Disialosyl Antibodies Research Articles

Antibodies in Autoimmune Neuropathies: What to Test, How to Test, Why to Test.

Autoimmune neuropathies are a heterogeneous group of immune-mediated disorders of the peripheral nerves. Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are the archetypal acute and chronic forms. Over the past few decades, pathogenic antibodies targeting antigens of the peripheral nervous system and driving peripheral nerve damage in selected patients have been described. Moreover, the detection of these antibodies has diagnostic and therapeutic implications that have prompted a modification of the GBS and CIDP diagnostic algorithms. GBS diagnosis is based in clinical criteria, and systematic testing of anti-ganglioside antibodies is not required. Nonetheless, a positive anti-ganglioside antibody test may support the clinical suspicion when diagnosis of GBS (GM1 IgG), Miller Fisher (GQ1b IgG), or acute sensory-ataxic (GD1b IgG) syndromes is uncertain. Anti-myelin-associated glycoprotein (MAG) IgM and anti-disialosyl IgM antibodies are key in the diagnosis of anti-MAG neuropathy and chronic ataxic neuropathy, ophthalmoplegia, M-protein, cold agglutinins, and disialosyl antibodies spectrum neuropathies, respectively, and help differentiating these conditions from CIDP. Recently, the field has been boosted by the discovery of pathogenic antibodies targeting proteins of the node of Ranvier contactin-1, contactin-associated protein 1, and nodal and paranodal isoforms of neurofascin (NF140, NF186, or NF155). These antibodies define subgroups of patients with specific clinical (most importantly poor or partial response to conventional therapies and excellent response to anti-CD20 therapy) and pathologic (node of Ranvier disruption in the absence of inflammation) features that led to the definition of the "autoimmune nodopathy" diagnostic category and to the incorporation of nodal/paranodal antibodies to clinical routine testing. The purpose of this review was to provide a practical vision for the general neurologist of the use of antibodies in the clinical assessment of autoimmune neuropathies.

Efficacy of Rituximab in CANOMAD: A Systematic Review.

CANOMAD, characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M (IgM) paraprotein, cold agglutinins, and disialosyl antibodies, encompasses a clinical, radiological, and laboratory diagnosis. CANOMAD is a rare condition, with fewer than 100 cases reported in the literature. The understanding and diagnosis of the disease have improved in the last few years, but the treatment of CANOMAD is mainly unknown, and there is not a clear consensus about it. We conducted a systematic review regarding the efficacy of rituximab in CANOMAD's treatment to investigate the clinical and biological response of CANOMAD in patients treated with rituximab. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines for this systematic review. To analyze the bias of the study, we used the Joanna Briggs Institute's (JBI) Critical Appraisal Checklist to analyze the bias of the case reports, and we used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for the observational studies. We only included case reports, case series, and observational studies written in English with patients formally diagnosed with CANOMAD and treated with rituximab. We excluded systematic reviews, literature reviews, and meta-analyses. We investigated the clinical and biological responses of the patients to rituximab. The clinical response was classified as complete recovery (CR), partial response (PR), stable disease (SD), and non-response (NR). We gathered 34 patients. The literature uses a modified Rankin score to define complete improvement (CR), partial response (PR), stable disease (SD), and progression. Clinically, there were three patients with CR, five with PR, 15 with SD, and 11 with progression. The biological response was assessed by measuring the decrease in antibody titers in 27 patients. Among those, six patients had CR, 12 had PR, eight had SD, and one had progression. Among 15 patients with neurological evaluation, 10 had ocular symptoms, and two presented with bulbar symptoms. Seven of the ten patients with ocular symptoms had SD, two had PR, and one had progression. Only 14 patients had a report of demyelinating features. Three had an axonal pattern, six had a demyelinating pattern, and five had a mixed pattern. Among patients with an axonal pattern, three had an SD. Among patients with a demyelinating pattern, three had a PR, two had an SD, and one had progression. Among patients with a mixed pattern, four had SD, and one had progression. We concluded that patients with CR have a shorter disease duration than patients with PR, SD, or progression. In addition, patients with CR had longer follow-ups than the other groups, suggesting that being treated early with rituximab improves the clinical outcome and has a sustained effect. There were no differences in the frequency of ocular and bulbar symptoms among patients with CANOMAD. The axonal pattern is more common in patients with SD, suggesting that axonal and mixed patterns could be markers of a bad prognosis.

