Review: Treatment of Inflammatory Neuropathies

Abstract & Commentary

Michael Rubin, MD, Professor of Clinical Neurology, New York-Presbyterian Campus. Dr. Rubin is on the speaker’s bureau for Athena Diagnostics and does research for Viatris.

Synopsis: Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown.

Source: Finsterer J. Treatment of Immune-Mediated, Dysimmune Neuropathies. Acta Neurol Scand. 2005;112: 115-125.

Immune-mediated, inflammatory neuropathies may be acute or chronic and occur with an incidence of 2-4/100,000 worldwide. All are potentially treatable, and a timely review of this topic is presented.

Guillain-Barre syndrome (GBS) may involve the myelin (acute inflammatory demyelinating polyradiculoneuropathy) or the axon (acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, AMAN and AMSAN, respectively) and, in two-thirds of cases, is preceded by C. jejuni, cytomegalovirus, Epstein-Barr, or M. pneumoniae infection. When the autonomic nervous system is the primary target, acute pandysautonomia results, while Miller Fisher syndrome comprises ophthalmoplegia, ataxia, and areflexia. Clinical trials have demonstrated that plasma exchange and intravenous immune globulin (IVIG, 0.4 mg/kg/day for 5 days) are equally efficacious for moderate or severe disease, including acute pandysautonomia. No convincing evidence justifies the administration of oral or intravenous corticosteroids, even in combination with IVIG. Interferons are of no proven benefit, and may even trigger GBS.

Chronic inflammatory demyelinating polyneuropathy (CIDP) includes several entities whose treatment differs. Classic, idiopathic CIDP is an acquired, immune mediated, symmetric neuropathy causing proximal and distal weakness with sensory impairment. By definition, it progresses over at least 8 weeks, thereby differentiating it from the more acute GBS, which nadirs by 4 weeks. Controlled clinical trials have proven the efficacy of oral prednisone, plasma exchange, and IVIG for the majority of CIDP patients. For the one-third that do not respond, cyclophosphamide, cyclosporine, or etanercept (Enbrel) may be beneficial, but azathioprine, methotrexate, and mycophenolate mofetil (CellCept) are not. Interferons are under investigation, but do not look promising. Rituximab, a monoclonal antibody against CD20, has shown promise in individual case reports.

Up to 22% of CIDP patients demonstrate a monoclonal gammopathy, IgM, IgG, or IgA, having no autoantibody activity and not associated with underlying hematologic malignancy. Termed CIDP with monoclonal gammopathy of undetermined significance (MGUS), its treatment is identical to idiopathic CIDP, as it responds to corticosteroids, plasma exchange, and IVIG. Azathioprine may be used as a steroid-sparing agent, but is contraindicated together with allopurinol.

CIDP develops in 17% of diabetics, and electrodiagnosis of CIDP in these patients is challenging, given the frequent presence of underlying diabetic polyneuropathy. Progressive symmetric or asymmetric motor and sensory neuropathy, despite good diabetic control, and in the presence of elevated cerebrospinal fluid protein, should alert the physician to possible concomitant CIDP. CIDP diabetics respond best to corticosteroids, and less often to plasma exchange or IVIG, compared to idiopathic CIDP.

Multifocal motor neuropathy with conduction clock (MMNCB) is a slowly progressive disorder predominantly affecting young adults, resulting in asymmetric weakness in the distribution of individual nerves, usually worse in the distal arms, and often mimicking motor neuron disease. Unlike CIDP, cerebrospinal fluid protein is usually normal, as are sensory nerve conduction studies, and patients do not respond to corticosteroids or plasma exchange. IVIG is the controlled-trial-proven treatment of choice for 80% of cases, with refractory patients responding to cyclophosphamide or rituximab, and perhaps interferon-beta. Mycophenolate mofetil appears ineffective.

Multifocal-acquired demyelinating sensory and motor neuropathy (MADSAM or Lewis-Sumner syndrome) presents as a mononeuropathy multiplex, affecting both motor and sensory fibers in an asymmetric pattern, with a laboratory profile and therapeutic response pattern similar to CIDP. It may indeed simply be asymmetric CIDP. Sensory impairment and elevated cerebrospinal fluid protein in up to 80%, distinguish it from MMNCB, a critical distinction as one-third of MADSAM patients respond to corticosteroids. IVIG benefits two-thirds. MADSAM with axonal, rather than demyelinating features is designated MASAM (multifocal acquired sensory and motor neuropathy), and also responds well to IVIG.

DADS denotes distal-acquired demyelinating sensory neuropathy, and presents with prominent sensory symptomatology, while affecting both sensory and motor fibers. As distinct from CIDP, IgM kappa monoclonal gammopathy is present in nearly two-thirds, of which 67% have anti myelin-associated glycoprotein (MAG) antibodies. Response to immunomodulating therapy is poor in those with gammopathy. DADS without gammopathy respond to corticosteroids, IVIG, or plasmapheresis.

Paraproteinemic neuropathies may be associated with underlying hematologic malignancy, and treatment of the neuropathy is directed at the underlying condition. Among others, these include Waldenstrom’s macroglobulinemia, which may rarely be associated with a painful sensory axonal neuropathy, possibly due to underlying vasculitis. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) is associated with a monoclonal lambda sclerotic plasmacytoma in over 95%, and dramatically responds to thalidomide, itself neurotoxic. Mixed cryoglobulinemia may be associated with polyneuropathy, and rituximab shows promise for its treatment. GALOP (gait ataxia and late-onset polyneuropathy) demonstrates a monoclonal IgM-kappa protein and specific IgM binding to the central nervous system white matter antigen, galopin. IVIG is beneficial.


Rituximab (Rituxan) is the first monoclonal antibody approved by the FDA for cancer therapy, and may also be effective in autoimmune diseases. Genetically engineered, it is a human-mouse chimeric monoclonal antibody, containing human heavy-chain and light-chain constant-region sequences and murine variable-region sequences (Annu Rev Med. 2004;55;477-503). CD-20, a 35-kDa transmembrane lymphocyte antigen involved in cell-cycle progression and differentiation, is its target, and accounts for rituximab’s specificity. It is present exclusively on B cells, from pre-B cells to activated B cells, but not differentiated plasma cells. B cells are depleted, but antibody production is maintained. Hematopoietic stem cells replenish normal peripheral B cells within 3-12 months post therapy.

Rituximab is relatively well tolerated, with the majority of adverse events being infusion-related and including fever and chills, with occasional dyspnea and hypotension, the latter sporadically mandating interruption of infusion and resumption at a slower rate. Rarely, death or tumor lysis syndrome encompassing acute renal failure, electrolyte abnormalities, and hyperuricemia are seen, particularly in the presence of a higher tumor burden. Mucocutaneous reactions are exceedingly rare and include Stevens-Johnson syndrome, toxic epidermal necrolysis, and paraneoplastic pemphigus.

Rituximab is efficacious for malignant, as well as non-malignant conditions, including autoimmune hemolytic anemia, refractory immune thrombocytopenia, refractory thrombotic thrombocytopenic purpura, rheumatoid arthritis, and systemic lupus erythematosus. Case reports suggest its may be beneficial for autoimmune neuropathy. Multiple sclerosis appears to be its next stop.