Pure Autonomic Failure

Pure autonomic failure is a rare sporadic neurodegenerative synucleinopathy with isolated progressive failure of sympathetic noradrenergic neurons, causing neurogenic orthostatic hypotension without central motor involvement. It begins in middle to late life, and affects men and women similarly.

Some patients (about 10 to 15% over years) convert to multiple system atrophy, Parkinson disease or dementia with Lewy bodies.

Pathophysiology. Alpha synuclein deposition in peripheral autonomic neurons causes postganglionic sympathetic denervation, with low supine noradrenaline levels.

Orthostatic hypotension with dizziness, visual blurring, neck and shoulder pain ("coat hanger"), fatigue and syncope, supine hypertension, anhidrosis, heat intolerance, constipation, urinary urgency or retention, erectile dysfunction, and REM sleep behaviour disorder in some. Symptoms are worse in the morning, after meals, in heat and after exercise.

Red flags.

• Recurrent syncope with injury.
• Parkinsonism, ataxia or stridor (suggesting multiple system atrophy).

Measure lying and standing blood pressure (fall of at least 20 mmHg systolic or 10 mmHg diastolic within 3 minutes) with minimal heart rate rise (less than 0.5 beats/min/mmHg), tilt table testing and Valsalva manoeuvre.

Plasma noradrenaline is low supine and fails to rise on standing. Cardiac MIBG scanning shows loss of sympathetic uptake. Skin biopsy shows phosphorylated alpha synuclein.

Exclude secondary causes:

• diabetes
• amyloidosis
• drugs
• autoimmune autonomic ganglionopathy (ganglionic acetylcholine receptor antibodies)
• paraneoplastic neuropathy
• Addison disease

Differential diagnosis.

• Multiple system atrophy, Parkinson disease and dementia with Lewy bodies.
• Diabetic and amyloid autonomic neuropathy.
• Autoimmune autonomic ganglionopathy, drug induced hypotension and hypovolaemia.

Non-drug measures. Gradual rising, avoid triggers (heat, large meals, alcohol, straining), fluids 2 to 3 litres daily, salt 6 to 10 g daily, waist high compression stockings or abdominal binder, head up tilt of the bed by 10 to 20 degrees, physical counter manoeuvres and small frequent meals.

Drugs.

• Midodrine 2.5 mg three times daily, increased to 10 mg three times daily, taken during the day, last dose at least 4 hours before bedtime.
• Droxidopa 100 mg three times daily, increased to 600 mg three times daily.
• Fludrocortisone 0.1 mg daily, increased to a maximum of 0.3 mg daily, with monitoring of potassium and oedema.
• Pyridostigmine 30 to 60 mg three times daily for mild cases.

Supine hypertension. Avoid lying flat, sleep with the head raised, and use short acting agents at night (such as losartan 25 mg or transdermal glyceryl trinitrate 0.1 mg/hour patch removed in the morning).

Other symptoms. Treat constipation, bladder dysfunction and erectile dysfunction.

Monitoring. Lying and standing blood pressure, electrolytes and progression to other synucleinopathy.

Referral and escalation. Refer to neurology or an autonomic service.