Autonomic Neuropathy

Autonomic neuropathy is damage to the peripheral autonomic nerves, causing failure of cardiovascular, gastrointestinal, urogenital, sudomotor and pupillary function. It ranges from mild symptoms to disabling orthostatic hypotension, gastroparesis and bladder failure.

Diabetic autonomic neuropathy affects about 20% of people with diabetes, with a rising rate over time. Other forms are rarer, and the incidence of autoimmune autonomic ganglionopathy is under 1 in 100,000 each year.

Causes. Diabetes (commonest), amyloidosis, alcohol, autoimmune and paraneoplastic disease, Sjögren syndrome, Guillain-Barré syndrome, HIV, chemotherapy, hereditary neuropathies and Parkinson disease or multiple system atrophy (central).

Course. Progressive in diabetes, usually years after onset; acute autoimmune forms may improve with treatment. Cardiovascular autonomic neuropathy is linked with higher mortality.

Pathophysiology.

Damage to small myelinated and unmyelinated autonomic fibres from metabolic injury, immune attack, amyloid deposition or toxins causes loss of sympathetic and parasympathetic control.

Denervation supersensitivity may explain blood pressure variability.

• Orthostatic hypotension: dizziness, visual dimming, neck pain and syncope on standing, worse after meals, heat or exertion.
• Supine hypertension, resting tachycardia and fixed heart rate.
• Gastrointestinal: early satiety, nausea, vomiting (gastroparesis), constipation or diarrhoea, dysphagia.
• Urogenital: urinary retention, incontinence, erectile dysfunction and anejaculation.
• Sudomotor: anhidrosis, heat intolerance, gustatory sweating; pupillary abnormalities and dry eyes and mouth.
• Hypoglycaemia unawareness in diabetes.

Red flags.

• Syncope, arrhythmia or QT prolongation.
• Rapid onset over days to weeks (autoimmune or paraneoplastic).
• Weight loss, systemic features or cranial nerve signs.

• Lying and standing blood pressure after 5 minutes supine, at 1 and 3 minutes standing: a fall of 20 mmHg systolic or 10 mmHg diastolic is orthostatic hypotension.
• Cardiovascular reflex testing: heart rate variability with deep breathing, Valsalva manoeuvre and tilt table.
• Sudomotor testing; gastric emptying study; bladder ultrasound and post-void residual; pupillometry.
• Blood tests: glucose, HbA1c, B12, thyroid function, serum protein electrophoresis, ESR, antinuclear antibodies, ganglionic acetylcholine receptor antibody, paraneoplastic panel.
• Review drugs that cause hypotension (diuretics, alpha blockers, antihypertensives, tricyclic antidepressants).

Differential diagnosis. Parkinson disease, multiple system atrophy, pure autonomic failure, drug induced hypotension, hypovolaemia, adrenal insufficiency, postural tachycardia syndrome and functional gastrointestinal disease.

• Treat the cause (glycaemic control, alcohol cessation, immunotherapy, amyloid specific therapy) and stop causative drugs.
• Orthostatic hypotension, non-drug measures first: raise the head of the bed by 10 to 20 degrees, fluids of 2 to 2.5 litres daily, salt 6 to 10 g daily if no hypertension or heart failure, abdominal binder and compression stockings, slow postural change, small frequent meals, avoid alcohol and heat.
• Fludrocortisone 100 micrograms orally once daily, increased by 100 micrograms each week to a usual 100 to 300 micrograms daily. Maximum 300 micrograms daily. Monitor supine blood pressure, potassium, oedema and heart failure. Avoid in heart failure, severe supine hypertension and systemic infection; use caution in renal impairment; avoid in pregnancy unless essential.
• Midodrine: 2.5 mg orally three times daily during the daytime, increased by 2.5 mg each week to a usual 10 mg three times daily. Maximum 30 mg daily. Give the last dose at least 4 hours before bedtime. Monitor supine hypertension, heart rate, urinary retention and piloerection. Avoid in severe cardiac disease, urinary retention, supine hypertension and acute renal disease; reduce dose in renal impairment (start 2.5 mg).
• Gastroparesis: small low fat meals and glucose control; domperidone 10 mg orally up to three times daily before food. Maximum 30 mg daily for a short course (usually up to 1 week). Monitor QT interval, potassium and magnesium. Avoid in QT prolongation, cardiac disease and with CYP3A4 inhibitors; reduce dose in severe renal and moderate hepatic impairment.
• Autoimmune autonomic neuropathy: intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, or plasma exchange, by a specialist.
• Urinary retention: intermittent self-catheterisation and bladder training. Erectile dysfunction: specialist treatment.
• Foot, eye and pressure injury care; avoid hypoglycaemia.

Monitoring. Check lying and standing blood pressure at each review; yearly review in diabetes; monitor weight, potassium and supine pressure on drugs.

Referral and escalation. Neurology or autonomic service for severe or rapid disease; cardiology for arrhythmia; gastroenterology for refractory gastroparesis.

Special groups. Older adults: fall prevention and a lower drug dose. Diabetes: hypoglycaemia unawareness and perioperative instability.