Anti-MAG neuropathy: From biology to clinical management.

The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations, mediated by distinct immune mechanisms, and responding to different therapies. After the discovery in the early 1980s, that the myelin associated glycoprotein (MAG) is a target antigen in an autoimmune demyelinating neuropathy, assays to measure the presence of anti-MAG antibodies were used as the basis to diagnose the anti-MAG neuropathy. The route was open for describing the clinical characteristics of this new entity as a chronic distal large fiber sensorimotor neuropathy, for studying its pathogenesis and devising specific treatment strategies. The initial use of chemotherapeutic agents was replaced by the introduction in the late 1990s of rituximab, a monoclonal antibody against CD20+ B-cells. Since then, other anti-B cells agents have been introduced. Recently a novel antigen-specific immunotherapy neutralizing the anti-MAG antibodies with a carbohydrate-based ligand mimicking the natural HNK-1 glycoepitope has been described.

Spinal fluid IgG antibodies from patients with demyelinating diseases bind multiple sclerosis-associated bacteria.

A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD). The anti-microbial ELISA assays follow on prior human brain tissue RNA sequencing studies that established multiple sclerosis (MS) microbial candidates. Lysates included in the ELISA panel were derived from Akkermansia muciniphila, Atopobium vaginae, Bacteroides fragilis, Lactobacillus paracasei, Odoribacter splanchnicus, Pseudomonas aeruginosa, Cutibacterium (Propionibacterium) acnes, Fusobacterium necrophorum, Porphyromonas gingivalis, and Streptococcus mutans. CSF responses from patients with demyelinating diseases (DD, N = 14) were compared to those with other neurological diseases (OND, N = 8) and controls (N = 13). Commercial positive and negative control CSF specimens were run with each assay. ELISA index values were derived for each specimen against each of the 10 bacterial lysates. CSF reactivity was significantly higher in the DD group compared to the controls against Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Four of the 11 tested DD group subjects had elevated antibody indexes against at least one of the 10 bacterial species, suggesting intrathecal antibody production. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients. KEY MESSAGES: A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases, including multiple sclerosis and acute disseminated encephalomyelitis. CSF reactivity was significantly higher in the demyelination group compared to the controls against the bacteria Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Several of the demyelination subjects had elevated antibody indexes against at least one of the 10 antigens, suggesting at least limited intrathecal production of anti-bacterial antibodies. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients.

Temporal evolution of nerve conduction study abnormalities in anti-myelin-associated glycoprotein neuropathy.

BACKGROUND: A distal-predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies. The literature however lacks longitudinal data to describe whether this is consistent over time. METHODS: From the Ottawa Neuromuscular Center database, we identified 23 patients with both immunoglobulin M gammopathy and anti-MAG antibodies. For median, ulnar and fibular motor conduction studies, we analyzed distal latency and amplitude, negative peak duration, terminal latency index (TLI), and conduction velocity. For median, ulnar, sural, and superficial fibular sensory conduction studies, we analyzed distal latency and amplitude. Results were compared for the earliest and the latest data sets. RESULTS: The mean time interval between the two assessment points was 6.5 years. Median and ulnar motor nerve conduction studies did not show a significant change for any of the parameters tested. There was disproportionate prolongation of median distal motor latency and reduction in TLI, compared to the ulnar nerve. Deep fibular motor conduction studies showed a marked reduction in amplitudes over time. Sensory potentials were recordable in the upper limb in less than 50% at the first study and less than 25% on the most recent study. There was an even larger attrition of recordable sural and superficial fibular sensory potentials. CONCLUSIONS: Our results highlight the stability of median and ulnar motor conduction study results over a mean observation period of 6.5 years. In contrast, lower limb motor and all sensory potentials show a marked trend toward becoming unrecordable.

Childhood-onset multifocal motor neuropathy with IgM antibodies to GM2 and GalNac-GD1a.

BACKGROUND: Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20-70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. CASE REPORT: A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. CONCLUSION: Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN.

Amphiphysin-IgG autoimmune neuropathy: A recognizable clinicopathologic syndrome.

OBJECTIVE: To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy. METHODS: Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. RESULTS: Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. CONCLUSION: Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.