Are Miller Fisher syndrome and CANDA due to a paranodopathy?

ObjectiveTo study the pathological characteristics of acute and chronic ataxic peripheral neuropathy at the level of the node of Ranvier. Study design and settingWe performed the pathological study (nerve biopsy of a sural nerve) of two patients, one with an acute form of ataxic peripheral neuropathy called ‘Miller Fisher syndrome’ (MFS), the other one with a chronic form called ‘chronic ataxic neuropathies with disialosyl antibodies’ (CANDA). ResultsA dysimmune process involving peripheral nerves commences in myelin, at the internodal area or/and in the paranodal and nodal regions. Our electron microscopic observations suggest that both patients present lesions in favor of a paranodopathy. ConclusionMany of the immune-mediated peripheral neuropathies are now classified as nodoparanodopathies. This subtype of auto-immune neuropathy may present various clinical phenotypes such as ‘Acute Motor Axonal Neuropathy’ (AMAN), ‘Acute Motor and Sensory Neuropathy’ (AMSAN) or ‘chronic inflammatory demyelinating polyradiculoneuropathy’ (CIDP), and are associated with anti-disialosyl antibodies. In our two cases, some paranodes seem to be associated with macrophages and we hypothesized that these lesions are in favor of a complement-mediated dysfunction/disruption of the nodal region due to disialosyl antibodies against gangliosides which are mainly located at the level of the axolemma of the paranode.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell–targeted therapies

AbstractCANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

Evolving Immunologic Perspectives in Chronic Inflammatory Demyelinating Polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest chronic idiopathic dysimmune neuropathy. Pathophysiologic processes involve both cellular and humoral immunity. There are various known forms of CIDP, likely caused by varying mechanisms. CIDP in its different forms is a treatable disorder in the majority of patients. The diagnosis of CIDP is clinical, supported routinely by electrophysiology. Cerebrospinal fluid analysis may be helpful. Routine immunology currently rarely adds to the diagnostic process but may contribute to the identification of an associated monoclonal gammopathy with or without hematologic malignancy and the consideration of alternative diagnoses, such as POEMS syndrome, anti-myelin associated glycoprotein (MAG) neuropathy or chronic ataxic neuropathy, with ophthalmoplegia, M-protein, cold aglutinins and disialosyl antibodies (CANOMAD). The search for antibodies specific to CIDP has been unsuccessful for many years. Recently, antibodies to paranodal proteins have been identified in a minority of patients with severe CIDP phenotypes, often unresponsive to first-line therapies. In conjunction with reports of high rates of antibody responses to neural structures in CIDP, this entertains the hope that more discoveries are to come. Although still arguably for only a small minority of patients, in view of current knowledge, such progress will enable earlier accurate diagnosis with direct management implications but only if the important, unfortunately and infrequently discussed issues of immunologic technique, test reliability and reproducibility are adequately tackled.

CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA).

CANOMAD/CANDA are syndromes characterized by ataxic neuropathy, ophthalmoplegia, monoclonal gammopathy, cold agglutinins and disialosyl antibodies. A retrospective review of our neuromuscular autoantibody panel database was performed. Anti-GD1b seropositive patients with ataxia were included. Eleven patients were identified. Median age at onset was 56years. Median disease duration was 6years. All patients had gait disorders. Nine had ocular motility abnormalities. Most had a monoclonal protein and all had elevated serum IgM. Electrodiagnostic studies showed a mixed axonal/demyelinating pattern (6), an axonal pattern (4), or a pure demyelinating pattern (1). Ultrasounds showed nerve enlargement patterns consistent with acquired demyelination. A nerve biopsy showed near complete loss of myelinated axons with preservation of smaller axons. Rituximab was the most effective immunotherapy. CANOMAD/CANDA are rare and debilitating disorders with characteristic clinical and diagnostic findings. In our cohort, nerve ultrasound showed regional nerve enlargement and rituximab was the most effective immunomodulatory therapy.

