Autonomic Neuropathy

Autonomic neuropathy affects the autonomic neurons of either or both of the parasympathetic and sympathetic nervous systems. They are usually accompanied by somatic neuropathy but can be autonomic only. Several syndromes and diseases exhibit autonomic neuropathies and there are a wide variety of clinical features and presentations.¹ In some patients the features are subclinical, whereas in others the dysfunction leads to significant disability. It is important to recognise and correctly diagnose autonomic neuropathy because successful treatments and management can be offered.

As might be expected a variety of pathophysiological processes are involved depending on the particular cause.² Although loss of somatic C fibres is associated with autonomic deficits, there is now known to be a more selective involvement of fibres in some conditions. Somatic and autonomic C fibre involvement is found in diabetic neuropathies. The exact mechanism has not been worked out for all conditions and causes. However the following have been identified and may be involved:

• Single gene defects
• Accumulation of toxins
• Autoantibodies. For example:
  • Autonomic ganglionic acetylcholine receptor antibody (Pandysautonomia)
  • Ganglionic receptor antibodies (Postural orthostatic tachycardia syndrome)
  • Ganglioside autoantibodies (Guillain-Barré syndrome)
  • Antibodies to presynaptic channels (Eaton-Lambert syndrome)
  • Antineuronal antibodies (Coeliac disease, paraneoplastic autonomic neuropathy)
• Prevention of presynaptic acetylcholine release (Botulism)
• Accumulation of toxic metabolites (for example in liver disease)
• Postganglionic abnormalities (connective tissue diseases, SLE, rheumatoid arthritis)
• Accumulation of glycolipids (Fabry-Anderson disease)

There is a long list of causes including hereditary and acquired conditions.³ The full spectrum includes:

• Ageing (postural hypotension and disordered thermoregulation are common in the elderly)
• Causes linked with systemic diseases:
  • Diabetic autonomic neuropathies⁴
  • Alcoholic neuropathy
  • Subacute combined degeneration
  • Hepatic disease
  • Uraemic neuropathy
  • Amyloid neuropathies
• Infectious causes:
  • Human immunodeficiency virus (HIV)
  • Lyme disease
  • Leprosy
  • Chagas disease
• Toxic causes:
  • Vincristine
  • Cisplatin
  • Amiodarone
  • Pyridoxine overdose
  • Thallium poisoning
  • Taxol
• immune-mediated causes:
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Systemic sclerosis
  • Autoimmune thyroiditis
  • Neuropathy related to inflammatory bowel disease
  • Postural orthostatic tachycardia syndrome (POTS)⁵
  • Guillain Barré
  • Chronic inflammatory demyelinating neuropathy
  • Acute pandysautonomia
  • Acute cholinergic pandysautonomia
  • Eaton-Lambert syndrome
  • Holmes-Adie syndrome
  • Paraneoplastic autonomic neuropathy
• Hereditary causes:
  • Fabry disease
  • Hereditary types (I to V)
  • Tangier disease
  • Multiple endocrine neoplasia (type 2b)
• Idiopathic causes:
  • Chronic idiopathic anhidrosis

In general these can occur in men and women at any age, but the epidemiology will depend on the particular cause. Some causes are very rare. However one of the most common causes of autonomic neuropathy is likely to be diabetes mellitus. Progressive autonomic failure usually becomes apparent in the sixth decade of life. Typically it manifests with genitourinary symptoms and orthostatic hypotension but without somatic symptoms.

History

Autonomic nerve fibres are affected in most symmetrical peripheral neuropathies, but involvement is often subclinical or mild.³Usually the onset of symptoms is slow and insidious. Occasionally the onset can be acute and dramatic in the acute forms. Usually there is sympathetic and parasympathetic dysfunction. Orthostatic or postural hypotension is the most commonly recognised symptom, but there are a wide variety of other possible symptoms. A family history and drug history may also be important.

Examination

There may be features on general examination which point to a specific disease. The neurological examination should be detailed and thorough incorporating motor and sensory examination. There are a few specific techniques which can be used for certain specific autonomic abnormalities.⁶

• General examination:
  • Stigmata of liver disease
  • Skin conditions (for example Lyme disease and leprosy)
  • Signs of connective tissue diseases (for example rheumatoid arthritis, SLE, Sjögren syndrome)
  • Features of unusual conditions (such as Fabry disease and amyloidosis)
• Neurological examination:
  • Motor examination (power, tone, coordination and reflexes)
  • Sensory examination (all modalities including proprioception)
  • It is important to identify stocking pattern of sensory loss (concurrent somatic neuropathy)
• More specific examination.
  

