Neuropathy and paraproteins: review of a complex association

Abstract

Coexistence of neuropathy and monoclonal gammopathy represents a common but complex problem in clinical practice. This association is here reviewed considering latest available literature. The association is not infrequent, and various possible syndromes need to be distinguished. However, coincidental co-occurrence also needs to be recognized. The monoclonal gammopathy may be a 'monoclonal gammopathy of uncertain significance' (MGUS) or occur in a context of malignancy such as multiple myeloma or Waldenström's macroglobulinaemia. IgM paraproteins can bind to myelin-associated glycoprotein (MAG) in peripheral nerve. In this case, the paraprotein is directly linked to the neuropathy, causing a specific phenotype. One randomized controlled trial of this ('Anti-MAG') neuropathy showed possible moderate effect of rituximab on disability. Results of another trial are awaited. IgM/G/A paraproteins can be associated with a polyneuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy. Axonal neuropathies may coexist with IgM/G/A MGUS. There is insufficient evidence about causality or effective treatment in such cases. Pain/dysautonomia with an axonal neuropathy and serum paraprotein raises the possibility of amyloidosis. Specific haematological treatment is required for malignant disorders, although caution is required with neurotoxic agents. Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome and chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl antibodies represent rare separate entities for which evidence-based treatment options are still lacking. The association of monoclonal gammopathy and neuropathy requires the appropriate neurological/haematological investigations for a precise diagnosis. Causality is only established in few cases. Adequate management ideally requires joint neurological/haematological input for diagnosis, monitoring and treatment.

Paraproteinemic neuropathy

“…A terminal latency index (TLI = distal distance/[forearm motor conduction velocity × distal motor latency]) of <0.26 is highly specific for anti-MAG antibody neuropathy with a demyelinating pattern. 16,22 The TLI has previously been found to be considerably lower in anti-MAG antibody neuropathy than in other demyelinating neuropathies such as CIDP and Charcot Marie-Tooth neuropathy type 1a. 26,27 This characteristic feature means that an electrophysiologic test is a suitable first step for distinguishing anti-MAG antibody neuropathy from the other demyelinating neuropathies.…”

“…The anti-MAG antibody neuropathies show absent or remarkably reduced sensory nerve action potentials that are indicative of axonal damage in diffuse nerves of the lower limbs. 22,24,25 Motor nerve conduction studies show greatly prolonged distal motor latencies suggestive of distal-dominant demyelination. A terminal latency index (TLI = distal distance/[forearm motor conduction velocity × distal motor latency]) of <0.26 is highly specific for anti-MAG antibody neuropathy with a demyelinating pattern.…”

“…IVIg showed a small effect from a functional perspective in a small double-blind RCT that did not include patients with anti-MAG reactivity, and also in an open-label study. 22,30 Only 2 trials of IVIg involving 33 participants (including 20 patients with anti-MAG antibodies) found short-term benefits (at 4 weeks) in the Neuropathy Impairment Score (NIS), the modified Rankin Scale (mRS) score, and the 10-meter walk time, and also relative safety. 31,32 Two RCTs of interferon alfa-2a produced conflicting results: interferon alfa-2a showed some benefit in treating anti-MAG antibody neuropathy in assessments using the NIS at 6 months in an open trial with IVIg, 32,33 while a double-blind placebo-controlled study found that interferon alfa-2a provided no significant benefit in both the NIS and mRS score at 6 months.…”

“…34 Plasma exchanges also exerted temporary effects in about 50% of patients in uncontrolled studies. 22,23 However, a prospective analysis found no efficacy in most anti-MAG-positive cases, and that the efficacy was no better for plasma exchanges in conjunction with chlorambucil than for chlorambucil alone (based on the NIS at 4 months). 22,35 A trial of the efficacy of combined cyclophosphamide and steroid produced some positive findings.…”

Extramedullary Waldenström macroglobulinemia

“…Approximately 20% of patients experience hepatosplenomegaly and lymphadenopathy, and some patients may present with B symptoms including night sweats, fever, and weight loss. Other common manifestations include neuropathy, cryoglobulinemia, skin rash (Schnitzler syndrome) [9], cold-agglutinin hemolytic anemia, and amyloidosis [10,11].…”