Mechanism and spectrum of anti‐glycolipid antibody‐mediated chronic inflammatory demyelinating polyneuropathy

AbstractThe pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) is composed of cellular and humoral immunities. Macrophages might play a crucial role in cellular immunity. In addition, autoantibodies participate in the pathogenesis of CIDP. To date, various autoantibodies have been reported to affect peripheral nerve myelin. Although antibodies to glycolipids are frequently identified in Guillain‐Barré syndrome and closely related to the development of neuropathies, these are detected in only a small percentage of CIDP instances. Among glycolipids, sialosylneolactotetraosylceramide (LM1) is predominantly localized in human peripheral nerve myelin. LM1‐related antibodies (e.g. anti‐LM1, GM1/LM1 and GD1b/LM1 antibodies) are detected in some patients with CIDP and Guillain‐Barré syndrome. CIDP patients with those antibodies frequently present ataxia, but rarely have cranial nerve deficits; these features are associated with the localization of LM1, which is more abundant in the dorsal root than the cranial nerves. In immunoglobulin M paraproteinemic neuropathies, except for the anti‐myelin‐associated glycoprotein neuropathies, antibodies to glycolipids with disialosyl residues, such as GD1b and GQ1b, are also detected on occasion. Notably, this feature is clinically characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M paraprotein, cold agglutinins and disialosyl antibodies. Such clinical features are related to the localization of GD1b or GQ1b in human peripheral nerves. Overall, these correlations suggest a direct involvement of the antibodies in the pathogenesis of those aforementioned neuropathies.

CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA) (P5.075)

CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA) (P5.075)

Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination.

See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1.2) at the juxtaparanode. Expression of type III neuregulin-1 (TIIINRG1) in induced pluripotent stem cell-derived sensory neurons strongly enhances myelination, while conversely pharmacological blockade of the NRG1-ErbB pathway prevents myelination, providing direct evidence for the ability of this pathway to promote the myelination of human sensory axons. The β-secretase, BACE1 is a protease needed to generate active NRG1 from the full-length form. Due to the fact that it also cleaves amyloid precursor protein, BACE1 is a therapeutic target in Alzheimer's disease, however, consistent with its role in NRG1 processing we find that BACE1 inhibition significantly impairs myelination in our co-culture system. In order to exploit co-cultures to address other clinically relevant problems, they were exposed to anti-disialosyl ganglioside antibodies, including those derived from a patient with a sensory predominant, inflammatory neuropathy with mixed axonal and demyelinating electrophysiology. The co-cultures reveal that both mouse and human disialosyl antibodies target the nodal axolemma, induce acute axonal degeneration in the presence of complement, and impair myelination. The human, neuropathy-associated IgM antibody is also shown to induce complement-independent demyelination. Myelinating co-cultures using human induced pluripotent stem cell-derived sensory neurons thus provide insights into the cellular and molecular specialization of axoglial signalling, how pharmacological agents may promote or impede such signalling and the pathogenic effects of ganglioside antibodies.awx012media15372351982001.

A Case of CANOMAD with Review of the Literature

Introduction: CANOMAD (an acronym for its full manifestation of chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is an uncommon paraproteinaemic neuropathy. Methods and Results: We present the case of a man of 58 years at presentation, with chronic ataxic neuropathy, ophthalmoplegia, and an IgM paraprotein who was found to have antibodies active against disialosylgangliosides. Despite treatment trials with a range of immunosuppressive therapies, intravenous immunoglobulin proved the only effective treatment strategy in his case. Conclusions: CANOMAD has been described in a growing number of individual reports and small series for which we have methodically searched the literature. In the absence of randomised trials of treatment for this disabling condition, we bring together these published clinical experiences, describing the degree of heterogeneity in the presentation/laboratory findings and demonstrating that intravenous immunoglobulin is the therapy found most frequently to be successful.

