eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes

Author: Jeffrey Tam Sing, MD, Consulting Physician, Neurology of the Rockies, Parker, Colorado
Coauthor(s): 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
Contributor Information and Disclosures

Updated: Dec 9, 2008

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.
  • For related information, see Medscape's CME activity, Multiple System Atrophy: A Clinical Review.
• 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.
• AAN: 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.
• MSA: 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.
• POTS: 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.

• Search for CME/CE on This Topic »