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.

[A case of polyradiculoneuritis associated with disseminated herpes zoster].

A 34-year-old man developed right-dominant lower limb paraplegia, and then upper limb paresis with radicular pain following disseminated herpes zoster (HZ) in his right forehead, back of the trunk, and lumbar and right lower limb regions. Cerebrospinal fluid (CSF) findings revealed an increase in lymphocytes (32 cells/µl) and protein content (50 mg/dl), and polymerase chain reaction (PCR) for varicella-zoster virus (VZV) DNA was negative in CSF, but VZV antigen was positive in the patient's vesicle smear. Lumbar root MRI using 3D Nerve VIEW (Philips) imaging showed high-intensity lesions on the L2-L5 spinal roots with contrast enhancements, and cervical MRI showed similar findings on both sides at the C4-Th1. Peripheral nerve conduction study revealed prolonged distal latency to 4.9 ms, decreased MCV to 38 m/s, and complete loss of F-wave was seen in the right peroneal nerve study. Minimal F-wave latency was prolonged in the right tibial nerve. Thus, the patient was diagnosed with VZV polyradiculoneuritis caused by disseminated HZ. Regarding the possible pathogenesis of polyradiculoneuritis in this patient with disseminated HZ, we speculate that VZV reached by retrograde transmission from the involved peripheral nerves to the spinal ganglia, which, then, produced polyradiculoneuritis.

Wernicke encephalopathy concurrent with polyradiculoneuropathy in a young man after bariatric surgery: A case report.

RATIONALE: Bariatric surgery is the recommended treatment for morbid obesity because of its rapid and sustained body weight loss effect. Nutrient deficiency-related neurological complications after bariatric surgery are often disabling. Thus, early recognition of these complications is important. Neurological complications involving the central and peripheral nerve system after bariatric surgery were reported. However, the report on the clinical course of the concurrent involvement of central and peripheral nervous system is limited. We present a rare case of a patient who developed Wernicke encephalopathy concurrent with polyradiculoneuropathy after receiving bariatric surgery. PATIENT CONCERNS: A 22-year-old man with a history of morbid obesity presented progressive bilateral lower limbs weakness, blurred vision, and gait disturbance 2 months after receiving laparoscopic sleeve gastrectomy. Bilateral lower limb numbness and cognition impairment were also noted. DIAGNOSIS: Brain magnetic resonance imaging and electrophysiologic studies confirmed the diagnosis of Wernicke encephalopathy concurrent with acute polyradiculoneuropathy. INTERVENTIONS: Vitamin B and folic acid were given since admission. He also received regular intensive rehabilitation program. OUTCOMES: The subject's cognitive impairment and diplopia improved 1 week after admission under medical treatments, yet lower limb weakness and gait disturbance were still noted. After a month of intensive inpatient rehabilitation, he was able to ambulate with a walker for 30 munder supervision. LESSONS: Nutrient deficiency-related neurological complications after bariatric surgery are often disabling and even fatal. Prevention of neurological complications can be improved through close postsurgical follow-up of the nutritional status. Recognizing the signs and symptoms and evaluating the medical history are critical to the early diagnosis and treatment of this potentially serious yet treatable condition.

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.

Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IgM-κ paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.

Lymphoproliferative disorders are often associated with autoimmune processes preceding or following the occurrence of a lymphoma. Here, we describe a patient with a history of recurrent diffuse large B-cell non-Hodgkin's lymphoma who suffered from an acute inflammatory neuropathy with specific monoclonal anti-GM2 IgM antibodies and associated IgM-κ paraprotein. It was possible in this case to prove that both, anti-GM2 IgM antibodies and IgM-κ paraprotein, share the same binding characteristic. In addition, the patient possibly suffered from an immune thrombocytopenia and an early-stage bullous pemphigoid with anti-BP-230 IgG antibodies. Intravenous immunoglobulin and plasmapheresis alleviated the acute neuropathy and thrombocytopenia, while the bullous pemphigoid has been aggravated. In summary, the simultaneous occurrence of multiple autoimmune processes was a sign of a dysfunctional immune system preceding the relapse of a B-cell non-Hodgkin's lymphoma.

Evidence-based review of therapeutic plasma exchange in neurological disorders.

Several neurologic disorders have been treated with therapeutic plasma exchange (TPE). Case reports, case series, and clinical trials have published results regarding the outcomes in such patients. The data gathered have been used to formulate evidence-based guidelines, which can be used to guide therapy in patients with these neurological disorders. Adequately designed and powered randomized controlled trials have proven the efficacy of TPE in some disease entities, while other diseases are lacking such data. In the latter, decisions for the use of TPE must be made using the limited published data available. In this review, we discuss the published evidence regarding the use of TPE in neurological disorders, focusing on the most recent guidelines published by the American Society of Apheresis in 2010 and the American Academy of Neurology in 2011.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.

