Axonal neuropathy in a patient with IgM M-protein reactive with nerve endoneurium

IgM M-proteins have been found in patients with axonal neuropathies, but it is not known whether these M-proteins bind to nerve components or actually cause the neuropathy. In one patient with axonal neuropathy studied, the IgM M-protein bound to chondroitin sulfate, and there were deposits of IgM in the endoneurium of the patient's nerve. A monoclonal anti-idiotype antibody generated against that M-protein was used to study the binding of the M-protein to normal nerve and to distinguish it from binding of other IgM species that might be present in the patient's serum. In immunofluorescence studies, the M-protein bound to the endoneurium in normal nerve and to connective tissue in other organs. In immunoblot studies, the M-protein bound to several protein bands in nerve and other tissues. The data suggest that the M-protein bound to mucopolysaccharides in nerve endoneurium and connective tissue.     

Anti-myelin-associated glycoprotein IgM antibody titers in neuropathy associated with macroglobulinemia

Twenty-seven patients with neuropathy and IgM monoclonal gammopathy were tested for antigen specificity of the M-protein and for anti-myelin-associated glycoprotein (MAG) IgM levels by immunoblot. In 16 patients (59.2%) the M-protein reacted with MAG and with cross-reactive glycoconjugates. Anti-MAG IgM titers in these patients ranged between 1:12,800 and 1:100,000. A fainter IgM reactivity with MAG and related glycoconjugates was detected in 3 additional patients with neuropathy, but also in 8 of 24 patients with IgM M-protein without neuropathy (33.3%). This reactivity was not due to the M-protein and corresponded to antibody titers of 1:400 or less in all but 1 patient with a titer of 1:3,200. Low titers of anti-MAG IgM (1:200 or less) were also detected in 17 of 101 control patients without IgM M-proteins (16.8%), while 1 patient with neuropathy of unknown cause had anti-MAG IgMK titers of 1:25,600. In 1 patient with neuropathy and IgM M-protein that was not anti-MAG, the M-protein bound to other antigens in nerve, while in 6, other possible causes or mechanisms for the neuropathy were found. In this study, high titers of anti-MAG IgM antibodies were always associated with neuropathy. The presence of low levels of anti-MAG IgM in a significant proportion of controls suggests that monoclonal expansion of naturally occurring B-cell clones secreting anti-MAG IgM may be responsible for the high incidence of this antigen specificity of the M-protein.     

Vasculitic neuropathy in a patient with cryoglobulinemia and anti-MAG IGM monoclonal gammopathy.

A patient with sensorimotor mononeuritis multiplex had a type II cryoglobulin with an IgM kappa M-protein that appeared to contain monoclonal anti-MAG antibodies of the same isotype. A sural nerve biopsy demonstrated necrotizing arteritis and features of both axonal degeneration and demyelination. IgM kappa and C3 deposits were present on the myelin sheath of some residual nerve fibers. The findings suggest that the anti-MAG antibodies contributed to the myelin damage, while cryoprecipitates may have caused the vasculitis and axonal degeneration.     

Chronic sensory ataxic neuropathy associated with IgM antibody against b-series gangliosides including GD1b]

We described a 62-year-old man with a 10 years history of chronic sensory ataxic neuropathy. His laboratory investigations revealed elevated serum IgM with IgM kappa paraproteinemia, IgM antibody against b-series gangliosides including GD3, GD2, GD1b, GT1b, GQ1b, GQ1b alpha, and high titer of cold agglutinin. The clinical and serological features in our patient were compatible with the diagnosis of CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, M-protein, agglutination, and disialosyl antibodies), proposed by Willison et al. IgM antibody against b-series gangliosides including GD1b appeared to play an essential role in developing autoimmune sensory ataxic neuropathy.     

Peripheral nerve binding patterns of anti-sulphatide antibodies in HIV-infected individuals.

HIV-positive plasma samples from patients with and without neuropathy and with high titre anti-GalS antibodies showed strong binding to the myelin membrane of both fixed and unfixed human sciatic nerve specimens. This staining pattern was also seen with a plasma sample from a patient with IgM paraproteinaemic inflammatory demyelinating neuropathy with anti-GalS IgM antibody. Teased nerve fibres incubated with these anti-GalS antibodies from both HIV and non-HIV plasma samples showed immunofluorescence at the paranodal regions and Schmidt-Lanterman incisures. These data support a potential role for these antibodies in the aetiology of HIV-associated immune mediated neuropathies.     

Multiple exercise-related mononeuropathy with abdominal colic

Hereditary neuropathy with liability to pressure palsies (NLPP) is a rare disease characterized by recurrent sensory-motor deficits precipitated by exposure to minor pressure.

