Paraproteinemic Neuropathy: A Practical Review

Richard A. Rison; Said R. Beydoun


BMC Neurol. 2016;16(13) 

In This Article

Paraproteinemic Disorders

Each of the individual paraproteinemic disorders exhibits a distinct neuropathic phenotype, and the typical clinical features are described below. The prognosis is often not well-defined and unknown in many cases.

Anti-MAG neuropathy is described as "distal acquired demyelinating symmetric" (DADS) sensory and motor neuropathy. It is usually very slowly progressive and predominately distal with sensory ataxia, little or no weakness, and frequent tremor. This condition usually has a benign course with little functional deterioration over time; however, the neuropathy may evolve more rapidly at certain stages. At least one report showed that 10 and 15 years after onset, 24 % and 50 % of patients were disabled, respectively.[18]

IgG/A MGUS with associated neuropathy resembling chronic inflammatory demyelinating polyneuropathy (CIDP) is a relapsing or progressive sensori-motor disorder involving the peripheral nerves with symmetrical proximal and distal weakness of the four limbs, sensory involvement and areflexia. About 80 % of patients respond to one of the typical CIDP treatments (please see the treatment section). Some patients stabilize without therapy.[19]

IgG/A MGUS with associated axonal neuropathy is a sensory or sensori-motor axonal neuropathy involving distal extremities in a length-dependent fashion. Initial presentation typically entails distal lower limb sensory symptoms and signs, with motor weakness at later stages. The progression is slow and often does not require any treatment.[17]

Cryoglobulinemia (most frequently mixed cryoglobulinemia) with neuropathy is characterized by multifocal axonal neuropathy, as a mononeuropathy multiplex pattern, secondary to necrotizing vasculitis. Pain can be a distinguishing feature of cryoglobulenic neuropathy. Sensory fibers are more commonly affected than motor fibers, with approximately 5 % of patients experiencing pure motor neuropathy.[20–22]

Primary (AL) amyloidosis coexists with multiple myeloma in 10 % of cases, and 20 % of patients with AL present with a neuropathy.[14] The neuropathy itself is mostly symptomatic in the distal lower limbs, predominately sensory, and of the small fiber painful type. Autonomic dysfunction is frequent. Symptoms of amyloidosis include pain, weight loss, macroglossia, organomegaly, or cardiomyopathy. If left untreated, it has a poor prognosis with median survival less than 18 months from onset.[23–25]

CANOMAD syndrome (Chronic Ataxic Neuropathy with Ophthalmoplegia, M-protein, cold Agglutinins and Disialosyl antibodies [anti-ganglioside, anti-GD1b, and anti-GQ1b]) is a rare phenotype associated with an IgM MGUS.[26] It may correspond to a chronic form of Miller Fisher syndrome, a rare variant of Guillain–Barré syndrome that manifests with ataxia, areflexia, and ophthalmoplegia. Ataxia is profound, severely impairing function, but motor strength remains relatively spared.[27]

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) syndrome is a rare entity featuring sclerotic bone lesions, Castleman's disease (a very rare disorder characterized by non-cancerous growths that may develop in the lymph node tissue at a single site or throughout the body), papilledema, ascites, and skin changes including nail clubbing and hyperpigmentation.[28,29] Neuropathy is the main feature and often precedes the diagnosis of osteosclerotic myeloma. Positive sensory symptoms and slowly progressive, predominately distal weakness occurs.[30] If untreated, POEMS syndrome has a poor prognosis with a median survival of 12–33 months.[31]

Neuropathies associated with lymphoma are heterogeneous with variable prognosis depending on the type. Demyelinating forms may have a more favorable prognosis.[32] Aggressive B cell lymphoma, usually associated with proximal infiltration suggested by isolated radiculopathy, has a poor prognosis. Axonal multiple mononeuropathies related to distal infiltration have better outcomes.[33–35]

Waldenstrom macroglobulinemia (WM) can result in peripheral neuropathy in up to 47 % of patients. Most patients with WM-related neuropathy complain of sensory loss and unsteady gait. Less commonly there is a predominant motor neuropathy which may be associated with elevated titers of IgM antibodies targeting ganglioside GM1.[36]