The author: Professor Yasser Metwally
http://yassermetwally.com
INTRODUCTION
December 12, 2009 — Autonomic failure has many causes and manifestations. It may result from a primary disturbance of autonomic regulation or as a secondary effect of another systemic disorder (eg, diabetes, amyloidosis). This chapter will focus on the 3 primary syndromes of autonomic failure: acute or subacute idiopathic pandysautonomia; pure autonomic failure (PAF); and, multiple system atrophy (MSA). Pure autonomic failure and multiple system atrophy are chronic syndromes of primary autonomic dysfunction. Included under the rubric of pure autonomic failure is idiopathic Orthostatic hypotension, which has Orthostatic hypotension as its only clinical feature.
The hypothalamus, midbrain, brain stem and intermediolateral cell columns in the spinal cord are the major regions within the central nervous system (CNS) that are important in regulating autonomic activity. Sympathetic nervous system outputs arise in the cerebral 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 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.
All other postganglionic sympathetic synapses are noradrenergic. Autonomic failure may be caused by dysfunction of the central or peripheral nervous system pathways. The function of all major organ systems is modulated by a precise balance of sympathetic and parasympathetic inputs. Primary disorders of autonomic function almost never exclusively affect sympathetic or parasympathetic function.
Symptoms typically 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. Thus, in some organ systems (eg, gastrointestinal) parasympathetic inputs may predominate. In other systems (eg, cardiovascular), absence of sympathetic input may be more clinically significant.
The features of autonomic involvement may be extensive in all of these conditions. Common manifestations include orthostasis, nausea, constipation, urinary retention or incontinence, nocturia, impotence, heat intolerance, and dry mucous membranes. Less commonly, there may be periods of apnea or inspiratory stridor.
In acute idiopathic dysautonomia, limb numbness, tingling, or pain are sometimes seen. In PAF, there are no other neurologic symptoms. Formerly, pure autonomic failure (PAF); was considered by some practitioners synonymous with idiopathic Orthostatic hypotension. Because many affected individuals have other areas of autonomic involvement in addition to blood pressure abnormalities (eg, pupillary, sweating, bowel and bladder, and sexual dysfunction), the term "pure autonomic failure" is preferred over the original term "idiopathic Orthostatic hypotension."
Multiple system atrophy (MSA) is a syndrome of chronic autonomic dysfunction and parkinsonism or ataxia. A subset of patients with PAF may progressively develop MSA, but no clinical or diagnostic markers exist to identify this group at the outset. MSA is a chronic, progressive disorder of adulthood. Autonomic dysfunction is a common finding in MSA but not essential to the diagnosis. Depending on their clinical features, patients with MSA may be categorized into 3 different groups:
1- Shy-Drager variants: predominant autonomic symptoms
2- Striatonigral degeneration: predominant parkinsonian symptoms
3- Olivopontocerebellar atrophy: predominant cerebellar symptoms
Symptoms of decreased sympathetic function may include the following:
1- Orthostatic hypotension
2- Decreased sweating
3- Impotence
4- Ptosis associated with a Horner’s syndrome
Symptoms of decreased parasympathetic function may include the following:
1- Constipation
2- Nausea
3- Urinary retention
4- Impotence
Acute and subacute idiopathic pandysautonomia are manifested clinically as
1- 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 min of standing.
2- Gastroparesis is common and associated with nausea or constipation. Diarrhea is infrequent. The abdomen may be distended, and patients may have discomfort on palpation. An acute abdomen is unusual.
3- Urinary retention is seen frequently and may cause bladder distention. A distended bladder can be percussed or palpated on examination.
4- Decreased sweating manifests as heat or exercise intolerance. Patients may have noticeably warm and/or dry skin.
5- The eyes may be affected. Careful ophthalmologic examination may reveal ptosis, anisocoria, a Horner’s syndrome or tonic pupils.
6- Impotence due either to a failure of erection or ejaculation is a common physical manifestation in males. Female sexual dysfunction is not well-documented in the literature.
In pure autonomic failure (PAF), the physical findings are similar to those observed in acute idiopathic dysautonomia.
In MSA, the autonomic manifestations are similar to those observed in acute idiopathic dysautonomia and PAF. However, additional neurologic features may be present that include.
1- Patients with Shy-Drager syndrome may have pyramidal or cerebellar abnormalities on examination. Weakness, ataxia, incoordination, and eye-movement abnormalities may precede the prominent autonomic features by up to 2 years.
2- Patients with Striatonigral degeneration: have parkinsonian findings, including rigidity, bradykinesia, tremor and truncal instability.
3- Patients with olivopontocerebellar degeneration have evidence of cerebellar dysfunction that manifests as ataxia, dysmetria, dysdiadokinesia and incoordination. Eye-movement abnormalities are frequently present.
The cause of acute autonomic failure is unclear. The syndrome is considered by some to be a variant of Guillain-Barré syndrome (GBS). Some cases may arise from an acquired presynaptic defect in autonomic ganglia. The precise role of infection and other immune factors remains uncertain, but the lack of other CNS manifestations suggests that the lesion localizes to the peripheral nervous system (PNS).
Pure autonomic failure (PAF) and MSA are sporadic disorders of uncertain etiology.
1- Intermediolateral cell column involvement with the loss of small sympathetic neurons has been observed in pure autonomic failure (PAF).
2- In MSA with autonomic involvement, changes in the intermediolateral cell column also may be seen; in addition, widespread abnormalities are apparent in the brain.
3- The associated clinical findings are related to the constellation of affected areas.