93. CANOMAD: Clinical and neurophysiological findings in two cases

The acronym CANOMAD (Chronic Ataxic Neuropathy, Ophthalmoplegia, IgM paraproteinemia, cold Agglutinin and Disialosyl antibodies) refers a rare immune-mediated peripheral neuropathy, whose clinical spectrum has still to be fully delineated. Herein we report the clinical and neurophysiological features of two CANOMAD patients. A 52-year-old man suffering from distal sensory symptoms and ataxia had received a first diagnosis of chronic inflammatory prominent-sensory polyneuropathy 11 years ago. High-dose i.v. steroid treatment resulted in paradoxical severe worsening with ophthalmoplegia and ambulation loss. Based on immunological and clinical–neurophysiological revaluation a diagnosis of CANOMAD was made. Since then IVIg periodic infusions had allowed good clinical remission up to-day, although minor degree of motor impairment and ataxia relapsed during last years. This 62-year-old man had a 5-year history of mild lower limb ataxia. More recently, a fluctuating bilateral ptosis was seen. Serum was positive for anti-disialosyl IgM antibodies and cold agglutinins. NCS/EMG showed a mild chronic sensory-motor neuropathy. Cortical somatosensory evoked potentials by tibial nerve stimulation at the ankle were deranged, whereas responses at the popliteal fossa and sural NCS were largely preserved. This suggests a proximal alteration of peripheral sensory conduction. These data further confirm the heterogeneous presentation of CANOMAD.

Acute and chronic ataxic neuropathies with disialosyl antibodies: A continuous clinical spectrum and a common pathophysiological mechanism

Acute ataxic neuropathies with disialosyl antibodies include Fisher syndrome, ataxic Guillain-Barré syndrome (GBS), and acute sensory ataxic neuropathy. Fisher syndrome and ataxic GBS are more strongly associated with IgG anti-GQ1b and anti-GT1a than with anti-GD1b antibodies, whereas the association is reversed in the case of acute sensory ataxic neuropathy. Chronic ataxic neuropathy with disialosyl antibodies is associated with IgM paraprotein to GD1b and GQ1b, which occasionally reacts with GT1a. The clinical, electrophysiological, and pathological features, along with experimental findings, suggest that acute and chronic ataxic neuropathies with disialosyl antibodies form a continuous clinical and pathophysiological spectrum characterized by a complement-mediated disruption at the nodal region and are better classified in the new category of nodo-paranodopathies.

Comparison of Commercial Tests for Detecting Multiple Anti-Ganglioside Autoantibodies in Patients with Well-Characterized Immune-Mediated Peripheral Neuropathies

To assess the performance of commercial anti-ganglioside antibody assays, we determined anti-ganglioside antibody IgG and IgM isotype profiles of patients with acute and chronic well-characterized immune-mediated peripheral neuropathies by one immunodot assays (Zentec/Ingen: Dotzen Ganglio Profile Ab, Euroimmun/BioAdvance: Euroline ganglioprofile), two line-immuno assay (GA Generic Assays/Labodia: Anti-Gangli osid Dot, Euroimmun/BioAdvance: Euroline ganglioprofile), and one enzyme-linked immunosorbent assay (ELISA) (Bühlmann: GanglioCombi). Specific antibody profiles were compared with those obtained by our validated standard in-house immunodot assay (IDA). We selected 33 sera with high levels of IgG and IgM anti-ganglioside antibodies from 15 patients with Guillain-Barre syndrome (GBS) subtypes and variants, 12 patients with CANOMAD syndrome (chronic ataxic neuropathy with ophthalmoplegia, M-paraprotein, cold agglutinins, disialosyl antibodies), 5 patients with chronic motor peripheral neuropathies, and 1 patient with sensory neuropathy and a control group composed of 10 patients with non-autoimmune neuropathy. The 3 commercial IDAs employing hydrophobic membranes and the ELISA demonstrated different carbohydrate epitopes on 6 to 12 glycolipid antigens used for anti-ganglioside antibody detection. Comparison with the validated in-house IDA showed large variations in sensitivity between tests and a more diverse reactivity to gangliosides than expected. The test with the largest panel of glycolipids detecting 11 anti-ganglioside antibody reactivities (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b, and sulfatide) revealed the best concordance with our in-house assay. However, even with this test, differences were observed in the immunoreactivity against some gangliosides and weakly stained bands were not easy to interpret. Our data suggest an urgent need for standardization of commercial anti-ganglioside assays and the introduction of international anti-ganglioside antibody reference standards.

