy, pure autonomic failure, Shy-Drager syndrome, striatonigral degeneration, postural tachycardia syndrome, autoimmune autonomic neuropathy, autoimmune autonomic ganglionopathy, acute pandysautonomia, acute panautonomic neuropathy

Contributor Information and Disclosures

Author

Jeffrey Tam Sing, MD, Consulting Physician, Neurology of the Rockies, Parker, Colorado
Jeffrey Tam Sing, MD is a member of the following medical societies: American Academy of Neurology and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Bjorn E Oskarsson, MD, Assistant Professor, Department of Neurology, University of California Davis
Bjorn E Oskarsson, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center
Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: e-medicine Honoraria Other

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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