Diffuse large B-cell lymphoma involving peripheral nervous system with IgM antibodies against GM1 and GD1b: A case report.

RATIONALE: The occurrence of peripheral neuropathy associated with non-Hodgkin's lymphoma (NHL) is uncommon. And autoimmunity may play an important role. We report a case of the patient with NHL, has sensorimotor demyelinating polyneuropathy. PATIENT CONCERNS: The patient presented with a 1-month history of progressive numbness at the distal extremities and motor weakness of the lower limbs. Meanwhile, patient also endorsed a painful lump on her right cheek. And then the enlarged cervical and supra clavicular lymph nodes were observed on admission. Biopsy of the lymph nodes showed NHL. Serum IgM antibodies against GM1 and GD1b were also positive. DIAGNOSIS: Biopsy of the lymph nodes showed NHL. Serum IgM antibodies against GM1 and GD1b were also positive. Thus, the patience was diagnosed with lymphoma and sensorimotor polyneuropathy. INTERVENTIONS: Patient refused the further treatment. OUTCOMES: After 11-month follow-up, the weakness of bilateral lower limbs worsens. LESSONS: We have presented a case of NHL involving peripheral polyneuropathy with IgM antibodies against GM1 and GD1b. Patients may initially present with peripheral nerve complications or develop them during the course of lymphoma, even when in remission. This could complicate the diagnosis of peripheral polyneuropathy secondary to NHL.

Anti-Neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo.

Neurofascin-155 (Nfasc155) is an essential glial cell adhesion molecule expressed in paranodal septate-like junctions of peripheral and central myelinated axons. The genetic deletion of Nfasc155 results in the loss of septate-like junctions and in conduction slowing. In humans, IgG4 antibodies against Nfasc155 are implicated in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies are associated with an aggressive onset, a refractoriness to intravenous immunoglobulin, and tremor of possible cerebellar origin. Here, we examined the pathogenic effects of patient-derived anti-Nfasc155 IgG4. These antibodies did not inhibit the ability of Nfasc155 to complex with its axonal partners contactin-1/CASPR1 or induce target internalization. Passive transfer experiments revealed that IgG4 antibodies target Nfasc155 on Schwann cell surface, and diminished Nfasc155 protein levels and prevented paranodal complex formation in neonatal animals. In adult animals, chronic intrathecal infusions of antibodies also induced the loss of Nfasc155 and of paranodal specialization and resulted in conduction alterations in motor nerves. These results indicate that anti-Nfasc155 IgG4 perturb conduction in absence of demyelination, validating the existence of paranodopathy. These results also shed light on the mechanisms regulating protein insertion at paranodes.

The clinical features of combined central and peripheral demyelination in Chinese patients.

BACKGROUND: Combined central and peripheral demyelination (CCPD) is rare and has never been reported as a spectrum disease in Han Chinese population. OBJECTIVES: To study the clinical features of CCPD in Han Chinese patients. METHODS: Twenty-two CCPD patients were selected from 788 demyelination cases. We reviewed and compared the clinical manifestation, laboratory data, electrophysiological examination, MRI and the prognosis. RESULTS: CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), abnormal deep tendon reflexes (72.7%). CSF data showed increased CSF protein in 81% patients. Oligoclonal IgG bands (OB) were negative. Cortical or juxtacortical, periventricular, infratentorial lesions, thoracic and cervical spinal cord were mostly affected. Visual evoked potentials indicated optic nerves demyelinating in 50% cases. 21 CCPD patients were treated with intravenous immunoglobulin or steroids or both of them, and the efficacy was 33.3%, 54.5%, 71.4%, respectively. One case that showed no response to steroids plus intravenous immunoglobulin treatment was improved significantly after using cyclophosphamide. CONCLUSIONS: CCPD is a spectrum disease that can't be regarded as a simple combination of MS and CIDP. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis.

Immunohistochemistry and electrophysiological findings in swine abattoir workers with immune-mediated polyradiculoneuropathy.

