Chronic Ataxic Neuropathy Research Articles

Optic neuropathy associated with CANOMAD: Description of 2 cases

CANOMAD is a chronic ataxic neuropathy associated with IgM paraproteinemia and reactivity against disialosyl gangliosides. Ophthalmoplegia is a typical feature, but optic pathway involvement has not been reported previously. We describe 2 cases of CANOMAD associated with optic neuropathy. Severe visual loss was present in 1 case. We postulate that optic nerve damage may be related to antibody reactivity against gangliosides. Our report broadens the spectrum of cranial nerve involvement in this rare entity.

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.

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy

Objective:To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies.Methods:Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in...

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

Complete recovery of an aged patient with Guillain–Barré syndrome associated with multiple IgM anti‐ganglioside antibodies

In this report we describe a 72-year-old woman who had cytomegalovirus infection-related Guillain-Barré syndrome (GBS) associated with multiple immunoglobulin M (IgM) anti-ganglioside antibodies. She became tetraplegic with respiratory failure, but recovered completely after intravenous immunoglobulin therapy and plasmapheresis. The serum contained high-titer IgM antibody activities to several gangliosides with disialosyl residues (GD1b, GD3, GT1b, GQ1b, and GT1a) and GD1a. These antibodies are often found in sera from patients with chronic sensory ataxic neuropathy, but they occur rarely in GBS.

Guillain-Barre Syndrome Complicating Multiple Myeloma

Background: Although neuropathies complicating multiple myeloma (MM) are common as a result of medications and spinal cord compression, neuropathy as a consequence of cross reactivity between the paraprotein and neural tissues is rare. In CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, M-protein, agglutination, anti-disialosyl antibodies) IgM paraproteins with shared reactivity between Campylocacter jejuni lipopolysaccharides and human peripheral nerve disialylated gangliosides including GQ1b have been described. In POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) cerebral spinal fluid concentrations of vascular endothelial growth factor (VEGF) may be markedly elevated, similar to other inflammatory polyneuropathies. Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyradiculopathy yielding flaccid areflexic paralysis that, to our knowledge, has only been reported once as a complication of MM.Case reports: At Hackensack University Medical Center we have observed 5 cases of GBS complicating MM since 2002 (approximate incidence <0.5%). Details are described below. In all five cases, blood and cerebrospinal fluid cultures, anti-GQb1, anti-GM1, and anti-MAG antibodies were negative and radiographic imaging including computerized axial tomographic scan (CT) of the head and magnetic resonance imaging (MRI) of the brain were unrevealing. In four patients cerebrospinal fluid examination showed albumin/cytologic dissociation.Conclusions: Our observation represents the first series of patients with GBS complicating MM, and suggests that GBS, although rare, should be considered as part of the neurologic complications of plasma cell dyscrasias.CaseAgeSexType of MyelomaMM TherapyPresenting symptoms168MIIIB IgD lambdaVAD, Mel 200 PBSC, month 9, recurringCN VI palsy, areflexia upper extremities, hyporeflexia lower extremities, paresthesias feet & side face263MIIIA IgA kappaDex-Thal, Mel 200 PBSC, week 2Parasthesias hands, legs, and feet. Motor weakness lower extremities ascending.368MIIIA IgG kappaDex-Thal, CDEP, Mel 200 PSCT, wk 3Bilateral facial, sternocleidomastoid, neck muscle weakness with sluggish gag reflex. Upper and lower muscles weak and hyporeflexic.481FIII A IgA kappa + urineDex-LenolidomideLower extremity weakness, with areflexia and severely ataxic gait. Sensory defects in LE.525MIgA lambda plasma-cytomasNone (GBS presenting feature)Marked LE weaknessCSF proteinMotor Nerve ConductionsSensory Nerve ConductionsTreatment & Response1126 mg/dlProlonged median F wave latencyProlonged DSL superficial peronealPlasmapheresis, dex, thalidomide (improved)277 mg/dlSeverely prolonged DML, Reduced CMAP amplitudes, Slow CV, Conduction blockAbsent SNAPsPlasmapheresis (no response), IVIG (improved)376 mg/dlProlonged F wave latencies, Slow CV, Reduced CMAP amplitudesAbsent SNAPsIVIG (minimal response), plasmapheresis (slow improvement)4202 mg/dlProlonged distal motor latencies, Reduced amplitudes of CMAPS in lower extremities, Prolonged F wave latencies, Slow CV in lower extremitiesAbsent or reduced amplitudes of SNAPsIVIG (no response), plamapheresis (improved)559 mg/dlProlonged DML, Prolonged F wave latencies or absent F waves, Mild slowing CV, Mild reduction of CMAP amplitudesNormalIVIG and plasmapheresis (no response, paraplegia), Mel 200 PBSC X2 (improved)

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...

