Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes Workup

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• 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.

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• 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.

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• 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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• 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.

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.