IMPORTANCE: Workers exposed to aerosolized brain in a swine-processing plant developed immune-mediated polyradiculoneuropathy (IP) possibly triggered by an immune response. OBJECTIVE: Immunohistochemistry results were correlated with electrophysiological variables to examine the immunopathogenesis of this disorder. DESIGN/SETTING: Laboratory studies used normal nerve tissue that was exposed to sera from 12 IP patients; 10 exposed controls; and 10 unexposed controls. Clinical and electrophysiological data from IP patients were obtained from medical record reviews. MAIN OUTCOME MEASURES: Analysis included electromyography results of IP patients and nerve conduction studies examining CMAP amplitude, distal motor latency, motor conduction velocity, F-wave latency, sensory nerve action potential amplitude, and sensory nerve conduction velocity. Case and control results were compared relative to distance from exposure. RESULTS: Electrodiagnostic findings revealed prolongation of the distal and f-wave latencies suggestive of demyelination at the level of the nerve root and distal nerve terminals. Immunohistochemical results identified an antibody to the peripheral nerve, with staining at the level of the axolemma. Thus, IP may be a primary axonopathy with secondary paranodal demyelination causing the conduction changes. Staining of the distal and proximal portions of the nerve appears consistent with easier access through the blood-nerve barrier. CONCLUSIONS AND RELEVANCE: IP is an immune-mediated neuropathy related to antibodies to an axon-based antigen on peripheral nerves. Secondary paranodal demyelination is likely. Further studies to identify the primary axonal antigenic target would be useful.

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.

Anti-MAG (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. Because the pathogenicity and demyelinating properties of anti-MAG autoantibodies are well established, current treatments are aimed at reducing autoantibody levels. However, current therapies are primarily immunosuppressive and lack selectivity and efficacy. We therefore hypothesized that a significant improvement in the disease condition could be achieved by selectively neutralizing the pathogenic anti-MAG antibodies with carbohydrate-based ligands mimicking the natural HNK-1 glycoepitope 1. In an inhibition assay, a mimetic (2, mimHNK-1) of the natural HNK-1 epitope blocked the interaction of MAG with pathogenic IgM antibodies from patient sera but with only micromolar affinity. Therefore, considering the multivalent nature of the MAG-IgM interaction, polylysine polymers of different sizes were substituted with mimetic 2. With the most promising polylysine glycopolymer PL84(mimHNK-1)45 the inhibitory effect on patient sera could be improved by a factor of up to 230,000 per epitope, consequently leading to a low-nanomolar inhibitory potency. Because clinical studies indicate a correlation between the reduction of anti-MAG IgM levels and clinical improvement, an immunological surrogate mouse model for anti-MAG neuropathy producing high levels of anti-MAG IgM was developed. The observed efficient removal of these antibodies with the glycopolymer PL84(mimHNK-1)45 represents an important step toward an antigen-specific therapy for anti-MAG neuropathy.

Immunotherapy-responsive allodynia due to distal acquired demyelinating symmetric (DADS) neuropathy.

INTRODUCTION: Distal acquired demyelinating symmetric (DADS) neuropathy is a distal variant of chronic inflammatory demyelinating polyradiculoneuropathy. It is characterized by chronic distal symmetric sensory or sensorimotor deficits. Sensory ataxia is a common clinical presentation. Nerve conduction studies typically show markedly prolonged distal motor latencies. METHODS: We report 2 patients with chronic progressive generalized pain and fatigue, with normal neurological examinations except for allodynia. RESULTS: Nerve conduction studies were typical of DADS neuropathy. Monoclonal protein studies were negative. Cerebrospinal fluid protein levels were elevated. Sural nerve biopsies revealed segmental demyelination and remyelination. One biopsy had marked endoneurial and epineurial lymphocytic infiltration. Immunomodulatory therapy alleviated the pain and fatigue and markedly improved distal motor latencies in both patients. CONCLUSIONS: DADS neuropathy can present with pain and a normal neurological examination apart from allodynia. Nerve conduction studies are necessary for diagnosis. These patients respond to immunotherapy better than typical DADS neuropathy patients with sensory ataxia. Muscle Nerve 54: 973-977, 2016.

[Refractory encephalitis because of seronegative celiac disease: a case report]. / Encefalitis refractaria debido a enfermedad celíaca seronegativa: caso clínico.