Identification and characterization of a monoclonal IgM reacting with disialylated gangliosides recognizing the CANOMAD syndrome

We reported the laboratory phenotype of a monoclonal IgM-lambda against disialylated gangliosides, in a 81-year-old man admitted to a neurological department because of the progressive development of distal paresthesias, gait unsteadiness, difficulty to walk and having falls. Serological studies revealed an IgM monoclonal protein with lambda light chain component of MGUS type. IgM level was 4g/L. The positive laboratory studies showed high titers of IgM antibodies in excess of 1/10(5) against specific disialylated gangliosides including GD1b, GD3, GT1b and GQ1b. There was no serum IgM binding to MAG and SGPG/SGLPG. Clonality by in-house immunodot of ganglioside antibodies was demonstrated using kappa and lambda light chain specific antibodies. Light chain subtype of the anti-ganglioside antibody activity and monoclonal IgM was lambda subtype. The reactivity at high titers was against gangliosides containing the disialosyl epitope. The clinical and laboratory features have been described under the acronym CANOMAD: Chronic Ataxic Neuropathy with Ophthalmoplegia, M proteins, cold Agglutinins and Disialosyl antibodies. Administration of IVIg produced a significant neurological improvement during six years. Then the neuropathy became refractory in the IVIg and worsened in severity, a cure by Rituximab® was established. The patient died from a pneumopathy only two months later. Monoclonal IgM binding to disialylated gangliosides have high level of specificity for diagnosis of the CANOMAD syndrome.

Neuropathy and paraproteins: review of a complex association

Coexistence of neuropathy and monoclonal gammopathy represents a common but complex problem in clinical practice. This association is here reviewed considering latest available literature. The association is not infrequent, and various possible syndromes need to be distinguished. However, coincidental co-occurrence also needs to be recognized. The monoclonal gammopathy may be a 'monoclonal gammopathy of uncertain significance' (MGUS) or occur in a context of malignancy such as multiple myeloma or Waldenström's macroglobulinaemia. IgM paraproteins can bind to myelin-associated glycoprotein (MAG) in peripheral nerve. In this case, the paraprotein is directly linked to the neuropathy, causing a specific phenotype. One randomized controlled trial of this ('Anti-MAG') neuropathy showed possible moderate effect of rituximab on disability. Results of another trial are awaited. IgM/G/A paraproteins can be associated with a polyneuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy. Axonal neuropathies may coexist with IgM/G/A MGUS. There is insufficient evidence about causality or effective treatment in such cases. Pain/dysautonomia with an axonal neuropathy and serum paraprotein raises the possibility of amyloidosis. Specific haematological treatment is required for malignant disorders, although caution is required with neurotoxic agents. Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome and chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl antibodies represent rare separate entities for which evidence-based treatment options are still lacking. The association of monoclonal gammopathy and neuropathy requires the appropriate neurological/haematological investigations for a precise diagnosis. Causality is only established in few cases. Adequate management ideally requires joint neurological/haematological input for diagnosis, monitoring and treatment.

Neuropathy with anti-disialosyl IgM antibodies and multifocal persistent motor conduction blocks

In 1985, circulating IgM antibodies reacting with NeuAc(alpha2–8)NeuAc(alpha2–3)Gal-configured disialosyl gangliosides (including GD1b, GD3, GT1b, and GQ1b) were first described in a patient with chronic sensory neuropathy.1 The typical clinical picture...

SIADH in a patient with sensory ataxic neuropathy with anti-disialosyl antibodies (CANOMAD)

