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Background Patients with anti-MAG neuropathy present with distal demyelinating polyneuropathy, IgM monoclonal gammopathy, and elevated titers of anti-MAG antibodies.

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Detection of antibodies to glycolipids of peripheral nerves following clinical and neurophysiological data makes it possible to verify the autoimmune nature of neuropathy, confirmation of which entails consideration of the issue of prescribing specific therapy, which can potentially and significantly improve the general condition and quality of life of the patient. This leads to the continuation of our research and to the next stage. [ABSTRACT FROM AUTHOR]

Introduction: Anti-MAG neuropathies are associated with an IgM monoclonal gammopathy of undetermined significance (MGUS) or with a malignant haemopathy. Our objective was to determine whether the presence of a haemopathy or somatic mutations of MYD88 and CXCR4 genes influences disease presentation and response to rituximab (RTX). Methods: We included 79 patients (mean age 74 years, disease duration 9.68 years) who had a bone marrow aspiration with morphologic and immunophenotypic analysis. MYD88L265P and CXCR4 mutations were analysed in peripheral B cells. Information collected included: inflammatory neuropathy cause and treatment sensory sum score (ISS), MRC testing, overall neuropathy limitation scale (ONLS), Rash-built Overall Disability Score (RODS), ataxia score, anti-MAG titres, peak IgM dosage, neurofilament light chain levels, motor and sensory amplitudes, motor unit index (MUNIX) and motor unit size index (MUSIX) sum scores. Efficacy of RTX was evaluated at 12 months in 26 patients. Results: Malignant haematological disorders were discovered in 17 patients (22%): 13 Waldenstrom macroglobulinemia, 3 marginal zone lymphoma and one mantle cell lymphoma. MYD88L265P mutation was detected in 29/60 (48%) patients and CXCR4 in 1 single patient. Disease severity, biological and electrophysiological data and response to RTX were comparable in patients with MGUS/lymphoma and patients with/without MYD88L265P mutation. ISS was lower and MUSIX higher in patients improved by RTX. Conclusions: MYD88L265P mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Background: Anti-MAG neuropathy is a slowly progressive demyelinating neuropathy that can lead to disability. The neuropathy is thought to be caused by monoclonal IgM antibodies that target the Myelin Associated Glycoprotein (MAG) in peripheral nerves. Therapy is directed at lowering the autoantibody concentrations with B-cells depleting agents, most often rituximab, based on case series and uncontrolled trials reporting improvement. There are no FDA approved treatments for anti-MAG neuropathy, however, and two relatively short duration randomized controlled trials with rituximab failed to achieve their pre-specified primary endpoints. There is also little information regarding the number or duration of treatments that are required to effectively reduce the antibody concentrations. Case presentations: We report the time course of the anti-MAG antibody response in two patients with anti-MAG neuropathy that were treated with rituximab for several years. A reduction of 50% in the anti-MAG IgM was seen after 19 and 58 months respectively, and of 70% after 74 or 104 months of treatment respectively. Titres remained low, without evidence of recurrence after the treatments were discontinued. Conclusion: Therapy of anti-MAG neuropathy with rituximab may require repeat treatments over more than one year to achieve a significant reduction in autoantibody concentrations. These considerations should inform treatment decisions and the design of clinical trials.

With increasing age, the chances of developing either MGUS or polyneuropathy increase as well. In some cases, there is a causative relationship between the IgM M-protein and polyneuropathy. In approximately half of these cases, IgM targets the myelin-associated glycoprotein (MAG). This results in chronic polyneuropathy with slowly progressive, predominantly sensory neurological deficits and distally demyelinating features in nerve conduction studies. Despite the disease being chronic and developing slowly, it can cause considerable impairment. We reviewed English medical publications between 1980 and May 2022 on IgM gammopathy-associated polyneuropathy, with special attention to studies addressing the pathophysiology or treatment of anti-MAG polyneuropathy. Treatment options have been limited to a temporizing effect of intravenous immunoglobulins in some patients and a more sustained effect of rituximab but in only 30 to 55 percent of patients. An increase in our knowledge concerning genetic mutations, particularly the MYD88L265P mutation, led to the development of novel targeted treatment options such as BTK inhibitors. Similarly, due to the increasing knowledge of the pathophysiology of anti-MAG polyneuropathy, new treatment options are emerging. Since anti-MAG polyneuropathy is a rare disease with diverse symptomatology, large trials with good outcome measures are a challenge.