  Looking for signs of autonomic dysfunction Testing for abnormalities of blood pressure regulation: Look for postural drop of systolic blood pressure >20 mm Hg (lying and sitting) or >10 mm Hg with presyncopal symptoms7 Measure blood pressure after isometric exercise (in the opposite arm). BP should increase by >16 mm Hg in the opposite arm. Measure postprandial blood pressures to detect >20 mm Hg 20 minutes after meal (abnormal). Detect >15 mm Hg diurnal variation of blood pressure (suggests autonomic neuropathy). Measure BP after hand immersion in ice cold water for 1 minute. Contralateral arm shows >10 mm Hg diastolic drop as normal response. Detection of normal pulse variation with breathing (increases inspiration, decreases during expiration). Blood pressure recovery after Valsalva manoeuvre.8 Skin examination: Palms, soles and axillae (sweating?) Skin shrivelling after prolonged immersion in water? Eye examination: Pupil responses (to light and accommodation) Look for Horner syndrome Examine for effects of reduced eye secretions (cornea) Mouth examination: Look for excessive dental decay (an effect of dry month) Abdominal examination: Looking for enlarged bladder

• Alcohol related neuropathy
• Cauda equina syndrome
• Charcot-Marie-Tooth
• Hereditary motor and sensory neuropathies
• Conus medullaris syndrome
• Parkinson disease
• Spinal cord trauma
• Surgical sympathectomy

Patients with Parkinson disease can have autonomic dysfunction (constipation and urinary retention) but unlike peripheral autonomic neuropathies have extrapyramidal dysfunction (akinesia, tremor, rigidity).

There are no specific tests and those suggested are to assist in diagnosis. The particular selection of tests is dependent on the clinical presentation but may include⁹:

• Full blood count and differential
• Fasting blood glucose
• HIV testing
• Immunoelectrophoresis of blood and urine
• Plasma norepinephrine (supine and standing)
• Porphyria investigations
• Genetic testing for inherited neuropathies
• Amyloid investigation
• Autoantibody assessment: antinuclear antibody, Rheumatoid factor, Anti-Ro/SS-A, Anti-La/SS-B, antibodies to acetylcholine receptor, paraneoplastic antibodies-anti-Hu (type 1 anti-neuronal nuclear antibody, ANNA-1), Purkinje-cell cytoplasmic antibodies type 2 (PCA-2), collapsin response-mediator protein 5 (CRMP-5).
• ECG:
  • Variation in heart rate with respiration of less than 10 beats per minute is abnormal
  • Measure beat to beat variation of R-R interval (with respiration and during Valsalva manoeuvre)
• Nerve conduction studies (often normal as affected fibres are small and not assessed by this or EMG studies)
• Cystometry (bladder pressures)
• CSF examination (lumbar puncture):
  • Protein changes with dorsal root ganglia damage
  • Changes of HIV or AIDS
  • Changes consistent with paraneoplastic neuropathies (not specific)
• Imaging studies:
  • Barium swallow
  • Urodynamic studies (ultrasound may be employed)
  • PET scanning for cardiac sympathetic dysfunction (diabetes)
• Vascular studies:
  • Doppler studies
  • Infrared thermometry
  • Skin blood flow measures (transcutaneous oxygenation, skin temperature)
• Some more specific tests that have been suggested:
  • Sympathetic skin responses (using EMG equipment)
  • Quantitative sensory testing (comparison of sensory thresholds)
  • Thermoregulatory sweat test
  • Quantitative sudomotor axon reflex test (tests thermoregulatory pathways)

There are a variety of diseases associated with autonomic neuropathy. This can be appreciated from the causal conditions listed above.

Management should start from initial diagnosis and incorporate patient education about the condition and implications for the patient. This may range from measures to prevent orthostatic hypotension to improvements in self care (from hygiene to care of diabetes mellitus).

• Treatment of underlying cause.
• Orthostatic hypotension:
  • Head-up tilt of the bed at night
  • Stand up slowly
  • Volume replacement (increase fluid intake)
  • Salt supplementation
  • Medication (such as fluorohydrocortisone, midrodine)
  • Wearing compressive stockings
• Gastrointestinal dysfunction:
  • Gastroparesis in patients with diabetic autonomic neuropathy is improved by rigorous control of blood glucose concentrations.⁴
  • Eat small meals and eat often.
  • Lower the fat content of the diet.
  • Prokinetic agents for gastroparesis can be used (metoclopramide, domperidone and erythromycin). A jejunostomy tube may rarely be required.
  • Bowel hypomotility. This can be helped with :
    • Increased dietary fibre and an increase in fluid intake.
    • Use of stool softeners and/or an osmotic laxative.
    • Gluten-free diet and restriction of lactose should be tried.
    • Cholestyramine, clonidine, somatostatin analogues, pancreatic enzyme supplements, and even antibiotics (such as metronidazole) have been tried.³
• Genital autonomic neuropathy:
  • Treatment of the erectile dysfunction.
  • Vaginal lubricants and oestrogen creams may help.
• Autonomic dysfunction of the urinary tract:
  • Timed voiding schedules and bladder contractions increased by a Valsalva manoeuvre.
  • Clean intermittent self-catheterisation.
  • Cholinergic agonists (for example bethanechol-limited role).
• Hyperhidrosis:
  • Anticholinergic agents(for example trihexyphenidyl and propantheline) may be helpful but doses required may limit use (anticholinergic side-effects).
  • Intracutaneous injection of botulinum toxin type A is often beneficial.
  • Sympathectomy is rarely required.
  • There is no effective treatment for hypohidrosis.

Many complications exist. The most severe are:

• Cardiac arrest, cardiac dysrhythmias, sudden cardiac death.^3,10
• Blood pressure fluctuations and the risk of cerebral and cardiac ischaemia.

The prognosis is determined by the particular cause of the autonomic neuropathy. In most cases the course is one of gradual progression. In the case of diabetes mellitus the prognosis is improved with good control of diabetes. Other measures to halt progression may be applicable, such as abstinence from alcohol or by treatment of correctable syndromes.