Dear Sirs, CANOMAD (chronic ataxic neuropathy, opthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare variant of IgM paraproteinaemic neuropathy in which the paraprotein fraction contains antibodies against specific disialylated gangliosides, including GD1B, GD3, GT1B and GQ1B [1]. This disorder has so far not been reported in association with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here we describe a patient who developed SIADH during the first relapse of CANOMAD. A 57-year-old woman was admitted to our department because of the progressive development of gait unsteadiness and distal paresthesias over the past 2 years. Neurological examination showed a mild sensory ataxia (Table 1) and a stable exotropia with ambliopia in her left eye due to infantile strabismus; nerve conduction studies documented the absence of SAPs, consistent with a sensory neuropathy (Table 1). A diagnostic screening ruled out malignancies, malabsorption or systemic autoimmune disorders. Serum immuno-fixation electrophoresis revealed an IgM monoclonal gammopathy with k light chain component. Serum testing for anti-gangliosides antibodies [1] showed high titers of anti-GD1b, -GT1b, -GQ1b of IgM type ([1:12,500, n.v. IgM \ 1:500), while anti-MAG antibodies were negative. Serum test for cold agglutinins also resulted positive. One week later, she subacutely manifested a severe neurological deterioration (Table 1) and also developed a hypertensive state treated by calcium-antagonists and clonidine. Arterial blood gas analysis was normal. Routine blood studies documented severe hyponatremia (120 mEq/l) and hypokalemia (2.9 mEq/l), low levels of uric acid (1.3 mg/ dl) and urea nitrogen (7 mg/dl); urinary osmolality (570 mOsm/kg) was increased despite a low plasmatic osmolality (274 mOsm/kg) in clinical conditions of euvolemia, and natriuresis increased ([40 mmol/l) with unaltered dietary salt intake. These parameters indicated the occurrence of SIADH, which was successfully treated according to reported protocols [2]. In order to define the etiology of SIADH, brain and spinal cord MRI with i.v. gadolinium, thyroid and adrenal functions, serum AVP levels and urinary excretions of porphobilinogen and aminolevulinic acid were performed, all with normal results. A lumbar puncture documented a mild hyperproteinorrachia (59 mg/dl, n.v 20–40) with normal cell count; search for infections and oligoclonal bands were negative. Neurophysiologic studies suggested the development of proximal demyelination associated with axonal degeneration (Table 1): in fact, we documented a mild reduction of the CMAP amplitude of the axillary nerve, and the R. Iorio F. Capone E. Iannaccone A. Modoni P. A. Tonali G. Silvestri Department of Neurosciences, Institute of Neurology, Catholic University, Rome, Italy

Chronic ataxic neuropathy mimicking dorsal midbrain syndrome

We describe the clinical course, with special attention to the disturbance of eye movements, of a 29-year-old man with chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins and anti-GD1b...

Relapsing sensorimotor neuropathy with ophthalmoplegia, antidisialosyl antibodies, and extramembranous glomerulonephritis

A 72-year-old man presented with oculomotor dysfunction, subacute relapsing sensorimotor neuropathy, elevated erythrocyte sedimentation rate, IgM monoclonal paraprotein, cold agglutinins, and antidisialosyl IgM antibodies, features previously described by the acronym CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, M protein, agglutination, and disialosyl antibodies). The patient also had extramembranous glomerulopathy associated with this syndrome. Treatment with corticosteroids improved both the neuropathy and glomerulopathy. This case suggests that the spectrum of neuropathy associated with monoclonal gammopathy may be broader than originally believed.

Neuropathie ataxiante associée à des anticorps anti-gangliosides disialylés : description de nouvelles formes cliniques et biologiques

Polyneuropathies associated with IgM monoclonal gammopathy were recently recognized. Antibodies can react with glycoproteins such as myelin associated glycoprotein (MAG), or gangliosides containing one sialosyl epitope such as GM1 or several sialosyl epitopes (polysialyted gangliosides) including GD2, GD3, GT1b, GT1a, GQ1b.We report on three patients presenting oculomotor dysfunction, chronic sensitive ataxic polyneuropathy, high sedimentation rate, IgM monoclonal paraprotein of unknown signification and antidisialosyl IgM antibodies and for two of them cold agglutinins. Such features have been previously described under the acronym "CANOMAD" (chronic ataxic neuropathy with ophthalmoplegia, M protein, agglutination and disialosyl antibodies).One of the patients presents extramembranous glomerulopathy and severe motor disability associated with this syndrome. The pathophysiology of the glomerulopathy seems to be linked with the polyneuropathy. Patients were treated either by intravenous immunoglobulin, corticosteroids or cyclophosphamid. Response to treatment differs in the three cases and there is currently no consensus.Our study demonstrates that spectrum of polyneuropathy associated with monoclonal polyneuropathy may be larger than originally described.