With increasing age, the chances of developing either MGUS or polyneuropathy increase as well. In some cases, there is a causative relationship between the IgM M-protein and polyneuropathy. In approximately half of these cases, IgM targets the myelin-associated glycoprotein (MAG). This results in chronic polyneuropathy with slowly progressive, predominantly sensory neurological deficits and distally demyelinating features in nerve conduction studies. Despite the disease being chronic and developing slowly, it can cause considerable impairment. We reviewed English medical publications between 1980 and May 2022 on IgM gammopathy-associated polyneuropathy, with special attention to studies addressing the pathophysiology or treatment of anti-MAG polyneuropathy. Treatment options have been limited to a temporizing effect of intravenous immunoglobulins in some patients and a more sustained effect of rituximab but in only 30 to 55 percent of patients. An increase in our knowledge concerning genetic mutations, particularly the MYD88L265P mutation, led to the development of novel targeted treatment options such as BTK inhibitors. Similarly, due to the increasing knowledge of the pathophysiology of anti-MAG polyneuropathy, new treatment options are emerging. Since anti-MAG polyneuropathy is a rare disease with diverse symptomatology, large trials with good outcome measures are a challenge. [ABSTRACT FROM AUTHOR]

• In anti-MAG neuropathy; widenings of myelin lamellae (WML) are classically observed in the nerve biopsy (electron microscopy). • WML may be observed in polyneuropathy associated to IgM monoclonal gammopathy without anti-MAG activity. • IgM may target an unknown myelin antigen responsible for the nerve lesions similar to those observed in anti-MAG polyneuropathy. • The good response to plasma exchange and/or rituximab suggests an autoimmune origin. • Nerve biopsy may help to confirm the dysimmune process and to select an efficient treatment. We report the case of a patient with a very severe predominantly demyelinating sensorimotor polyneuropathy (with axonal loss) that had developed over several months, along with an immunoglobulin-M monoclonal gammopathy without anti-myelin associated glycoprotein antibodies (or other antibodies against myelin). Widening of myelin lamellae were frequently observed by electron microscopic examination of a nerve biopsy: immunoglobulin-M targeting an unknown myelin antigen appears to be responsible for the nerve lesions similar to those observed in anti-myelin associated glycoprotein polyneuropathy. Usually, if in anti-myelin associated glycoprotein neuropathy the response to immunotherapies is not optimal, in this case the combination of plasma exchanges and rituximab was effective, suggesting an autoimmune origin. [ABSTRACT FROM AUTHOR]

Les syndromes lymphoprolifératifs (myélomes, maladie de Waldenström, leucémie lymphoïde chronique, lymphomes) peuvent s'associer à la survenue de neuropathies périphériques. Le mécanisme est variable : il peut être dysimmunitaire, associé ou non aux gammapathies monoclonales ; paranéoplasique ; infiltratif ; ou plus communément, iatrogène ou carentiel. Le diagnostic peut être complexe, notamment lorsque la neuropathie est inaugurale, nécessitant une coopération étroite entre internistes et neurologues. Le diagnostic positif de la neuropathie repose sur une enquête électroclinique systématique, qui précise la topographie et le mécanisme de l'atteinte nerveuse, parfois aidé par des examens d'imagerie notamment une IRM nerveuse et/ou plexique. L'imputabilité de la neuropathie à un syndrome lymphoprolifératif repose sur un faisceau d'arguments comprenant le contexte clinique (symptômes B, syndrome tumoral), des examens biologiques de première intention (hémogramme, électrophorèse des protides sériques, sérologies virales, dosage du complément), des auto-anticorps discutés en fonction de la neuropathie (anti-MAG, anti-gangliosides) et parfois des examens plus invasifs (biopsies médullaires ou neuromusculaires). Lymphoproliferative syndromes (multiple myeloma, Waldenström's disease, chronic lymphocytic leukemia, lymphomas) may be associated with peripheral neuropathies. The mechanism can be dysimmune, associated or not with monoclonal gammopathies; paraneoplastic; infiltrative; or more commonly, iatrogenic or due to vitamin deficiency. The diagnosis can be complex, especially when the neuropathy is the presenting manifestation, requiring a close cooperation between internists and neurologists. The positive diagnosis of the neuropathy is based on a systematic electro-clinical investigation, which specifies the topography and the mechanism of the nerve damage, sometimes reinforced by imaging examinations, in particular, nerve and/or plexus MRI. The imputability of the neuropathy to a lymphoproliferative syndrome is based on a set of arguments including the clinical context (B signs, tumour syndrome), first-line laboratory tests (hemogram, protein electrophoresis, viral serologies, complement), auto-antibodies discussed according to the neuropathy (anti-MAG, anti-gangliosides) and sometimes more invasive examinations (bone marrow or neuro-muscular biopsies). [ABSTRACT FROM AUTHOR]