This report describes a variant of this neuropathy in 5 siblings suffering from painful palsies after strenuous work with concurrent episodes of abdominal colic resembling that of acute intermittent porphyria. Electrophysiological studies of the index case showed the typical abnormalities of motor and sensory nerve conduction, including clinically non-affected nerves. Light and electron-microscopic examination showed the characteristic lesions of the NLPP with sausage-like swelling of the myelin sheaths. In addition, non-compacted, “loose” myelin lamellae were frequently observed in association with distended Schmidt-Lantermann incisures. Non-compacted myelin was a prominent finding in this type of demyelinating neuropathy.

We suggest that an unknown metabolic factor may induce both demyelination of peripheral nerve fibers and functional disturbance in autonomic nerves leading to attacks of abdominal pain.     

Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti-MAG IgM M-protein

Demyelination of feline sciatic nerve was induced by intraneural injection of serum from three patients with neuropathy and an IgM M-protein that reacted with myelin-associated glycoprotein (MAG). Demyelination exceeded that induced by serum from 18 other individuals, including six IgM M-proteins unreactive with MAG. The myelinolytic effect required active human complement and was abolished by exposure of serum to homogenate of human peripheral nerve that removed 90% of the M-protein. Immunofluorescence studies demonstrated deposition of the injected M-protein and complement on the surface of myelin sheaths, implying that the M-protein reacted with epitopes of myelin exposed to the extracellular space.     

Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy

We report here on a patient with anti-myelin-associated glycoprotein (MAG) neuropathy in whom examination of a sural nerve biopsy by multichannel confocal microscopy showed a partly overlapping distribution of MAG and IgM deposits in myelinated fibers. Our data demonstrate that MAG in Schmidt-Lanterman incisures and paranodal loops, as well as some additional HNK-1-positive components of the basal lamina, are the major targets of the anti-MAG monoclonal IgM autoantibodies in this neuropathy in vivo. Perforation of the basal lamina can allow the penetration and binding of anti-MAG IgM inside myelinated fibers. Our results support and extend the notion that the production of monoclonal anti-MAG IgM may be antigenically driven by MAG molecules and that this process may occur in the immunologically privileged environment of the nerve prior to the appearance of a genuine gammopathy in serum. Received: 12 May 1997 / Revised: 13 August 1997 / Revised, accepted: 19 November 1997     

Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies

In an unselected series of patients with monoclonal gammopathy of undetermined significance (MGUS) we found neuropathy in 2 of 34 patients with IgG (6%), 2 of 14 with IgA (14%), and 8 of 26 with IgM MGUS (31%). The neuropathy was subclinical in 6 patients (1 IgG, 1 IgA, and 4 IgM). Patients with IgG or IgA MGUS had a prominent motor impairment with electrophysiologic and morphologic findings suggestive of predominant axonal degeneration. No deposit of the M-protein in sural nerve and no reactivity of the M-protein with nerve was detected in these patients. Patients with IgM MGUS had a prominent sensory impairment with evidence of predominant demyelination. In 6 of these patients the M-protein reacted with the myelin-associated glycoprotein (MAG). The higher prevalence of neuropathy in patients with IgM MGUS may be related to the frequent reactivity of IgM M-proteins with MAG.     

The neuropathy of plasma cell dyscrasia: binding of IgM M-proteins to peripheral nerve glycolipids

In some patients with neuropathy and plasma cell dyscrasia, the M-proteins bind to peripheral nerves. Binding of M-proteins to peripheral nerve glycolipids was examined by immunostaining after thin-layer chromatography. The IgM from 16 patients with anti-MAG M-proteins bound to the same two glycolipid bands in peripheral nerve. The IgM that bound to the glycolipids had the same idiotype as the anti-MAG M-protein, indicating that it was the M-protein that bound to both glycolipids. The reactive glycolipids did not contain sialic acid and were not gangliosides. No immunostaining of peripheral nerve glycolipids was observed with IgM from patients with neuropathy and IgM M-proteins that did not bind to MAG, and the anti-MAG antibodies did not bind to brain glycolipids. Anti-MAG M-proteins probably bind to the same or closely related carbohydrate determinants that are shared by a number of glycoproteins and glycolipids of peripheral nerve.     