The aim of this guideline is to update the 2006 EFNS/PNS guideline on management of patients with a demyelinating neuropathy and a paraprotein (paraproteinemic demyelinating neuropathy [PDN]) by review of evidence and expert consensus. In the absence of adequate evidence, the panel agreed on good practice points: (1) patients with PDN should be investigated for a malignant plasma cell dyscrasia; (2) a monoclonal gammopathy of undetermined significance is more likely to be causing the neuropathy if it is immunoglobulin (Ig)M, anti-neural antibodies are present, and the clinical phenotype is chronic distal sensory neuropathy; (3) patients with IgM PDN usually have predominantly distal sensory impairment, prolonged distal motor latencies, and often anti-myelin-associated glycoprotein antibodies; (4) IgM PDN may respond to immunomodulatory therapies. Their potential benefit should be balanced against possible side effects and the usually slow disease progression; (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy; and (6) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes syndrome is a multi-system malignant PDN.

Neurological impairment and arthritis in an immunocompetent child with human parvovirus B19 chronic infection.

Human parvovirus B19 (HPV-B19) is usually a self-limiting infection in immunocompetent children. In this case report, instead, we describe an immunocompotent child with evidence of persistent HPV-B19 infection, arthritis and neurological impairment. He was first admitted to hospital for HPV-B19 infection and sent home in good clinical condition after anti-inflammatory therapy. Eight months later he was re-admitted to hospital for episodes of arthritis and weakness, myalgia, tremors in his legs and hands, and was unable to walk unaided. In both plasma and serum, HPV-B19 DNA, detected by polymerase chain reaction, was still present. For neurological symptoms, he underwent magnetic resonance, which showed increased signal intensity at the spinal roots in the lumbar region, compatible with polyradiculoneuritis. After immunoglobulin therapy he had an excellent response in clinical and radiological terms, suggesting an association between neurological impairment and HPV-B19 infection. Eleven months after the second admission, the patient was still in good clinical condition.

Influence of impaired T- and B-cell compartments on efficacy of IVIg in dysimmune neuropathies.

Autoimmune mechanisms are postulated to play a role in the development and progression of dysimmune neuropathies (DN). We investigated the relation between lymphocyte number and marker expression, and disease activity in 20 patients with DN under intravenous immunoglobulins (IVIg) treatment. B- and T-lymphocyte markers were studied by flow cytometry of the expression of CD5, CD25, CD23 and CD38 markers on B cells and of CD3, CD4 and CD8 markers, respectively. These parameters were compared with those obtained from matched healthy volunteers. The proportions of CD38+ B cells were higher in patients compared with those of controls. Proportions of activated CD4+ and CD8+ T cells were comparable in peripheral blood mononuclear cells of patients and controls, but a significant reduction of the absolute numbers of CD3+, CD4+ and CD8+ cells were observed in DN patients. The percentages of CD25+ memory T cells were instead significantly increased in DN patients. Lastly, T-cell reduction and the CD19/CD38 ratio over total B (CD19+) cells directly correlated with a poor response to IVIg therapy. In DN, whereas T-cell number is reduced, activated T and B cells are increased, thus suggesting an intrinsic defect of the immune response.

[Crohn's disease presenting with recurrent acute polyradiculoneuropathy]. / Polyradiculonévrite à rechutes révélant une maladie de Crohn.

INTRODUCTION: The neurological manifestations of Crohn's disease are rare, dominated by multiple mononeuropathies and the abnormalities of the white matter. Polyradiculoneurities remain exceptional. OBSERVATIONS: We report the case of a 33-year-old patient admitted for an ascending weakness of all four limbs. Eight years earlier he had presented a similar episode which had regressed spontaneously. The neurological examination revealed a tetraparesis with areflexia and hypotonia. These manifestations were concomitant with chronic diarrhea which had been neglected to date. The electrophysiological aspect was compatible with an acute polyradiculoneuritis. The analysis of the cerebrospinal fluid showed an albumino-cytological dissociation. The existence of the diarrhea directed the investigations towards an inflammatory enteropathy, which was attested later on by the endoscopic, radiologic and histological data leading to the diagnosis of active Crohn's disease. The diagnosis of a relapsing polyradiculoneuritis associated with Crohn's disease was retained. The patient was treated by salazopyrine-budesonide with improvement in the digestive and neurological manifestations after 3 years. CONCLUSION: The frequency of neurological features in Crohn's disease is not well documented. The incriminated mechanisms are either directly related to the disease (deficit in B12 vitamin or folic acid and/or by the means of an auto-immune vascularitis) or secondary to long-term treatment with metronidazole. The course of neurological manifestations is largely dependent on the course of the inflammatory disease.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.