Introduction: We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls.Methods: We enrolled 106 incident patients-32 patients with IgM neuropathy, 42 treatment-naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally.Results: We found widespread nerve enlargement in IgM neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP), with specific enlargement of brachial plexus and proximal segments of median nerve but not in axonal disease controls (P < .001). Sonographic nerve hypertrophy in IgM neuropathy was not associated with nerve conduction, clinical, or laboratory characteristics.Discussion: Immunoglobulin M neuropathy is characterized by widespread nerve enlargement indistinguishable from CIDP. Our data provide evidence to confirm that the disease process is not confined to the more distal parts of nerves in either classical demyelinating or axonal variants of neuropathy with associated IgM. [ABSTRACT FROM AUTHOR]

Anti-Myelin Associated Glycoprotein (anti-MAG) neurological involvement classically manifests as a peripheral neuropathy with prominent sensitive symptoms. We describe a case report of a patient with positive anti-MAG antibodies presenting with clinical and neurophysiological evidence of spinal cord impairment. A 69-year-old woman came to our attention with subacute onset of dysesthesias at lower limbs and ataxia. Blood routine tests and hematological work-up led to a diagnosis of monoclonal gammopathy of undetermined significance. High titers of anti-MAG antibodies was revealed (34,594.70 BTU/mL, normal range 0–1000). Nerve conduction studies (NCS) ruled out a polyneuropathy at lower limbs. Somatosensory evoked potentials (SSEPs) showed prolonged central conduction time (CTT) at lower limbs, suggesting a dorsal column damage. Brain and spinal cord Magnetic Resonance Imaging (MRI) did not reveal any significant lesion. Analysis of cerebrospinal fluid (CSF) evidenced an albumin-cytologic dissociation. She was treated with corticosteroids with temporary remission of sensory symptoms and normalization of CTT. Subsequently, she developed a multineuropathy which was successfully treated with Rituximab. We discuss the potential role of anti-MAG antibodies in the pathophysiology of dorsal column impairment and the clinical usefulness of SSEPs in monitoring the evolution of anti-MAG neuropathy.

Background and purpose: The frequency of pain and cramps is uncertain in anti-myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown. Methods: A cross-sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy. Results: Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P < 0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P = 0.006) and 10-m timed walk (P = 0.019). An independent association was ascertained with I-RODS (P = 0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P = 0.004). Cramp severity correlated with ONLS (P = 0.04) and I-RODS (P = 0.028) and inversely with level of physiotherapy input (P = 0.009). Cramp frequency was associated with tremor score (P = 0.004) and multiple SF-36 HR-QoL subsections. Conclusions: Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research. [ABSTRACT FROM AUTHOR]

The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are associated with IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia. Establishing a causal link between a paraprotein and neuropathy can be challenging but is necessary to adopt an appropriate therapeutic approach. The most common type of IgM-PN is Antimyelin-Associated-Glycoprotein neuropathy, but half of the cases are of other causes. Progressive functional impairment is an indication for treatment, even when the underlying disorder is IgM MGUS, involving either rituximab monotherapy or combination chemotherapy to achieve clinical stabilization., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.

