This article reviews recent clinical updates and research on the evaluation and management of patients with peripheral neuropathy in association with monoclonal gammopathies. Recent studies have elucidated pathogenic mechanisms of IgM paraprotein associated neuropathies, including nodal and paranodal targets and complement mediated processes, suggesting novel therapeutic targets. New chemotherapeutic regimens have improved outcomes and neurotoxic side effect profiles in the treatment of patients with light chain (AL) amyloidosis and POEMS syndrome. Establishing when a monoclonal gammopathy is causative of a peripheral neuropathy remains a clinical challenge. New therapeutic drugs for treatment of IgM paraprotein associated neuropathies show promise. Identifying AL amyloidosis and POEMS early in patients presenting with neuropathy are important. Clinical phenotyping and antibody testing are critical to evaluating patients with paraproteins and peripheral neuropathy.

Antimyelin-associated glycoprotein (MAG) neuropathy is a rare autoimmune demyelinating peripheral neuropathy caused by IgM autoantibodies targeting MAG. The typical presentation is that of a slowly progressive, distal, length-dependent, predominantly sensory, sometimes ataxic neuropathy, frequently accompanied by upper limb tremor. Distal motor weakness may subsequently occur. The clinical presentation may vary and rarely be consistent with that of typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), as well as have an aggressive and rapidly disabling course. The diagnosis of anti-MAG neuropathy is based on the detection of anti-MAG antibodies through ELISA or western blot analysis, primarily in presence of an IgM monoclonal gammopathy. Anti-MAG neuropathy may occur without or with haematological malignancy. Electrophysiology is characteristic of a predominantly distal demyelinating neuropathy. Intravenous immunoglobulins and plasma exchange have unproven benefits, but may provide short-term effects. Cytotoxic therapies are commonly used, although without an evidence base. Rituximab, an anti-B-cell monoclonal antibody was studied in two randomised controlled trials, neither of which achieved their primary outcome. However, a meta-analysis of these two studies demonstrated improvement of disability at 8-12 months. A recent trial with lenalidomide was interrupted prematurely due to a high rate of venous thromboembolism. There are currently two ongoing trials with Bruton's tyrosine kinase inhibitors. Symptom control is otherwise frequently needed. Outcome measures used for other inflammatory neuropathies present limitations in anti-MAG neuropathy. International registries such as the planned IMAGiNe study may, in future, provide answers to the many remaining questions.

Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity. We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics. IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation. Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

IgM monoclonal gammopathy-associated polyneuropathy with(out) anti-myelin associated glycoprotein (±anti-MAG) is a rare immune-mediated disease that may cause severe limitations in daily activities and quality of life. The absence of a systematic comparison between patients with/without anti-MAG IgM polyneuropathy, no disease-specific functional metric, and lack of international consensus regarding assessment and treatment of these patients are factors obstructing future clinical trials. Therefore, it was decided to develop an interval Rasch-built activity/participation scale specifically for IgM polyneuropathy ±anti-MAG (IgM-RODS) and examine its clinimetric properties. A pre-phase IgM-RODS questionnaire containing 146 activity/participation items, based on the WHO International Classification of Functioning, Disability and Health, was completed by participants (≥ 18 years) of the IMAGiNe observational registry that fulfilled international criteria for IgM-polyneuropathy ±anti-MAG. Data was subjected to Rasch analyses, and reliability/validity studies were performed as well. The pre-RODS data of 259 subjects (originating from 8 different countries) underwent quality assessment, and 244 remaining records were submitted to the Rasch model, evidencing the model's expectations. Based on requirements like exceeding fit residuals, misfit statistics, item bias, local dependency, and less face validity, we systematically removed items until the final 36-item IgM-RODS fulfilled all Rasch requirements and showed acceptable test-retest reliability, cross-cultural, construct and discriminant validity, and unidimensionality. Compared to the Inflammatory-RODS, the IgM-RODS showed lower standard errors across the metric, indicating greater sensitivity. The 36-item IgM-RODS is a disease-specific interval measure suitable for detecting functional deficits in patients with IgM-polyneuropathy ±anti-MAG. Future studies are needed to determine its responsiveness.

Chronic Dysimmune Polyneuropathies (CDP) encompass a group of conditions characterized by autoimmune etiology targeting myelin and/or axonal components. Subgroups include Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and paraproteinemic neuropathies associated with IgM monoclonal gammopathy of undetermined significance, with anti-MAG antibodies (IgM-MGUS anti-MAG+) and without anti-MAG antibodies (IgM-MGUS anti-MAG-). Their identification is crucial for determining the most suitable treatment options, yet it poses significant challenges. In this study, an electrophysiological-based automatic classification through machine learning models is proposed. This study included 67 patients, 29 diagnosed with CIDP, 20 with polyneuropathy associated with IgM-MGUS anti-MAG+, and 18 with CIDP-like polyneuropathy associated with IgM-MGUS anti-MAG-. Five different classification algorithms based on electrophysiological data (conduction velocity, latency, and amplitude of sensory and motor responses from different nerves) were implemented to classify three types of neuropathies and identify discriminative neurographic parameters. The best performance in stratifying the three classes was achieved by Random Forest in terms of both validation and test accuracy (86.5% and 80.6%). The predictor analysis on the best-performing model revealed the significance of F-wave latencies, distal latencies, and conduction velocities for group discrimination. The study is the first to apply computational methods to identify electrophysiological parameters most frequently altered in different forms of polyneuropathy, to support clinical diagnosis and decision-making. The online version contains supplementary material available at 10.1186/s12984-025-01685-x.