INTRODUCTION: The celiac disease is an autoimmune bowel disease trigger by gliadine proteins, that can has systemic involvement with varied neurological manifestation since polineuropathy, ataxia, epilepsy, migraine to encephalitis. The aim of the current work is to report a case of possible refractory encephalitis due to celiac disease. CASE REPORT: A 45 years-old man with histopathologic diagnosis of celiac disease but negative celiac antibodies developed encephalic, brainstem and periphery nervous system manifestations: cognitive declaim and seizures, diplopia and ataxia, polyneuropathy and polyradiculopathy respectively; inflammatory cebrospinal fluid and cortico-subcortical and multiple brainstem lesions with mild contrast enhancement; the neurologic deficits progress in spite of gluten a free diet and immuno-suppressive treatment. During the illness process some pathologies with nervous system and intestinal involvement were discarded: sarcoidosis, systemic lupus; Sjogren syndrome, paraneoplastic syndromes, Whipple disease, AIDS and B12 vitamin deficit. CONCLUSION: The encephalitis is an infrequent clinical manifestation of the celiac disease despite the high prevalence of the celiac disease in the general population. It presents with numerous differential diagnosis, with requires high suspicious diagnosis.

TITLE: Encefalitis refractaria debido a enfermedad celiaca seronegativa: caso clinico.Introduccion. La enfermedad celiaca es una enteropatia inducida por el gluten por mecanismos inmunes, que puede presentar afectacion sistemica y producir un amplio espectro de manifestaciones neurologicas, que van desde polineuropatia periferica, ataxia, epilepsia y migraña hasta encefalitis. El objetivo es informar de un caso de posible encefalitis refractaria por enfermedad celiaca. Caso clinico. Varon de 45 años con diagnostico histopatologico de enfermedad celiaca y anticuerpos anticeliaquia negativos que intercurre con encefalitis, manifestaciones del tronco encefalico y del sistema nervioso periferico, entre las que se incluyen deterioro cognitivo y convulsiones, diplopia y ataxia, y polirradiculopatia y polineuropatia, respectivamente; liquido cefalorraquideo inflamatorio y multiples lesiones corticosubcorticales supratentoriales y en el tronco encefalico con leve realce con contraste. Los deficits neurologicos progresan a pesar de una dieta libre de gluten y el tratamiento farmacologico inmunosupresor. Durante el curso de la enfermedad se estudian patologias con afectacion simultanea intestinal y del sistema nervioso, como sarcoidosis, lupus eritematoso sistemico, enfermedad de Sjogren, sindrome paraneoplasico, sida, enfermedad de Whipple y deficit de vitamina B12. Conclusion. La encefalitis es una manifestacion clinica infrecuente en la enfermedad celiaca, con pocos casos notificados a pesar de la alta prevalencia de la enfermedad. Los diagnosticos diferenciales son dificiles y exigen una alta sospecha diagnostica, por lo que es un reto terapeutico.

Drugs for the treatment of peripheral neuropathies.

Peripheral neuropathies are frequent in association with systemic diseases as well as isolated disorders. Recent advances in the therapy of specific neuropathies led to the approval of new drugs/treatments. This review selected those peripheral neuropathies where the most recent approvals were provided and revised the potential future developments in diabetic and toxic-induced neuropathies, although they do not have a currently available causal therapy in view of their epidemiological and social relevance. Data have been extracted from the most important published trials and from clinical experience. In addition, data from the Food and Drug Administration and European Medicine Agency indications on the treatment of the selected peripheral neuropathies and from recently updated international guidelines have also been included. The website of the U.S. National Institutes of Health www.clinicaltrials.gov registry has been used as the reference database for phase III clinical trials not yet published or ongoing. This review gives a general overview of the most recent advances in the treatment of amyloid, inflammatory, and paraproteinemic peripheral neuropathies. Moreover, it briefly describes the unmet medical need in disabling and frequent conditions, such as diabetic and chemotherapy-induced neuropathy, highlighting the most promising therapeutic approaches to their treatment.

Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies.