To report the frequency of the different patterns of sensory and motor electrophysiological demyelination distribution in patients with anti-MAG neuropathy in comparison with patients with IgM neuropathy without MAG reactivity (IgM-NP). Thirty-five anti-MAG patients at early disease stage (20.1 months) were compared to 23 patients with IgM-NP; 21 CIDP patients and 13 patients with CMT1a neuropathy were used as gold standard neuropathies with multifocal and homogeneous demyelination, respectively. In all groups, standard motor and sensory electrophysiological parameters, terminal latency index and modified F ratio were investigated. Motor electrophysiological demyelination was divided in four profiles: distal, homogeneous, proximal, and proximo-distal. Distal sensory and sensorimotor demyelination were evaluated. Anti-MAG neuropathy is a demyelinating neuropathy in 91 % of cases. In the upper limbs, reduced TLI is more frequent in anti-MAG neuropathy, compared to IgM-NP. But, predominant distal demyelination of the median nerve is encountered in only 43 % of anti-MAG neuropathy and is also common in IgM-NP (35 %). Homogeneous demyelination was the second most frequent pattern (31 %). Concordance of electrophysiological profiles across motor nerves trunks is low and median nerve is the main site of distal motor conduction slowing. Reduced sensory conduction velocities occurs in 14 % of patients without evidence of predominant distal slowing. Simultaneous sensory and motor distal slowing was more common in the median nerve of anti-MAG neuropathy than IgM-NP. Electrophysiological distal motor demyelination and sensory demyelination are not a distinctive feature of anti-MAG reactivity. In anti-MAG neuropathy it is mainly found in the median nerve suggesting a frequent nerve compression at wrist. [ABSTRACT FROM AUTHOR]

Introduction:IgM monoclonal gammopathy with anti-MAG (myelin associated glycoprotein) antibodies is associated with demyelinating polyneuropathy. MAG mediates adhesion between the Schwann cell membrane (non-compact myelin) and axons. Various drugs have been tried in this form of neuropathy, with varying responses, but to date there is no consensus on the treatment of this disease. Areas covered:Based on the medical literature and the experience of our group of clinicians, we offer some proposals for the management of anti-MAG neuropathy. Expert commentary:It is not certain that anti-MAG antibodies are the only factor responsible for symptoms of this clinically heterogeneous neuropathy. Some patients with mild non-evolving symptoms do not require treatment; for more severe cases, treatment should be prompt: intravenous immunoglobulins (or sometimes therapeutic plasma exchange) as first line treatment, then immunosuppressant in refractory forms (such as rituximab). [ABSTRACT FROM PUBLISHER]

Background and purpose For several decades an association between MGUS, IgM-MGUS in particular, and peripheral neuropathy has been suspected. Several histopathology studies have shown binding of IgM to myelin and a secondary widening of myelin lamellae in cutaneous nerves and in the sural nerve of patients with IgM-MGUS, or Waldenström's Macroglobulinaemia (WM), and peripheral neuropathy. In this retrospective study we investigated the value of skin biopsy examination in the diagnosis of MGUS- and WM-associated peripheral neuropathy. Methods A total of 117 patients, who were examined for an M-component in serum with associated nerve symptoms, had a skin biopsy taken and examined for immunoglobulin deposition in cutaneous nerves. Thirty-five patients were diagnosed with MGUS or WM and peripheral neuropathy with no other cause of neuropathy. Nineteen patients had MGUS but no peripheral neuropathy. Results Of the 35 patients with MGUS or WM and peripheral neuropathy, four had immunoglobulin deposition in the skin biopsy, all of whom had an IgM gammopathy. In the control group of 19 without peripheral neuropathy, three had immunoglobulin deposition in the skin biopsy, all of whom had IgM-MGUS. In both groups, there was a trend towards higher IgM blood levels in patients with immunoglobulin deposition. Half of the patients with IgM gammopathy in the neuropathy group had anti-MAG reactivity, whereas only one in the control group had weak anti-MAG reactivity. Conclusion Our study indicates that examination of skin biopsies for immunoglobulin deposition does not add significant diagnostic value in the evaluation of neuropathies suspected to be caused by MGUS or WM. IgM immunoglobulin deposition in skin biopsy might merely be an epiphenomenon secondary to high IgM blood levels. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective The involvement of optic and auditory pathways has rarely been studied in demyelinating polyneuropathies. We here aimed to study this further in a cohort of patients with acquired and gentic demyelinating neuropathy. Methods We studied eight patients with hereditary neuropathy with liability to pressure palsies ( HNPP), six with Charcot-Marie-Tooth disease type 1A ( CMT1A), ten with chronic inflammatory demyelinating polyneuropathy ( CIDP) and seven with antimyelin-associated glycoprotein ( MAG) neuropathy using visual evoked potentials and brainstem auditory evoked potentials. Results Optic pathway dysfunction was detected in 6/7 anti- MAG neuropathy patients, about half of those with CIDP and HNPP, but only in 1/6 patients with CMT1A. Peripheral auditory nerve dysfunction appeared common in all groups except HNPP. Brainstem involvement was exceptional in all groups. Conclusions We conclude optic nerve involvement may be frequent in all demyelinating polyneuropathies, particularly anti- MAG neuropathy, except in CMT1A. Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression. Evidence for central brainstem pathology appeared infrequent in all four studied neuropathies. This study suggests that acquired and genetic demyelinating polyneuropathies may be associated with optic and auditory nerve involvement, which may contribute to neurological disability, and require greater awareness. [ABSTRACT FROM AUTHOR]

