Autoimmune Autonomic Ganglionopathy

Autoimmune autonomic ganglionopathy is an acquired immune mediated disorder in which antibodies to the ganglionic nicotinic acetylcholine receptor (alpha-3 subunit) block neurotransmission in autonomic ganglia. It causes subacute or chronic sympathetic, parasympathetic and enteric failure.

It is rare, with an estimated prevalence of under 1 in 100,000. It affects adults of any age (mean around 50 years), with a female predominance of about 2 to 1.

Antibody. Ganglionic acetylcholine receptor antibodies are found in about 50% of patients with the phenotype, and higher titres are linked to more severe disease. Seronegative cases also occur.

Associations. Preceding viral infection in about half, Sjögren syndrome, systemic lupus erythematosus, and rarely cancer (small cell lung cancer, thymoma) in paraneoplastic forms.

Course. Acute or subacute onset over days to weeks (monophasic or relapsing) or chronic and insidious. About one third recover substantially with treatment, but many stay disabled.

Pathophysiology.

Antibodies reduce the number and function of ganglionic acetylcholine receptors at synapses in the autonomic ganglia, impairing fast transmission to postganglionic neurons.

The loss of transmission produces pan autonomic failure without structural damage in the early disease.

• Severe orthostatic hypotension with presyncope and syncope.
• Gastrointestinal dysmotility: gastroparesis, constipation, pseudo obstruction, early satiety and weight loss.
• Dry mouth and eyes (sicca), fixed dilated pupils with poor light and accommodation responses, anhidrosis and heat intolerance.
• Urinary retention and erectile dysfunction.
• Fixed heart rate and absent heart rate variability; some have encephalopathy or sensory neuropathy.

Red flags.

• Syncope with injury or arrhythmia.
• Intestinal pseudo obstruction or severe weight loss.
• Cough, weight loss or a smoking history (paraneoplastic).

• Clinical syndrome of pandysautonomia confirmed by autonomic testing: tilt table or active stand with orthostatic hypotension and no compensatory rise in heart rate, abnormal Valsalva, absent sudomotor response, and pupillometry.
• Serum ganglionic acetylcholine receptor (alpha-3) antibody; titre has prognostic value.
• Blood tests: antinuclear antibodies, extractable nuclear antigens (Ro, La), anti-neuronal antibodies (Hu, CRMP5), glucose, B12, thyroid function, serum protein electrophoresis, and amyloid screening.
• Cancer screening (CT chest, abdomen and pelvis; PET if antibodies of paraneoplastic type).
• Gastric emptying studies, bladder ultrasound with post-void residual, and nerve conduction studies for neuropathy.

Differential diagnosis. Diabetic autonomic neuropathy, amyloid neuropathy, multiple system atrophy, pure autonomic failure, paraneoplastic autonomic neuropathy, Guillain-Barré syndrome with dysautonomia, Sjögren syndrome neuropathy, drug induced orthostatic hypotension and postural tachycardia syndrome.

• Immunotherapy, started early: intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, then 1 g/kg every 4 weeks for 3 to 6 months if there is a response. Maximum 2 g/kg in any 4 week period. Monitor renal function, thrombosis, hypersensitivity and aseptic meningitis; check IgA before the first dose. Avoid in IgA deficiency with anti-IgA antibodies; use caution in renal impairment and heart failure.
• Methylprednisolone 1000 mg intravenously once daily for 3 to 5 days, then prednisolone tapered, or plasma exchange (5 exchanges over 10 days) for severe disease. Maximum 5 g of methylprednisolone in a course. Monitor blood pressure, glucose, mood and infection. Avoid with active untreated infection.
• Rituximab 1000 mg intravenously on days 1 and 15 for refractory disease, repeated every 6 months if effective. Maximum 1000 mg for each dose. Screen for hepatitis B before treatment; monitor infusion reactions and infection. Avoid in active infection and pregnancy.
• Orthostatic hypotension: 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 heart failure or hypertension, compression garments, small frequent meals and slow postural change.
• 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 and oedema. Avoid in heart failure and severe supine hypertension.
• Midodrine 2.5 mg orally three times daily in 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 and urinary retention. Avoid in severe cardiac disease, urinary retention and acute renal disease.
• Pyridostigmine 30 mg orally twice daily, increased to 60 mg three times daily if needed. Maximum 240 mg daily. Monitor abdominal cramps, diarrhoea, bradycardia and salivation. Avoid in mechanical bowel or urinary obstruction and asthma; reduce dose in renal impairment.
• Dry mouth: pilocarpine 5 mg orally three times daily. Maximum 30 mg daily. Monitor sweating, bradycardia and bronchospasm. Avoid in asthma, angle closure glaucoma and acute iritis; reduce dose in hepatic impairment.
• Bowel care and nutrition; clean intermittent catheterisation for retention.

Monitoring. Check lying and standing blood pressure at each visit; review at 4 to 6 weeks and every 3 months; repeat antibody titre to guide treatment.

Referral and escalation. Neurology and autonomic specialist for all; gastroenterology for pseudo obstruction; oncology for suspected cancer.

Special groups. Pregnancy: immunoglobulin preferred; avoid rituximab. Older adults: falls prevention and lower starting doses.