Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

SYNOPSIS: Anti-MAG antibody-associated neuropathy may present as many disorders, including small fiber neuropathy, sensorimotor neuropathy, Guillain-Barré-like syndrome, and multifocal motor neuropathy. Rituximab appears to be the best therapeutic option.

SOURCE: Svahn J, Petiot P, Antoine JC, et al. Anti-MAG antibodies in 202 patients: Clinicopathological and therapeutic features. J Neurol Neurosurg Psychiatry 2018;89:499-505.

Considered to be distinct from chronic inflammatory demyelinating neuropathy (CIDP) because of its resistance to standard immunomodulatory therapies to which CIDP usually responds, distal acquired demyelinating symmetric neuropathy often is associated with an IgM protein, and approximately 50% of these patients also demonstrate anti-myelin associated glycoprotein (anti-MAG) antibodies. It is unclear whether the presence of these antibodies alters the clinical features of this condition.

To address this question and to determine the clinical, pathological, and therapeutic features of patients with low (≥ 1,000 to < 10,000 Bühlmann Titer Units [BTU]), medium (10,000 to 70,000 BTU) or high (≥ 70,000 BTU) anti-MAG antibody titers, a retrospective and prospective analysis of the medical records of 202 patients from 14 neuromuscular centers was undertaken between March 2014 and April 2016 in Lyon, France. Neuropathy was classified as acute (progression < 1 month), subacute (progression over > 1 month but < 6 months), or progressive (progression over ≥ 6 months), and the Overall Neuropathy Limitations Scale score and modified functional impairment scale score, ranging from 0 to 5 at the most severe, were ascertained. Patients were defined as typical if they presented with sensory ataxic distal polyneuropathy or sensory or sensorimotor length-dependent polyneuropathy without ataxia. Patients were classified as atypical if they presented with a Guillain-Barré-like syndrome, chronic sensorimotor polyradiculoneuropathy, small fiber neuropathy, asymmetric or multifocal neuropathy, or associated motor neuron disease. Where available, electrodiagnostic studies, cerebrospinal fluid, and nerve biopsies were reviewed, and types of treatment were assessed to determine if they were administered for neurologic or hematologic considerations. Statistical analysis comprised Fisher’s exact test, the Mann-Whitney test, and the Kruskal-Wallis test, with significance set at P = 0.05.

Among 202 patients, 133 men and 69 women, whose data were collected, mean age at symptom onset was 62.6 years, with a mean of 3.1 years to time of diagnosis as an anti-MAG neuropathy. Anti-MAG antibody titers at diagnosis were low, medium, or high in 11%, 51%, and 38%, respectively. Thirty-four patients (16.8%) presented with an “atypical” phenotype, without significant differences of anti-MAG antibody titers, including a Guillain-Barré syndrome-like presentation in four (2%), chronic sensorimotor polyradiculoneuropathy in 22 (10.9%), multifocal or asymmetric neuropathy in six (3%), and small fiber neuropathy or sensory neuropathy with amyotrophic lateral sclerosis in one each (0.5%). No difference in anti-MAG titers was seen between the typical or atypical variants. Rituximab was the treatment modality used most often (n = 92, 45.5%) and resulted in an objective clinical response in 31.5%, stabilization in 29.3%, and transient, reversible worsening in 12% (n = 11). Other treatment modalities included chlorambucil, cyclophosphamide, fludarabine, and dexamethasone. Anti-MAG antibody titers did not correlate with the clinical spectrum of neuropathy, but rituximab may be beneficial if used early in the course of disease.

COMMENTARY

In approximately 75% of polyneuropathy patients with immunoglobulin M (IgM) monoclonal gammopathy, the most common paraproteinemic neuropathy, the monoclonal IgM reacts with MAG, sulfoglucuronyl glycosphingolipid, or other peripheral nerve glycolipids that serve as antigens. When deposited on the myelin sheath with complement, splitting of the myelin lamellae occurs, arguing that these antibodies are pathogenic. Sensory ataxia results when adoptive transfer of patients’ IgM is performed on susceptible host animals, further supporting their pathogenicity. Nevertheless, immunotherapy remains disappointing. Chlorambucil, cladribine, cyclophosphamide, and intravenous immunoglobulin may be somewhat beneficial, but rituximab shows the most promise.