Highlights: [•] Polyneuropathy associated with IgM monoclonal gammopathy is an immune-mediated polyneuropathy clinically characterized by symmetrical, distal polyneuropathy with predominant sensory ataxia. [•] Many cases of IgM-related neuropathy with a clinical phenotype not fitting the classic sensory-ataxic form have been described in literature. [•] Present findings suggest that demyelinating abnormalities in nerve conduction studies are more often associated with classical forms while axonal impairment occurs more often in atypical phenotypes. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are found in approximately 10% of patients with peripheral neuropathy (PN) of unknown etiology. Several autoantibodies, including anti-MAG (myelin-associated glycoprotein) antibodies, have been reported to induce neuropathy. It has been suggested that over 50% of patients with PN and IgM monoclonal gammopathy (MG) have anti-MAG IgM antibodies in their sera. This work aimed at studying the frequency and characteristics of PN in a group of Egyptian patients with MGs and to estimate the serum level of anti-MAG antibodies and its relationship to peripheral nerve dysfunction. Forty patients with MGs were enrolled in the study. Their mean age was 56.65 ± 8.55 years. There were 17 males and 23 females. Patients were subjected to complete general and neurological examination, laboratory investigations including serum LDH, β2 microglobulin, serum protein electrophoresis, urinary Bence-Jones protein, bone marrow aspiration and/or trephine biopsy, quantitative estimation of serum IgM and IgG by nephelometry, detection of anti-MAG antibodies by indirect immunofluorescence, radiological assessment and nerve conduction study of both upper and lower limbs. Clinical and electrophysiological evidences of PN were found in 32 (80%) out of the 40 patients with MG. Twenty-five patients (62.5%) had distal symmetrical polyneuropathy and seven (17.5%) had mononeuritis or mononeuritis multiplex. The majority of patients (65%) had sensory or predominantly sensorimotor polyneuropathy. The neuropathy was mainly demyelinating in 22 patients (55%) and axonal in the other 10 (25%) patients. Anti-MAG antibodies were positive in nine patients (22.5%) and six of them (66.6%) had PN. The latter was predominantly demyelinating motor neuropathy in 4 and axonal in the remaining 2. However, the relationship between the presence of anti-MAG antibodies and the development and type of PN was not statistically significant. Anti-MAG showed significant association with IgM level ( P = 0.003**) and the MG subtypes: Waldenström's macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) ( P = 0.004**). The present study showed high frequency (>60%) of distal symmetrical polyneuropathy in Egyptian patients with MG. The neuropathy was predominantly sensory and demyelinating. Anti-MAG antibodies were detected only in 22.5% of the patients, especially those with WM and MGUS and were associated with more motor and demyelinating neuropathy. We recommend that patients with chronic polyneuropathies should be evaluated for underlying plasma cell dyscrasia. [ABSTRACT FROM AUTHOR]

The article reports on clinical response and biological effects of treatment with rituximab and fludarabine (RF) in five patients with IgM anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. It mentions that between November 2006 and October 2009, four men and one woman aged 52-85 years received intravenous rituximab at 375 mg/m2 on day 1 and oral fludarabine at 40 mg/m2/day from days 1 to 5, in a treatment cycle that was repeated every month for up to 6 months.

