Neuropathies associated with monoclonal gammopathies (paraproteinemias) are relatively uncommon. Paraprotein subtypes most frequently associated with polyneuropathy include heavy chains (IgM, IgA, and IgG) and light chains (kappa or lambda). Determining whether a paraproteinemia is clinically significant requiring specific treatment or is an unrelated finding can be complex. Hematologic consultation is often necessary to determine whether the paraprotein is the consequence of hematologic malignancy.
Nerve conduction studies are helpful in differentiating demyelinating from axonal neuropathies. Disorders resulting in loss of myelin result in prolonged distal latencies greater than 150% of normal, slowing of conduction velocity to less than 70% of normal, and partial conduction block. Pure axonal neuropathies cause reduced or absent sensory and/or motor responses with normal or mildly slowed conduction velocities or prolonged distal latencies.
IgA M-proteins generally require further evaluation with bone marrow biopsy regardless of their concentration.
Light chain paraproteins occur when a monoclonal protein is produced without an associated heavy chain component; these can form into fibrils, which may be deposited in tissues causing multisystem disease as seen in AL amyloidosis. This fibril deposition may be seen on a fat pad or nerve and muscle biopsy. If there is a high clinical suspicion, AL amyloid should still be considered even with negative biopsies. Not all light chain overproduction results in amyloidosis. As seen with heavy chain overproduction, light chain paraproteins may be produced in monoclonal gammopathy of undetermined significance (MGUS) or in clonal plasma cell disorders. Light chain ratios are often helpful to determine the presence of a true monoclonal protein from polyclonal immune responses or impaired light chain excretion due to renal dysfunction.
IgG paraproteins are most commonly associated with MGUS, but all heavy and light chain subtypes can be produced at low levels without clear systemic effects as seen in MGUS. The majority of patients with MGUS have a monoclonal protein of less than 1.0 g/dL; by definition, all MGUS patients have a monoclonal protein concentration less than 3.0 g/dL. The particular concentration of monoclonal protein chosen here for further workup (1.5 g/dL) is somewhat arbitrary, and evaluation should be planned in partnership with a hematologist. All patients with suspected MGUS should undergo an evaluation for “CRAB” signs: hyper C alcemia, R enal insufficiency, A nemia, and B one lesions.
Waldenstrom macroglobulinemia (WM) is a disorder of lymphoplasmacytic cell proliferation and IgM protein production. Most patients with WM present with nonspecific fatigue, though they may demonstrate weight loss, bleeding (e.g., nose bleeds), hepatomegaly, or splenomegaly. The neuropathy associated with WM is sensory predominant and typically unresponsive to immune modulation or chemotherapy.
Type 1 cryoglobulinemia produces symptoms related to vascular occlusion in the setting of cryoprecipitation. These symptoms include skin necrosis, livedo reticularis, and ischemia of the digits. A significant minority of these patients develop a peripheral neuropathy, which typically presents as mononeuropathy multiplex.
POEMS is an acronym for P eripheral neuropathy, O rganomegaly, E ndocrinopathy, M onoclonal gammopathy, and S kin changes. Most patients do not have all of these clinical features. A diagnosis of POEMS requires the presence of peripheral neuropathy and a monoclonal protein along with one other major criteria (sclerotic bone lesions, Castleman disease or elevated vascular endothelial growth factor [VEGF]) and one minor criteria (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, or thrombocytosis/polycythemia). The monoclonal heavy chain subtype is typically IgG or IgA. IgM heavy chains are rare in POEMS. The light chain is almost always lambda. Isolated sclerotic bone lesions can be treated with radiation whereas more diffuse disease is treated with chemotherapy with or without hematopoietic cell transplantation.
CANOMAD syndrome ( C hronic A taxic N europathy, O phthalmoplegia, Ig M paraprotein, cold A gglutinins, and D isialosyl antibodies) results in sensory ataxia and ophthalmoplegia. Polyclonal IgM antibodies that react with disialosyl epitopes of gangliosides are common. Additionally, most patients have IgM monoclonal antibodies.
Distal acquired demyelinating symmetric (DADS) neuropathy is characterized by insidiously progressive predominant sensory symptoms with minimal or no weakness. Sensory symptoms can be severe and cause a sensory ataxia. On examination there is sensory loss along with areflexia. Nerve conduction studies often demonstrate absent sensory responses with prolongation of the distal motor latencies, though there may be other signs of demyelination. Approximately two-thirds of patients with a DADS phenotype have a monoclonal protein, which is overwhelmingly IgM kappa, and these patients appear refractory to immunomodulatory treatment. Approximately 50% of patients with IgM kappa DADS have myelin-associated glycoprotein (MAG) antibodies. Patients with a DADS phenotype without a monoclonal protein appear to have a similar response rate to chronic inflammatory demyelinating polyneuropathy.