4- There may be neuronal loss in the basal ganglia, pons, cerebellum, substantia nigra, locus ceruleus, nucleus of Edinger-Westphal, hypothalamus, thalamus, and vestibular complex.
There is no diagnostic laboratory study that is specific for acute idiopathic dysautonomia. The evaluation of Orthostatic hypotension and autonomic failure must be directed by the clinical history.
An explosive or subacute onset of autonomic symptoms without other neurological features should prompt an evaluation for treatable causes of acute dysautonomia.
A more chronic onset should trigger a search for other neurological abnormalities.
Drug or toxin exposure may cause acute autonomic dysfunction that is generalized or organ-specific. The predominant abnormality (ie, increased or decreased sympathetic or parasympathetic activity) should be identified. The patient’s existing list of medications should be reviewed carefully. Drugs that might cause acute autonomic dysfunction include:
1- Increased sympathetic activity may be caused by amphetamines, cocaine, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and beta-adrenergic agonists.
2- 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) also may cause a similar picture.
3- 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.
4- Decreased parasympathetic activity may be seen in the setting of antidepressants, phenothiazines, anticholinergic agents, and botulism toxicity.
Lambert-Eaton Myasthenic Syndrome (LEMS), a presynaptic disorder of neuromuscular transmission, is sometimes associated with acute or subacute autonomic symptoms. In half of cases, patients have an associated neoplasm. Up to 80% of these may be small cell lung cancer. In the case of Lambert-Eaton Myasthenic Syndrome (LEMS), anti-calcium channel antibody testing is sensitive but not specific. Patients may give a history of smoking or recent weight loss.
Botulism is another presynaptic disorder of neuromuscular transmission that may be associated with autonomic symptoms. An assay is available to screen the stool for botulism toxin. However, a negative result does not exclude the possibility of botulism.
Urinary porphyrins and erythrocyte porphobilinogen deaminase levels are indicated, if the clinical history suggests the possibility of porphyria.
Further tests may be ordered to screen other systemic disorders that cause secondary pandysautonomia that include.
1- Glycosylated hemoglobin to test for diabetes
2- Serum and urine protein electrophoresis to evaluate for myeloma with amyloidosis
3- RPR or VDRL to test for syphilis
4- HIV test
5- Autoimmune screen to evaluate for collagen vascular disease. This may include antinuclear antibody erythrocyte, sedimentation rate, and other autoimmune tests (eg, rheumatoid factor, SS-A and SS-B antibodies), as dictated by the clinical syndrome.
Patients with chronic progressive autonomic failure must be carefully evaluated for evidence of other neurological deficits or associated medical conditions. In particular, evaluation for Parkinson’s disease is essential, as a small group of patients with classical idiopathic Parkinson’s disease have autonomic failure late in the course of the disease. As is the case in acute disease, no specific laboratory tests exist to confirm the diagnosis.
Brain magnetic resonance imaging (MRI) may be useful, particularly in cases of centrally mediated dysautonomia. In particular, if cerebellar or other motor findings are present, brainstem or cerebellar atrophy may be identified.
1- In addition to supine and standing blood pressure measurements, more extensive cardiovascular evaluation (eg, ECG or cardiac telemetry) may be indicated to identify tachycardia, bradycardia or other dysrhythmias.
2- Assessment of heart rate variability with deep breathing or Valsalva maneuver can further define the extent of cardiac involvement.
3- If the patient is unable to stand, 45o head-up tilt testing can be performed.
4- Nerve conduction studies (NCS) and electromyography (EMG) are important to document any coexisting neuropathy or disorder of neuromuscular transmission.
5- Additional autonomic testing is available in some electrodiagnostic laboratories. Sweat testing should be performed even if the patient does not complain specifically of sweating abnormalities.
6- Gastrointestinal motility can be evaluated in a number of ways, including an upper or lower GI series, videocinefluoroscopy, endoscopy, gastric-emptying studies and endoscopy.
7- Bladder ultrasound and post-void residual volumes should be assessed in patients with urinary symptoms. Urodynamic studies and IV urography may also help to define the cause of urinary retention or incontinence.
8- Male impotence can be evaluated using penile plethysmography and response to intracavernosal papaverine.
9- Measurement of supine levels of plasma noradrenaline may help distinguish central from peripherally mediated autonomic failure.
10 In PAF, levels should be low as compared to normal levels in Shy-Drager syndrome.
11- In both conditions, the normal increase in noradrenaline levels with standing is attenuated.
1- Due to the frequency of occurrence in GBS, autonomic dysfunction must prompt consideration of this disorder in the differential diagnosis.
2- Cerebrospinal fluid (CSF) studies, with particular attention to the cellular and protein content, may reveal abnormalities.
3- Patients with Guillain-Barré syndrome typically have an acellular fluid with elevated protein (albuminocytologic dissociation).
4- A highly cellular CSF suggests alternative diagnoses.
5- Sural nerve biopsy may be indicated, if there is a clinical suspicion for amyloidosis or if an unexplained axonal neuropathy is present on NCS or EMG testing.
6- If the clinical suspicion for amyloidosis is high and no amyloid is found in the nerve biopsy, abdominal fat pat or rectal biopsy should be performed to look for amyloid deposits.
7- Nerve biopsy is unnecessary, if there is clear evidence of focal demyelination on NCS.
Biopsy of the central nervous system is never part of the routine evaluation for these disorders (see the Procedures section).
In chronic syndromes of primary autonomic failure, loss of small sympathetic neurons in the intermediolateral cell mass of the spinal cord is a common feature.
Other limited data for pure autonomic failure demonstrate additional nerve cell loss and Lewy bodies, which stain for ubiquitin in the paravertebral sympathetic ganglia.
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