Amyloid Polyneuropathy

Amyloid polyneuropathy is a progressive, length dependent sensorimotor and autonomic neuropathy from deposition of amyloid fibrils. Main causes are hereditary transthyretin (ATTRv, many variants, commonest p.Val30Met, endemic in Portugal, Sweden, Japan and Brazil), light chain (AL) amyloidosis from plasma cell dyscrasia, and, rarely, wild type transthyretin or other forms.

Pathophysiology. Misfolded protein deposits in peripheral nerves, dorsal root ganglia and autonomic ganglia, causing axonal degeneration, especially of small fibres early.

Painful small fibre neuropathy with loss of pain and temperature in feet, ascending to large fibre loss, weakness and sensory ataxia. Autonomic failure (orthostatic hypotension, sexual dysfunction, gastrointestinal dysmotility with alternating diarrhoea and constipation, urinary retention). Carpal tunnel syndrome often precedes neuropathy. Cardiomyopathy (heart failure, arrhythmia), nephrotic syndrome (AL), weight loss, vitreous opacities and leptomeningeal involvement.

Red flags.

• Rapidly progressive painful neuropathy with autonomic failure and weight loss.
• Heart failure or arrhythmia with neuropathy.
• Bilateral carpal tunnel syndrome in a man over 50 years.

Exclude AL amyloidosis first: serum and urine immunofixation and serum free light chains (abnormal ratio), with bone marrow biopsy. Tissue biopsy (fat pad, salivary gland, nerve or involved organ) shows amyloid by Congo red staining, with typing by mass spectrometry. TTR gene sequencing for ATTRv. Nerve conduction studies show axonal sensorimotor neuropathy. Cardiac evaluation: ECG, echocardiography, troponin, natriuretic peptide, cardiac MRI and technetium pyrophosphate scintigraphy. Autonomic tests.

Differential diagnosis.

• Chronic inflammatory demyelinating polyneuropathy, diabetic and other small fibre neuropathy.
• Paraproteinaemic neuropathy, Fabry disease and idiopathic axonal neuropathy.
• Vasculitic neuropathy.

Treatment depends on the type of amyloid.

ATTRv polyneuropathy.

• Patisiran 0.3 mg/kg IV every 3 weeks (premedicate with dexamethasone, paracetamol and antihistamines), vutrisiran 25 mg SC every 3 months, or eplontersen 45 mg SC monthly. Take vitamin A supplementation as directed.
• Tafamidis 20 mg daily slows early disease (stage 1) where available.
• Liver transplantation for early p.Val30Met disease in selected patients.

AL amyloidosis. Haematology led treatment: daratumumab, bortezomib, cyclophosphamide and dexamethasone, with autologous stem cell transplantation in eligible patients.

Symptom treatment. Neuropathic pain: gabapentin or pregabalin, duloxetine 30 to 60 mg daily. Orthostatic hypotension: compression, fluids, fludrocortisone, midodrine. Diarrhoea: loperamide. Cardiac and renal care by specialists.

Rehabilitation. Physiotherapy, foot care and falls prevention.

Monitoring. Neuropathy score, autonomic function, cardiac imaging and biomarkers, and weight every 6 months.

Referral and escalation. Refer urgently to neurology, cardiology and haematology.

Special groups. Genetic counselling and cascade testing in ATTRv.