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PURPOSE OF REVIEW The diagnosis of Myelin-Associated Glycoprotein (MAG) neuropathy is based on the presence of elevated titers of IgM anti-MAG antibodies, which are typically associated with IgM monoclonal gammopathy, and a slowly progressive, distal demyelinating phenotype. The condition, however, can be under or over diagnosed in patients with mildly elevated antibody titers, absent monoclonal gammopathy, or an atypical presentation. The purpose of this paper is to examine recent advances in our understanding of the currently available anti-MAG antibody assays, their reliability, and their use in deciding treatment or monitoring the response to therapy. RECENT FINDINGS Higher titers of anti-MAG antibodies are more likely to be associated with the typical MAG phenotype or response to therapy. Mildly elevated antibody levels can occur in patients with chronic inflammatory demyelinating polyneuropathy. Testing for cross-reactivity with HNK1 can add to the specificity of the antibody assays. Patients with MAG neuropathy can present with an atypical phenotype and in the absence of a detectable monoclonal gammopathy. SUMMARY Assays for anti-MAG antibodies by Enzyme-Linked Immunosorbent Assay can be improved by testing for antibody binding at multiple serum dilutions, the inclusion of antigen-negative microwells as internal controls for each sample, testing for cross-reactivity with HNK1, and formal validation. The diagnosis needs to be considered in patients with demyelinating neuropathy, even in the absence of a monoclonal gammopathy or typical phenotype. The change in antibody levels needs to be considered in evaluating the response to therapy with B-cell depleting agents.

Infection with hepatitis C virus (HCV) can be associated with demyelinating polyneuropathy that may be responsive to immunomodulatory therapy. In this case report series, we review four patients (all male, ages 47-60 years) with HCV and demyelinating polyneuropathy. Two of the four patients were diagnosed with HCV during the course of initial neuropathy evaluation. All patients had sensory loss, absent/diminished reflexes, lower extremity weakness (except for one patient), and demyelinating electrodiagnostic features. Three patients had polyclonal hypergammaglobulinemia and one patient had IgM monoclonal gammopathy. Intravenous immunoglobulin resulted in improvement in three patients; one patient had no benefit from rituximab therapy, but his symptoms have been stable. Demyelinating neuropathy may develop in patients with HCV unrelated to antiviral therapy. Immunomodulatory therapy may be beneficial in some cases. Testing for HCV should be considered, especially in patients with hypergammaglobulinemia or IgM monoclonal gammopathy.

Purpose of review The management of peripheral neuropathy associated with monoclonal gammopathies has been advanced by recent clinical studies. We review the causal association between monoclonal gammopathy and neuropathy, and critically review the recent evidence on treatment. Recent findings IgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM monoclonal gammopathy of undetermined significance. Newer studies have shown promising results with rituximab, a monoclonal antibody which targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells. Summary There is a clear association between peripheral neuropathy and IgM MGUS with characteristic clinical, electrophysiology and pathologic features that make the disorder distinct from chronic inflammatory demyelinating polyneuropathy. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies.

Background: Detection of serum antibodies to myelin-associated glycoprotein (MAG) by Western blot (WB) is a valuable assay to diagnose a distinct type of demyelinating polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy. In this study, the diagnostic accuracy of a new and more practical ELISA to detect these antibodies was validated. Methods: Routine WBs from 2 independent laboratories and ELISA were used to detect anti-MAG IgM in serum from 207 patients with neuropathy and controls. The sensitivity and specificity of these assays were compared and related to the patient clinical and electrophysiologic characteristics. Results: In ELISA, anti-MAG antibodies were found in serum from 49 (72%) of 68 patients with demyelinating polyneuropathy and IgM monoclonal gammopathy. However, in this subgroup of patients, only 30 (44%) and 37 (54%) were positive in the 2 WBs. All of the patients positive in the 2 WBs were also positive in ELISA. A high correlation was found for IgM activity in ELISA to MAG and sulfate-3-glucuronyl paragloboside (SGPG) (Spearman rho = 0.72, p < 0.0001), supporting the notion that the shared sulfated glucuronic acid moiety of MAG and SGPG is preserved. Most patients positive in anti-MAG ELISA had a slowly progressive sensory-motor demyelinating polyneuropathy, even if the WB was negative. In control groups, however, 4 WB-negative patients with a nondemyelinating monoclonal gammopathy-related polyneuropathy were positive in anti-MAG ELISA. The remaining samples were negative in ELISA. Conclusion: ELISA is more sensitive than Western blot to diagnose anti-myelin-associated glycoprotein related polyneuropathy, although a positive serology may be found in other forms of polyneuropathy as well. Neurology (R) 2009; 73: 688-695