Hyperpyrexia-triggered relapses in an unusual case of ataxic chronic inflammatory demyelinating polyradiculoneuropathy

The ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (ataxic-CIDP) has been recently described as a subtype of chronic ataxic neuropathy, distinguished by steroid responsiveness and relative preservation of myelinated fibres at sural nerve biopsy. We report on a case of progressive, predominantly sensory, steroid-responsive neuropathy with clinical, laboratory, electrophysiological and pathological features of this uncommon form of CIDP. Moreover, the present case displays peculiar hyperpyrexia-triggered relapses leading to transitory severe tetraparesis, bilateral facial drooping, dysphonia, dysphagia and dyspnoea, which leave clinicians with some unresolved questions.

Les limites cliniques du concept de polyradiculonévrite chronique

Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease that target myelin sheats of peripheral nerves. Its diagnosis is often difficult to make, and a number of cases are probably not identified because of the clinical heterogeneity. Numerous sets of diagnostic criteria have sought to define CIDP but clinical criteria are generally not detailed. To review the main clinical characteristics suggestive of CIDP (that means not compatible with a length-dependent axonal process) and the critical clinical points of the neuropathy which make the differential diagnosis with the main other forms of chronic auto immune neuropathy sometimes difficult. The main clinical characteristic are: a symmetric proximal and distal motor weakness predominantly affecting the lower limbs, a diffuse areflexia, a sensory deficit characterized by a preferential involvement of large fibers, an evolution which may be either chronic progressive or recurrent. These aspects raise many questions concerning overlap with other inflammatory neuropathies such as Guillain Barre syndrome, Lewis-Sumner neuropathy, chronic ataxic neuropathy. The distinction of a subgroup of CIDP associated with other diseases such as diabetes or HIV are also controversial. The growing body of knowledge on the pathogenesis of CIDP and clinical or electrophysiological differentiation of subforms may help to develop more effective therapies for CIDP in the next few years.

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.

Another Treatable Sensory Variant of CIDP

Chronic ataxic neuropathy (CAN) is most commonly due to sensory ganglionopathy, which can be identified by the classic sensory neuronopathy pattern in nerve conduction study (NCS): a marked sensory nerve conduction abnormality in the presence of normal motor nerve conduction. However, treatment of sensory ganglionopathy has been disappointing, so CAN is therefore considered untreatable. Sinnreich and colleagues report data from 15 patients who clinically …

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.

Antibodies to dorsal root ganglia and olfactory cells in a patient with chronic sensory neuropathy and anosmia

We report the case of a 51-year-old woman with anosmia and chronic sensory ataxic neuropathy. Olfactory tests suggested neurosensory anosmia. Immunocytochemical analysis showed serum antibodies against dorsal root ganglion (DRG) cells and olfactory neurons, in the absence of other known causes of anosmia and sensory neuropathy. Clinical and laboratory data suggested a slow autoimmune process affecting dorsal root ganglion and olfactory cells.

Increase of pro‐inflammatory cytokines in chronic sensory ataxic neuropathies

Chronic sensory ataxic neuropathies (CSAN) are characterised by a predominant involvement of sensory large fibers. We previously demonstrated the presence of serum antibodies against neuropathy‐related antigens in about 50% of these patients. The aim of our study was to analyse peripheral T and B cell subsets and cytokine network in CSAN patients in order to evaluate their immunological profile. We studied 10 CSAN patients. ELISA test detected the presence of neuropathy‐related autoantibodies in 5 out of 10 patients. We evaluated, by flow cytometry, CD3+, CD3 + DRII+, CD4+, CD8+, CD16+ and CD19+ cells subset distribution, and intracellular IL2, INFg, IL1, IL6, IL10 and TNFa production by CD4+, CD8+ and CD14+ cells. Results were compared with healthy controls (HC); statistical analysis was performed. Compared to HC, CSAN patients showed no significant difference in lymphocyte subset distribution. We found a significant increase of IL6 in CD4+, CD8+ and CD14+ cells. INFg and TNFa were increased in CD4+ cells. TNFa was decreased in CD14+. Our results show an increase of pro‐inflammatory cytokines not associated with imbalance of T and B cells subsets. These data support an activation of the immune system in CSAN, as previously suggested by the detection of neuropathy‐related autoantibodies.