Neuropathy and anti-MAG antibodies without detectable serum M-protein

Anti-MAG IgM antibodies were detected by ELISA in a patient with slowly progressive peripheral neuropathy. Serum IgM content was normal, and no M-protein was detected by serum protein electrophoresis, immunoelectrophoresis, or immunostaining. By immunoblot analysis, the anti-MAG antibodies were IgMk; they reacted with human and bovine MAG but not with mouse MAG. The data suggest that there was an anti-MAG IgM M-protein in concentration too low to be detected by conventional techniques. Tests for anti-MAG antibodies should be done in patients with slowly progressive neuropathy of unknown etiology, even in the absence of detectable serum M-protein.     

Systemic passive transfer studies using IgM monoclonal antibodies to sulfatide

We present a patient with benign IgM-A anti-Sulfatide (SUL) whose neuropathy was transferred in newborn rabbits. The patient's clinico-pathological picture of anti-SUL-associated demyelinating neuropathy is reported. The monoclonal IgM antibodies prepared by Tatum's method, that retained their biological activity, were passively transferred to newborn rabbits. The passive transfer produced demyelinating nerve lesions very similar to the donor antibody neuropathy. In experimental lesions we observed the human IgM anti-SUL antibodies binding to Schmidt-Lanterman incisures and nodes of Ranvier. We postulate that the myelin-specific and complement-dependent lesions observed in the peripheral nerve support the potential demyelinating role of anti-SUL antibodies. Moreover, the pattern of the antibody binding to the perineuronal sheath of satellite cells in dorsal root ganglia strengthen the hypothesis that anti-SUL antibodies may have a pathogenetic role in this sensorimotor syndrome.     

Treatment of patients with neuropathy and anti-MAG IgM M-proteins

Five patients with neuropathy and IgM M-proteins that reacted with myelin-associated glycoprotein (MAG) were treated for 10 to 20 months with cytostatic agents. In 2 patients, a decrease in serum M-protein and in anti-MAG IgM levels coincided with a progressive improvement of neuropathy. No clinical improvement and no decrease of anti-MAG IgM were observed in the other patients. The close relationship between the decrease of anti-MAG M-proteins and clinical improvement in these patients supports the pathogenetic role of the M-protein in the neuropathy.     

Immunoelectron microscopic localization of monoclonal IgM antibodies in gammopathy associated with peripheral demyelinative neuropathy

Summary A sural nerve biopsy from a patient with benign monoclonal IgM kappa gammopathy and sensory-motor demyelinative neuropathy, revealed marked loss of myelinated fibers and focal axonal degeneration as well as widespread demyelination and remyelination with onion-skin formation. Almost all meylinated fibers displayed characteristic widening of the myelin lamellae as well as excessive thickness and/or exuberant outfoldings of myelin, reminiscent of that seen in tomaculous neuropathy. Many endoneurial capillaries were lined by fenestrated endothelium, indicating breakdown of a normal blood-nerve barrier. The endoneurium contained large amounts of extracellular proteinaceous material. Immunofluorescence and immunoelectron microscopy performed on the nerve of the patient, demostrated selective deposition of IgM kappa gammaglobulin, exclusively in the areas of splittings of the myelin lamellae. Schwann cells contained cytoplasmic myelin debris labelled with IgM kappa only. In the indirect immunofloorescence and immunoelectron microscopy, serum of the patient reacted with the whole thickness of compact peripheral myelin of a normal human nerve. There was no immunoreactivity with the central myelin, Schwannoma cells, glial cells, axons or neurons. Demonstration of the selective presence of monoclonal IgM in widened lamellae of myelinated fibers, as well as bound to the internalized myelin debris in Schwann cells and macrophages, indicates a pathogenetic role of monoclonal paraprotein in myelin injury. Demyelination is promoted by development of endothelial fenestrations in the endoneurial capillaries and breakdown of the blood-nerve barrier.Presented in part at Canadian Congress of Neuroscience, Ottawa, Canada September, 1989     

Glycosaminoglycan antigens in peripheral nerve: Studies with antibodies from a patient with neuropathy and monoclonal gammopathy

An immunoblot staining procedure was developed for the detection of antibody binding to glycosaminoglycans (GAGs). The method was used to study the binding of a human monoclonal antibody (M-protein) from a patient with peripheral neuropathy, previously found to react with proteoglycans (PGs). GAGs prepared from human peripheral nerve were separated by electrophoresis on cellulose acetate membranes, transferred onto nitrocellulose sheets, and immunostained with the M-protein. The M-protein bound to a single GAG band with intermediate mobility which eluted with 1.25 N NaCl on ion-exchange chromatography and was chondroitinase sensitive. The M-protein appeared to bind to chondroitin sulfate containing proteoglycans in peripheral nerve.     