Abstract: Antineural antibody activity is the implicated pathogenic mechanism in polyneuropathy associated with monoclonal gammopathy. Recognition of antigen depends on immunoglobulin variable regions, encoded by V genes. We studied VHDJH and VLJL gene use in monoclonal B cells by clonal analysis in 20 patients with polyneuropathy and IgM monoclonal gammopathy. V genes associated with bacterial responses appear over-represented and VH3–23 was preferentially used, without association with specific D, JH or VLJL. V genes revealed somatic mutation and intraclonal variation was found in 9 of 20 patients. Polyneuropathy associated with monoclonal gammopathy may be caused by an immune response to bacterial antigens, which recruit somatically mutated autoreactive B cells. [Copyright &y& Elsevier]

Research and development in the area of paraproteinemic demyelinating peripheral neuropathy is slower than for some of the other inflammatory neuropathy syndromes. However, 2007–2008 has produced developments in the understanding of the pathogenesis of the neuropathy and the paraprotein, a potential new animal model, easier diagnostics, and two randomized controlled trials with the results of others awaited. This short review summarizes these publications. [ABSTRACT FROM AUTHOR]

In chronic polyneuropathies associated with hematologic malignancy (HM) the optimal treatment management is primarily focused on the HM, but the parallel response of the neuropathy is still unclear. Rituximab is a recognized therapeutic choice in anti-MAG antibody polyneuropathy, that might be useful also in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with HM. The efficacy of immunochemotherapy, which is the standard approach to malignant lymphoproliferative diseases, has been poorly investigated in polyneuropathies. We describe a six-months combined bendamustine-rituximab (BR) treatment in nine patients affected by CIDP or paraproteinemic IgM neuropathies with antibodies to peripheral nerve antigens in course of malignant HM. All patients had a long-lasting response with an average relapse free-survival (RFS) time of 31.5 months. Clinical improvement was evident at 6 months from the beginning of therapy, even earlier in 6/9 patients (<2 months). Two patients dramatically improved the disabling attitudinal and intentional tremor and pathogenic autoantibodies significantly declined in 4/5 patients. Neurological relapses occurred in three patients after a mean of 38 months of sustained stability, even if HM remitted. In such cases rituximab was administered but was associated with a shorter RFS time (1 year) compared to the previous BR scheme (3 years). In our case series, the combined BR regimen was a valid option in immune-mediated neuropathies associated with HM. Moreover, in some patients BR scheme allowed an earlier response and a long-lasting improvement than rituximab alone. • Immunochemotherapy may be a valid option in neuropathies associated with hematological malignancy (HM). • Bendamustine-rituximab (BR) hematologic protocol may be useful in the neurological setting. • BR is associated to an earlier and longer lasting response than rituximab. • BR as first-line approach is advised when also aggressive HM must be controlled. [ABSTRACT FROM AUTHOR]

Anti-Myelin Associated Glycoprotein (anti-MAG) neurological involvement classically manifests as a peripheral neuropathy with prominent sensitive symptoms. We describe a case report of a patient with positive anti-MAG antibodies presenting with clinical and neurophysiological evidence of spinal cord impairment. A 69-year-old woman came to our attention with subacute onset of dysesthesias at lower limbs and ataxia. Blood routine tests and hematological work-up led to a diagnosis of monoclonal gammopathy of undetermined significance. High titers of anti-MAG antibodies was revealed (34,594.70 BTU/mL, normal range 0–1000). Nerve conduction studies (NCS) ruled out a polyneuropathy at lower limbs. Somatosensory evoked potentials (SSEPs) showed prolonged central conduction time (CTT) at lower limbs, suggesting a dorsal column damage. Brain and spinal cord Magnetic Resonance Imaging (MRI) did not reveal any significant lesion. Analysis of cerebrospinal fluid (CSF) evidenced an albumin-cytologic dissociation. She was treated with corticosteroids with temporary remission of sensory symptoms and normalization of CTT. Subsequently, she developed a multineuropathy which was successfully treated with Rituximab. We discuss the potential role of anti-MAG antibodies in the pathophysiology of dorsal column impairment and the clinical usefulness of SSEPs in monitoring the evolution of anti-MAG neuropathy. [ABSTRACT FROM AUTHOR]

Most patients with anti-MAG neuropathy complain of painful paresthesias or dysesthesias, but unlike diabetic neuropathy, these symptoms are not severe and do not affect quality of life as much as motor weakness. [ABSTRACT FROM AUTHOR]

Anti-MAG antibody-associated neuropathy may present as many disorders, including small fiber neuropathy, sensorimotor neuropathy, Guillain-Barré-like syndrome, and multifocal motor neuropathy. Rituximab appears to be the best therapeutic option. [ABSTRACT FROM AUTHOR]