OBJECTIVE: Autoantibodies against paranodal proteins have been described in patients with inflammatory neuropathies, but their association with pathology of nodes of Ranvier is unclear. We describe the clinical phenotype and histopathological changes of paranodal architecture of patients with autoantibodies against contactin-1, identified from a cohort with chronic inflammatory demyelinating polyradiculoneuropathy (n=53) and Guillain-Barré syndrome (n=21). METHODS: We used ELISA to detect autoantibodies against contactin-1. Specificity of the autoantibodies was confirmed by immunoblot assay, binding to contactin-1-transfected human embryonic kidney cells, binding to paranodes of murine teased fibres and preabsorption experiments. Paranodal pathology was investigated by immunofluorescence labelling of dermal myelinated fibres. RESULTS: High reactivity to contactin-1 by ELISA was found in four patients with chronic inflammatory demyelinating polyradiculoneuropathy and in none of the patients with Guillain-Barré syndrome, which was confirmed by cell binding assays in all four patients. The four patients presented with a typical clinical picture, namely acute onset of disease and severe motor symptoms, with three patients manifesting action tremor. Immunofluorescence-labelling of paranodal proteins of dermal myelinated fibres revealed disruption of paranodal architecture. Semithin sections showed axonal damage but no classical signs of demyelination. INTERPRETATION: We conclude that anti-contactin-1-related neuropathy constitutes a presumably autoantibody-mediated form of inflammatory neuropathy with distinct clinical symptoms and disruption of paranodal architecture as a pathological correlate. Anti-contactin-1-associated neuropathy does not meet morphological criteria of demyelinating neuropathy and therefore, might rather be termed a 'paranodopathy' rather than a subtype of demyelinating inflammatory neuropathy.

Nerve ultrasound findings in neuropathy associated with anti-myelin-associated glycoprotein antibodies.

BACKGROUND AND PURPOSE: No systematic nerve ultrasound (US) studies on patients with neuropathy and anti-myelin-associated glycoprotein (anti-MAG) antibodies are available. PATIENTS AND METHODS: Twenty-eight patients (18 men, 10 women, mean age 69.2 ± 10.9 years; mean disease duration 6.9 years) with anti-MAG neuropathy underwent nerve US. Echotexture, nerve cross-sectional area (CSA) and intra-nerve and inter-nerve CSA variability were assessed. The frequency (number of nerves with enlarged CSA, 'enlarged nerves sum score') and distribution (proximal versus distal, arms versus legs, symmetry) of US abnormalities were considered. Controls included two groups: four patients with immunoglobulin M (IgM) paraproteinaemic neuropathy without anti-MAG antibodies and five with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with IgM paraprotein. RESULTS: In all, 26/28 patients had increased CSA (23 with at least one nerve outside entrapment sites). Intra-nerve CSA variability was abnormal in 21/28 patients (in 14 for increased nerve CSA outside entrapment sites). Inter-nerve CSA variability was abnormal in 16 patients (of whom half for CSA increase out of entrapment sites). The enlarged nerves sum score in anti-MAG neuropathy patients was greater than in MAG-negative paraproteinaemic neuropathies and lower than in CIDP. Intra-nerve variability appeared instead similar in anti-MAG and controls. No correlation was found between US findings and Inflammatory Neuropathy Cause and Treatment Group (INCAT) disability score or disease duration. DISCUSSION: Amongst the different measures to assess the US pattern (symmetry/asymmetry, proximal/distal distribution and sum score), the enlarged nerves sum score was the most useful for differentiating the three groups of patients with demyelinating neuropathies and may contribute to diagnosis in a typical cases.

Distinct lymphocytes subsets in IgM-related neuropathy: clinical-immunological correlations.

IgM-related neuropathy generally presents as a late-onset demyelinating polyneuropathy with predominant sensory loss and ataxia. However, we recently reported the clinical, neurophysiological and pathological findings from our cohort and identified in about a third of patients an atypical phenotype. We analyzed by flow cytometry the different lymphocytes subsets in the peripheral blood of patients affected by IgM-related neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance and healthy subjects, to investigate whether different immunological patterns may differentiate the classical phenotype from atypical forms. IFN-gamma producing CD4+ and CD8+ T lymphocytes, as well as CD4+ and CD8+ T cells expressing T-bet (T-helper type 1, Th1) were increased in CIDP patients. The percentage of circulating CD4+ and CD8+ T cells producing IL-10 as well as the percentage of CD19+ cells expressing Blimp-1 were higher in patients with IgM-neuropathy. We did not find any significant differences in the different lymphocytes subsets in the IgM-related neuropathy between patients with classical and atypical phenotype. Th1 cells are increased in CIDP patients while a T helper type 2-phenotype seems to prevail in patients with IgM-neuropathy. Further studies involving a larger patient population are needed to evaluate if different lymphocytes subset may be involved in different clinical phenotypes of IgM-related neuropathy.