Neuropathy associated with cryoglobulinemia

A patient with severe subacute sensory ataxia was found to have an IgM (kappa) cryoglobulin. Clinical, electrophysiologic, and sural nerve biopsy studies indicated that axonal degeneration and segmental demyelination both played a role in the pathogenesis of this neuropathy. Corticosteroid therapy was associated with notable clinical improvement and a 50% decrease in cryoglobulin concentration.     

Demyelinating neuropathy due to primary IgM kappa B cell lymphoma of peripheral nerve

A 53-year-old man presented with a painful, demyelinating sensorimotor peripheral neuropathy with lymphomatous infiltration on sural nerve biopsy, but no evidence of systemic lymphoma. The neuropathy responded to cytotoxic therapy. Seven years later he developed generalized lymphadenopathy due to B cell lymphoplasmacytoid lymphoma, with a subpopulation of cells expressing a monoclonal pattern of IgM kappa. The lymphomatous infiltrate in the original nerve biopsy showed similar monoclonal IgM kappa reactivity. The mechanism of demyelination of the peripheral nerves may be similar to that described in patients with IgM kappa monoclonal gammopathies.     

IgM M-protein in a patient with sensory-dominant neuropathy binds preferentially to polysialogangliosides

A 77-year-old man presented sensory-dominant neuropathy associated with IgM M-protein reacting with various gangliosides. The M-protein bound to gangliosides with polysialosyl residue, such as GD1b, GD3, GT1b, GT3, GQ1b, and GQ1c. In addition, GD1a, GM3 and LM1, having a terminal monosialosyl epitope, were also recognized. Previously, Ilyas et al. described a similar case in which sensory symptoms were associated with IgM M-protein reacting with gangliosides containing a disialosyl group, such as GD3, GD1b, and GT1b, but not GM3 and GD1a. It is suggested that the reactivity of IgM M-protein with polysialogangliosides may be associated with the pathogenesis of sensory-dominant neuropathy.     

Amyloid-like IgM deposition neuropathy with multiple mononeuropathies and generalized neuropathy

Amyloid-like IgM deposition neuropathy is a distinct entity in the setting of IgM monoclonal gammopathy in which endoneurial perivascular entire IgM-particle accumulation leads to a painful sensory followed by motor peripheral neuropathy. We report a 77-year-old man presenting with progressive multiple mononeuropathies starting with painless right foot drop. Electrodiagnostic studies showed severe axonal sensory-motor neuropathy superimposed by multiple mononeuropathies. Laboratory investigations were remarkable for biclonal gammopathy of IgM kappa, IgA lambda and severe sudomotor and mild cardiovagal autonomic dysfunction. A right sural nerve biopsy showed multifocal axonal neuropathy, prominent microvasculitis, and prominent large endoneurial deposits of Congo-red negative amorphous material. Laser dissected mass spectrometry-based proteomics identified IgM kappa deposit without serum amyloid-P protein. This case has several distinctive features, including motor preceding sensory involvement, prominent IgM-kappa proteinaceous deposits replacing most of the endoneurium, a prominent inflammatory component, and improvement of motor strength after immunotherapy.     

Chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibody without any detectable M-protein

Previous case reports and studies have shown that anti-myelin-associated glycoprotein (MAG) antibody can be detected in patients with polyneuropathy without any detectable M-protein. Nevertheless, the frequency of and related factors have not yet been adequately investigated. The objectives of this study are to examine the prevalence of anti-MAG antibody in patients with demyelinating neuropathy without M-protein and to determine their clinical characteristics. From January, 2004, to September, 2016, consecutive patients with chronic demyelinating neuropathy were recruited. Anti-MAG antibody presence was tested at the first evaluation. We determined the prevalence of anti-MAG antibody without M-protein among included patients and evaluated the clinical characteristics. A total of 44 patients were included in the present study (12 women; median age at first visit 60 years [interquartile range 47–67 years]; median duration between onset and first visit 9 months [3–26 months]). M-protein was found in eight patients (18%) at the first evaluation. Anti-MAG antibody was present in 2 of remaining 36 (5.6 [95% confidence interval 0–13.0] %) patients without M-protein. Patients with anti-MAG antibody exhibited slowly progressive and distal dominant neuropathy with elevated serum IgM levels and refractory to immunotherapy. There were no differences in clinical features between patients having anti-MAG antibody without M-protein, and those with M-protein. One patient with the anti-MAG antibody showed a delayed appearance of M-protein during a 4-year follow-up after diagnosis. The prevalence of the anti-MAG antibody in chronic demyelinating neuropathy without any detectable M-protein was 5.6%. Anti-MAG antibody may be detectable earlier than M-protein.