Brief Alerts

Neuropathy News: CANOMAD

Source: Willison HJ, et al. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124:1968-1977.

With fewer than 10 cases reported in the literature, this descriptive paper characterizes 16 new (plus 2 previously reported) patients with partial or complete chronic ataxic neuropathy, ophthalmoplegia, M protein, agglutination, and disialosyl antibodies (CANOMAD). Another in the group of paraproteinemic neuropathies, CANOMAD is associated with IgM antibodies directed against disialosyl epitopes of several ganglisodes, including GD1b, GD3, GT1b, and GQ1b. All patients have slowly progressive sensory ataxia and areflexia with significant limb weakness in a minority (4/18). Only 2 of 18 noted significant sensory symptoms, but 8 noted perioral or acral paresthesiae. Men predominate (14/18) with a mean age of onset of 53 years, and most (16/18) demonstrate oculomotor (n = 9) or bulbar (n = 8) weakness, reminiscent of Miller Fisher syndrome (itself associated with anti-disialosyl IgG antibodies against GQ1b and GT1a). Significant disability is the rule, with only 3 of 18 able to walk unaided, and 5 of 18 wheelchair bound. High titer IgM antibodies, generally monoclonal with either kappa (8/16 tested by ELISA) or lambda (4/16), light chains are present, but occasionally (4/16) both kappa and lambda light chains coexist, implicating 2 distinct antibody clones. Eight of 17 demonstrated cold agglutination. Nerve conduction studies generally demonstrate demyelination with a minority showing axonopathy (n = 3). Cerebrospinal fluid (CSF) protein is usually elevated but may be normal (n = 5). CSF lymphocytic pleocytosis was seen in 3 but oligoclonal bands were absent in all. Of 8 patients who underwent brain MRI, 2 showed findings consistent with white matter demyelination. Three sural nerve biopsies were performed, one each demonstrating small onion bulb formations, nonspecific axonal degeneration, and large myelinated fiber dropout. No inflammatory cells or immunoglobulin deposits were seen. Patients with ataxic neuropathy and oculobulbar weakness should be screened for disialosyl IgM antibodies. No clinical treatment trials have yet been performed but intravenous immune globulin (IVIG) or plasma exchange may be beneficial. —Michael Rubin


Source: Hughes R, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001;50:195-201.

Thirty-two patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were randomized in a multicenter, double-blind, crossover trial to receive either intravenous immunoglobulin (IVIG) 2.0 g/kg over 1-2 days or oral prednisolone tapering over 6 weeks from 60 mg/d to 10 mg/d. Diagnosis of CIDP was based on a progressive or relapsing course of sensorimotor dysfunction over > 2 months, with hypo- or areflexia, cerebrospinal fluid with < 10 white cells/uL, and nerve conduction studies demonstrating demyelinating polyneuropathy. Exclusionary criteria included other diseases associated with neuropathy, pregnancy, recent (within 6 weeks) treatment with IVIG, steroids, or plasmapheresis, a history of nonresponse to IVIG or prednisolone, or a diagnosis of multifocal motor neuropathy with conduction block. Assessment of efficacy included a disability rating, timed 10-meter walk, 9-hole pegboard test, Medical Research Council (MRC) sum score, maximal grip strength, Rankin scale, and the short-form 36 (SF-36) quality-of-life scale.


Twenty-four patients completed the trial. Neither treatment demonstrated superiority over the other. Two weeks following randomization both produced significant improvement in the disability scale and in time to walk 10 meters. Disability grade was significantly diminished in both groups after 6 weeks. Treatment was generally well tolerated. Psychosis occurred in 1 prednisolone-treated patient. He was withdrawn. No serious adverse events were seen in the IVIG group. Both groups experienced equal incidences of headache (approximately 30%), indigestion (20%), fever, rash, and hypotension. Prednisolone and IVIG are equally efficacious for the treatment of CIDP. Although the former is inexpensive in the short term, long-term side effects of steroid treatment favor IVIG as the first-line therapy. —Michael Rubin

P0 and CIDP

Source: Yan WX, et al. P0 protein is a target antigen in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001;50:286-292.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the earliest described and best known form of a growing number of chronic acquired demyelinating polyneuropathies, including monoclonal gammopathy of undetermined significance (MGUS), polyneuropathy, organomegaly, endocrinopathy, M spike, skin changes (POEMS syndrome), multifocal motor neuropathy with conduction block (MMNCB), distal acquired demyelinating symmetric neuropathy (DADS), and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). All share the commonality of demyelination but their mechanisms remain unclear. Certain demyelinating neuropathies demonstrate an association with various antibodies, offering a clue to their pathogenesis. These include Miller Fisher syndrome with GQ1b ganglioside antibodies, acute motor axonal neuropathy with GD1a ganglioside antibodies, and MMNCB with GM1 ganglioside antibodies. CIDP has resisted any such association but new evidence points to protein zero (P0), the major (80%) integral membrane protein of peripheral nerve myelin, as the target antigen.

Immunofluorescence and Western blotting of 21 CIDP patients’ sera demonstrated 6 (28%) containing IgG antibodies directed against P0. Four of these were able to produce demyelination and partial conduction block following injection into rat sciatic nerve, while removal of P0 antigen by antigen absorption eliminated the demyelinative activity. P0 antibodies are present in a significant minority of CIDP patients and may play a role in its immunopathogenesis. —Michael Rubin

Dr. Rubin, Associate Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.