POEMS syndrome is a multiorgan disorder defined by the association of polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S).1 Serum levels of vascular endothelial growth factor (VEGF) are often markedly elevated in patients with POEMS,2-5 but not with other monoclonal gammopathies.2,4,5 Few patients with other neuropathies have been examined,2-5,6 so that the specificity of elevated VEGF levels for POEMS among patients with neuropathy remains unclear, especially when levels are moderately increased. ### Methods. We measured serum VEGF in 161 patients with neuropathy or related syndromes consecutively recruited and tested for antinerve antibodies at our neuropathy clinic. Six patients had POEMS diagnosed in the presence of at least four of the five features of POEMS, 13 had Guillain-Barre syndrome (GBS), 33 had chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with no other feature of POEMS, 13 had multifocal motor neuropathy (MMN), 19 had neuropathy associated with IgM monoclonal gammopathy of undetermined significance (MGUS) (PN+IgM) with anti-MAG or anti-sulfatide IgM, 49 had neuropathies of other (diabetes in 8, multiple myeloma or lymphoma in 8, systemic vasculitis or other rheumatic diseases in 5, amyloidosis in 3, toxic in 2, inherited in 2, paraneoplastic and small fiber neuropathy in 1 each) or of undetermined causes (19) (other PN), and 28 had amyotrophic lateral sclerosis (ALS). We also tested 21 patients with MGUS or multiple myeloma (MM) without neuropathy (MGUS/MM), and 22 …

Recent studies showed that rituximab, a chimeric anti-CD20 monoclonal antibody, reduces antibody levels and ameliorates neuropathy in two thirds of patients with neuropathy and anti-myelin-associated glycoprotein (MAG) monoclonal IgM.1–3 Few data are available on the long-term effects of this therapy.4 We report on the long-term follow-up of rituximab responders with anti-MAG polyneuropathy. ### Methods. Ten patients with anti-MAG polyneuropathy responding to rituximab, 375 mg/sq for four consecutive weekly infusions, were prospectively studied for 36 months. The effects of the initial treatment in 13 patients and the type of assessment were previously described.3 The baseline clinical and laboratory data of the 10 responding patients are reported in the table. All but one patient (no. 1) had an IgM monoclonal gammopathy of undetermined significance and a symptom duration of up to 2 years. Three patients had not been previously treated for the neuropathy, whereas seven were unresponsive to immune or cytostatic therapies. We considered as responders patients who improved at month 12 by at least one point in two clinical scales including MRC sumscore (appendix e-1 on the Neurology ® Web site at www.neurology.org), INCAT Disability Scale (appendix e-2), and INCAT sensory sumscore (ISS) …

Long-term chlorpromazine therapy has been associated with the asymptomatic development of a high incidence of antinuclear antibodies, coagulation inhibitors, and increased serum levels of IgM. The purpose of this study has been to characterize the natural history of this chlorpromazine-induced (CPZ) immunopathy. To this end we carried out a prospective study of schizophrenic patients with the immunopathy to compare the effect of continuing CPZ versus switching to haloperidol therapy. Although no marked differences were noted between the 2 groups at the end of 5 years, 6 of 29 patients who continued to receive CPZ, as compared to none of 14 patients on haloperidol, had progressive elevations of serum IgM. In spite of a high incidence of antinuclear antibodies, none of the patients developed a lupus-like syndrome. One patient, however, who had been maintained on CPZ for more than 15 years, developed Waldenstrom macroglobulinemia, as characterized by an IgM monoclonal gammopathy and a lymphocyte immunoglobulin heavy and kappa light chain gene rearrangement. Another CPZ-treated patient developed immune thrombocytopenia. Based on the potential serious sequelae of prolonged stimulation of the immune system by CPZ, we recommend that patients who develop an increase in serum IgM while on CPZ be switched to other types of anti-psychotic medications.