Peripheral nervous system neuroimmunology seen by a neuro-pathologist.

In most dysimmune neuropathies, historically the microscopical lesions were described prior to immunological studies. The latter along with neuropathological studies have found some immune, albeit incomplete, explanations of the mechanisms of these lesions which we will describe in two main syndromes: the primitive auto-immune inflammatory peripheral polyneuropathies (GBS and CIDP) and polyneuropathies induced by a monoclonal dysglobulinemia. In some patients who have to be discussed case by case pathology (nerve biopsy) will confirm the diagnosis, may help to delineate the molecular anomalies and identify lesional mechanisms. We will review the high variability of nerve lesions which is characteristic of dysimmune neuropathies. Pathological studies confirm that both humoral and cellular immune reactions against Schwann cell and/or axonal antigens are implicated in primitive dysimmune neuropathies due to a dysfunction or failure of immune tolerance mechanisms. In case of a polyneuropathy associated to a monoclonal dysglobulinemia, pathological and immunological studies have shown that in many patients, the dysglobulinemia did harm the peripheral nerve; knowledge of the pathological lesions and their mechanisms is of major interest for orienting specific treatments.

Immune-mediated neuropathies following stem cell transplantation.

OBJECTIVE: To study the clinical, electrophysiological and pathological characteristics and outcome of immune-mediated neuropathy (IMN) following stem cell transplantation (SCT). METHODS: Retrospective chart review of the Mayo Clinic Rochester SCT database between January 1997 and August 2012. RESULTS: Of the 3305 patients who underwent SCT, 12 patients (0.36%) had IMN. The median time from SCT to IMN was 7 months. IMN typically presented as an asymmetric radiculoplexus neuropathy (7/12 patients) or acute polyradiculoneuropathy (Guillain-Barré syndrome) (4/12). Neurophysiology showed demyelinating neuropathy in four patients and axonal neuropathy in eight. Cerebrospinal fluid protein was increased in five of six patients (median 67 mg/dL). The Neuropathy Impairment Score (NIS) improved in all patients (mean NIS 43-10, p=0.016). Six patients died. One patient died from complications of IMN and one died from complications of the haematological disease. Five patients had recurrence of their malignancy within 4 months of the IMN and of these, four died. CONCLUSIONS: IMN occurs rarely in patients after SCT. Two possible mechanisms include (1) an immune reconstitution syndrome, supported by stereotypical neuropathy types (radiculoplexus and polyradiculoneuropathies), monophasic course and temporal association with SCT and (2) a paraneoplastic phenomenon, supported by frequent early malignancy recurrence following IMN.

A case of severe chronic progressive axonal polyradiculoneuropathy temporally associated with anti-CV2/CRMP5 antibodies.

OBJECTIVES: The involvement of the peripheral nervous system by anti-CV2/CRMP5 paraneoplastic antibodies is typically encountered as a mixed sensorimotor polyneuropathy. We report a fatal case of severe chronic progressive axonal polyradiculoneuropathy in association with this antibody. METHODS: Review of the patient's chart, nerve conduction/electromyographic studies, and nerve biopsy. RESULTS: A 51-year-old man presented with a progressive quadriparesis over a 4-month period. Extensive evaluation for potential etiologies was significant only for positive anti-CV2/CRMP5 antibodies without detection of an underlying neoplasm. Despite multiple immunomodulatory therapies, the patient progressed and demonstrated electrodiagnostic evidence for a chronic axonal polyradiculoneuropathy with ongoing denervation. The patient eventually died of respiratory failure. CONCLUSIONS: This case adds to the clinical spectrum of the peripheral nervous system involvement in patients with paraneoplastic anti-CV2/CRMP5 antibodies.