Chronic ataxic neuropathy initially diagnosed as ataxic variant of guillain barré syndrome

Acute ataxic neuropathy is characterized by cerebellar‐like ataxia, insignificant weakness, areflexia, and mildly impaired sensation. Patients usually experience antecedent infections as in typical Guillain Barré syndrome. Clinical course is usually monophasic or relapsing with high titer of antiganglioside antibodies. A 40‐year‐old mildly hypertensive man was admitted because of acral paraesthesias, dysarthria, swallowing difficulties, and imbalance. On admission, the patient exhibited inconstant diplopia on lateral gaze, scanned speech, facial diplegia, cerebellar–like ataxia, tremor, areflexia, mild deep sensory loss, and nearly normal muscle weakness. Brain and spinal cord MRI was normal. Electrophysiology showed delayed F waves. Normal laboratory results included extensive hematologic tests, search for IgM paraprotein, antiganglioside antibodies, namely GT1a, GQ1b IgG, and cold agglutinins. CSF revealed albuminocytologic dissociation. A remote malignancy was excluded. Patient was treated with plasmaphoresis (PE) with transient benefit. Four weeks later, because of progression of cerebellar signs, the patient was newly admitted. Electrophysiology confirmed axonal and demyelinating features. CSF protein were 330 mg/dl (normal &lt;45). PE, IVIG, methylprednisolone e.v. (1 g daily for 3 days, 500 mg for 2 days switched to oral regimen) and oral chlorambucil gave transient improvement. Nine months after first onset, the patient suffered new relapse. Renal biopsy was performed showing focal glomerular changes. In conclusion, the patient exhibited a chronic relapsing ataxic neuropathy without ophthalmoparesis or significant deep sensory disturbances, accompanied during acute phase by bifacial weakness in absence of antiganglioside antibody activity.

Synthetic disialylgalactose immunoadsorbents deplete anti-GQ1b antibodies from autoimmune neuropathy sera.

Acute and chronic autoimmune neuropathies, including Guillain-Barré syndromes (GBS) are often characterized by the presence of autoantibodies that react with neural gangliosides. Evidence from human and animal studies indicates that anti-ganglioside antibodies play a primary neuropathogenic role, and their rapid elimination from the circulation through specific immunoadsorption therapy thus has the potential to ameliorate the course of the disease. Here we have tested this therapeutic principle in the Miller Fisher variant of GBS that is associated serologically with acute phase anti-GQ1b ganglioside immunoglobulin G (IgG) antibodies, and in chronic ataxic neuropathies associated with persistently elevated immunoglobulin M (IgM) antibodies that react with GQ1b, GD3 and other disialylated gangliosides. Human and mouse anti-GQ1b IgG and IgM antibodies may also react with GD3, suggesting the shared terminal disialoside epitope could be involved in antibody binding. We thus synthesized the terminal trisaccharide, NeuAc(alpha2-8)NeuAc(alpha2-3)Gal common to GQ1b and GD3, and conjugated it to bovine serum albumin (BSA). This disialylgalactose glycoconjugate (DSG-BSA) binds anti-GQ1b antibodies in 32/58 (55%) human sera containing IgG or IgM anti-GQ1b antibodies at titres up to 1/130 000; it also binds a wide range of mouse monoclonal anti-GQ1b and -GD3 antibodies. When conjugated to Sepharose as mock therapeutic immmunoaffinity columns, the immobilized trisaccharide (DSG-Sepharose) eliminates anti-GQ1b antibodies from positive sera in proportion to their level of binding to DSG-BSA. Oligosaccharide-specific immunoadsorption therapy thus provides a new therapeutic approach to anti-GQ1b antibody-associated syndromes that could be applied to clinical practice. Furthermore, modification of the immobilized oligosaccharide epitopes to incorporate other glycan structures may allow this approach to be adapted to other forms of autoimmune neuropathy associated with uniform anti-glycolipid antibody profiles.

Antidisialosyl antibodies in chronic idiopathic ataxic neuropathy.

Antidisialosyl antibodies were found in two out of 13 patients with chronic idiopathic ataxic neuropathy (CIAN) and not in 32 patients with different sensory neuropathies of known cause. This finding confirms the association of antidisialosyl antibodies and CIAN regardless of the absence of the M band. These antibodies may have pathogenic relevance; however, larger series are needed to establish their clinical significance.

Antiganglioside antibodies in acute self‐limiting ataxic neuropathy: incidence and significance

Antidisialosyl antibodies have been previously associated to chronic and acute ataxic neuropathies. We studied the presence of these antibodies in nine patients with acute self‐limiting ataxic neuropathy (ASLAN) using ELISA and TLC immunodetection. One patient showed serum IgG immunoreactivity against gangliosides GD3 and GQlb. The patient's IgG was able to bind to the nodes of Ranvier on frozen human dorsal root. Our studies confirmed that antidisialosyl reactivity is associated to ataxic neuropathy and its specific binding to the dorsal root could explain the predominant sensory involvement. Nevertheless, the low incidence of this reactivity indicates that a different pathogenic mechanism should be involved in most ASLAN patients.