Objective: We describe the patient with ophthalmoparesis, visual loss and ataxia suspected of Sjogren9s, whose symptoms improved with steroids and IVIg but evolved into severe ataxia, weakness and systemic symptoms consistent with POEMS, which lead to diagnosis of diffuse large B-cell non-Hodgkin9s lymphoma. Background Lymphoma and related lymphoproliferative disorders may involve peripheral nerves on immunological or infiltrative basis long before known malignancy. Examples include non-Hodgkin and Hodgkin9s lymphoma, CLL, Waldenstrom9s macroglobulinemia, and osteosclerotic myeloma. Different phenotypes of neuropathies associated with lymphomas are likely due to circulating monoclonal anti-nerve antibodies secreted by tumor cells, usually immunoglobulin-M paraproteins directed at specific antigens such as the ganglioside GM1 and myelin-associated glycoprotein. Design/Methods: Previously healthy a 61- year-old man developed visual disturbance and gait imbalance that improved initially with oral steroids and IVIg. Three months later, he became diffusely weak and ataxic, and did not respond to IVIg and later on to plasma exchanges with IV steroids. Diagnostic work up of neuropathy and weight loss was initially consistent with Sjogren9s and suggestive of POEMS, which prompted bone marrow and lymph node biopsies. Results: Markedly elevated SS-A/ SS-B and IgM GM1 antibodies with IgM monoclonal paraprotein lambda light chain were identified in serum, while VEGF was normal. Lip biopsy was consistent with Sjogren9s. Skeletal survey was negative for osteosclerotic lesions, while CT scans revealed diffuse lymphadenopathy. Subsequent bone marrow and lymph node biopsies were consistent with transformed marginal zone lymphoma. Repeated lymph node biopsy showed more aggressive diffuse B-cell lymphoma. Three courses of cyclophosphamide, dexamethasone, rituximab and doxorubicin resulted in marked clinical improvement. Conclusions: IgM monoclonal gammopathy and Sjogren9s-associated neuropathy may herald associated malignancy of B-cell lineage, and it can be refractory to immunotherapies but responsive to chemotherapy. Transformation of indolent marginal zone into more aggressive diffuse large B-cell lymphoma has less favorable prognosis and may require hematopoietic stem-cell transplantation. Disclosure: Dr. Snapp has nothing to disclose. Dr. Ambrose has nothing to disclose. Dr. Kremens has received personal compensation for activities with Teva Neuroscience, Novartis, Allergan, Inc., GlaxoSmithKline, Inc., and General Electric Healthcare. Dr. Marmura has received personal compensation for activities with NeurogesX and Iroko as a consultant. Dr. Marmura has received research support from Merck. Dr. Rakocevic has nothing to disclose.

IgM paraproteinemic neuropathy is a progressive and potentially disabling disorder. Treatment with alkylating agents, plasma exchange, corticosteroids, and IV immunoglobulin (IVIG) is frequently unsuccessful.1 Recently, improvement was observed with the purine analog fludarabine.2 We report a patient with IgM monoclonal gammopathy of undetermined significance neuropathy who had a prolonged remission after a short course of cladribine (2-chlorodeoxyadenosine; 2-CDA), a novel purine analog. A 53-year-old man presented with ascending tingling and numbness of his legs and later of his hands over a 14-month period. His legs felt unsteady, and climbing stairs and arising from a chair became difficult. He was clumsy with his fingers. On examination he had predominantly distal weakness in all limbs and also proximal leg weakness. Reflexes were symmetrically depressed or absent. Plantar responses were flexor. Joint position and vibration sensations in the feet were lost early. Neurophysiology suggested chronic demyelinating sensorimotor neuropathy. Investigations for neuropathy revealed only an IgM level of 2.67g/L (normal 0.5 to 2.2 g/L) but no other abnormality on protein electrophoresis. He gradually became …