Paraproteinaemic Neuropathy

Paraproteinaemic neuropathy is peripheral neuropathy associated with a monoclonal protein. Main types are IgM neuropathy with anti-myelin-associated glycoprotein (anti-MAG) antibodies (Waldenstrom macroglobulinaemia or IgM monoclonal gammopathy), POEMS syndrome, AL amyloidosis, cryoglobulinaemia, and IgG or IgA monoclonal gammopathy of undetermined significance with neuropathy.

It accounts for 10% of neuropathies of unknown cause in patients over 50 years. Monoclonal gammopathy of undetermined significance is found in 3% of adults over 50 years, and about 5 to 10% of those with idiopathic neuropathy.

Pathophysiology. Antibody binding to myelin glycoproteins, vascular endothelial growth factor overexpression (POEMS), amyloid deposition or hyperviscosity damage nerves.

Anti-MAG neuropathy: slowly progressive distal, symmetric sensory ataxic neuropathy with tremor, mild distal weakness and loss of vibration. POEMS: severe demyelinating polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes, papilloedema, oedema and sclerotic bone lesions. IgG or IgA gammopathy with neuropathy mimics chronic inflammatory demyelinating polyneuropathy.

Red flags.

• Neuropathy with weight loss, oedema, skin change or papilloedema (POEMS).
• Rapidly progressive neuropathy with autonomic failure (amyloid).

Serum protein electrophoresis with immunofixation, serum free light chains and quantitative immunoglobulins. Anti-MAG antibodies. Vascular endothelial growth factor level. Nerve conduction studies show distal demyelinating pattern with prolonged distal latencies in anti-MAG neuropathy. Skeletal survey or PET-CT for sclerotic lesions, bone marrow biopsy, and fat pad or nerve biopsy for amyloid. Check calcium, renal function, and cryoglobulins.

Differential diagnosis.

• Chronic inflammatory demyelinating polyneuropathy, diabetic and other axonal neuropathy.
• Amyloid neuropathy, vasculitic neuropathy and hereditary neuropathy.
• Lymphoma related neuropathy and monoclonal gammopathy unrelated to neuropathy.

Treatment depends on the type.

Anti-MAG neuropathy. Rituximab 375 mg/m2 weekly for 4 weeks, or 1 g twice, 2 weeks apart (screen for hepatitis B), with response over 6 to 12 months. Intravenous immunoglobulin and plasma exchange are less effective. Chemotherapy for Waldenstrom macroglobulinaemia with haematology.

POEMS syndrome. Radiotherapy for solitary plasmacytoma, and for disseminated disease lenalidomide with dexamethasone, bortezomib based regimens, or autologous stem cell transplantation. Haematology led.

IgG or IgA neuropathy with CIDP features. Use CIDP-type treatment: intravenous immunoglobulin 2 g/kg over 2 to 5 days, then 1 g/kg every 3 weeks, prednisolone, or plasma exchange.

AL amyloidosis. Haematology led chemotherapy (bortezomib, cyclophosphamide, dexamethasone, daratumumab).

Supportive. Pain relief, tremor treatment (propranolol), physiotherapy and falls prevention.

Monitoring. Paraprotein level every 6 to 12 months, neuropathy score, and transformation to lymphoma or myeloma.

Referral and escalation. Refer to neurology and haematology.