BACKGROUND: Paraprotein-associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological, and hematological features. OBJECTIVES: The aim of this guideline was to prepare evidence-based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein [paraproteinemic demyelinating neuropathy (PDN)]. METHODS: Disease experts and a representative of patients considered references retrieved from MEDLINE and the Cochrane Library and prepared statements that were agreed in an iterative fashion. RECOMMENDATIONS: In the absence of adequate data, evidence-based recommendations were not possible, but the Task Force agreed on the following good practice points: (1) patients with PDN should be investigated for a malignant plasma cell dyscrasia; (2) the paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin M (IgM), antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy; (3) patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti-myelin-associated glycoprotein antibodies; (4) IgM PDN sometimes responds to immunotherapies. Their potential benefit should be balanced against their possible side effects and the usually slow disease progression; (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy clinically, electrophysiologically, and in response to treatment; and (6) for POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with hemato-oncology advice.

Therapeutic apheresis in neurology critical care.

Therapeutic apheresis has been widely accepted in the treatment of neurological disorders that are understood to be mediated by humoral and/or cellular immunity. The clinical presumption is that well-established and/or unknown insults cause damage to nerves or their myelin sheaths. The rationale for apheresis treatments for these neurological disorders relates to removal of offending immune (or other) mediators, thus blunting the attack and permitting recovery of nerve and/or myelin. This review will concentrate on the role of therapeutic apheresis, in particular therapeutic plasma exchange, in neurological disorders that may frequently be seen by intensivists.

Treatment of immune-mediated, dysimmune neuropathies.

This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B-cell surface-membrane-marker CD20.

Subacute inflammatory demyelinating polyneuropathy.

OBJECTIVE: To report the clinical, electrophysiologic, and histologic characteristics of subacute inflammatory demyelinating polyneuropathy (SIDP) and to present the diagnostic criteria of this disease. METHODS: For a diagnosis of "definite SIDP," there were four mandatory criteria: 1) progressive motor and/or sensory dysfunction consistent with neuropathy in more than one limb with time to nadir between 4 and 8 weeks, 2) electrophysiologic evidence of demyelination in at least two nerves, 3) no other etiology of neuropathy, and 4) no relapse on adequate follow-up. Supportive criteria included high spinal fluid protein level (>55 mg/dL) and inflammatory cells in the nerve biopsy. A diagnosis of "probable SIDP" required progression of demyelinating neuropathy over a 4- to 8-week period. RESULTS: Sixteen definite SIDP patients were identified among 29 probable SIDP patients. An antecedent infection was found in 38% of cases. The two most common neuropathy types were a symmetric motor-sensory neuropathy and a pure motor neuropathy. Cranial nerve deficits and respiratory failure were rare. Spinal fluid protein was high in 93% of cases. Demyelination was documented by the motor nerve conduction in 88% of cases and by the near-nerve needle sensory nerve conduction in two cases. Almost all patients were treated with prednisone and some with additional immunotherapies. Complete recovery was achieved in 69% of cases and partial recovery in others. Definite SIDP had all the characteristics of CIDP with three exceptions: a higher rate of antecedent infection, no relapse rate, and a high rate of recovery to normal. CONCLUSION: Subacute inflammatory demyelinating polyneuropathy is a definite entity bridging the gap between Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

[Two distinct types of neuropathy associated with Sjögren's syndrome developed in one patient. The importance of the selection of an appropriate therapeutic regimen].

A 62-year-old woman was admitted to our hospital because of muscle weakness and sensory disturbance in extremities. She showed weakness, muscle atrophy and sensory abnormality in four limbs with patchy distribution, suggesting involvement of multiple peripheral nerve trunks. Serum titers of anti-SS-A, SS-B, and antinuclear antibody were elevated. Sural nerve biopsy showed recanalization and lymphocytic infiltration in the epineural small vessels, suggesting the presence of vasculitis. She was diagnosed as having vasculitic neuropathy complicated with Sjögren's syndrome. Methylprednisolone pulse therapy followed by oral prednisolone was started and these symptoms gradually improved in one month. At age 63, she felt dysesthesia in the right lower limb and this sensory abnormality spreaded to upper limbs. Two years later, she was admitted again due to clumsiness of hands and gait disturbance. Neurological examination showed decreased vibration and position sense of lower limbs and limb ataxia in addition to dysesthesia. Electrophysiological studies demonstrated significant decrease in amplitude of sensory nerve action potentials and delayed somatosensory evoked potentials after N13, indicating impairment of dorsal root ganglions. She was treated with intravenous immunoglobulin (400 mg/kg, total 15 g/day) for 5 days. One week later, sensory ataxia was improved. It has been known that Sjögren's syndrome is often complicate with various types of neuropathies including vasculitic neuropathy and sensory neuropathy. Our patient developed these two different types of neuropathies which were dramatically improved after two different therapeutic regimens; indicating the importance to select a suitable treatment regimen in accordance with the mechanism of neuropathy associated with Sjögren's syndrome.

Bone marrow transfer from wild-type mice reverts the beneficial effect of genetically mediated immune deficiency in myelin mutants.

Inherited demyelinating neuropathies are chronically disabling human disorders caused by various genetic defects, including deletions, single site mutations, and duplications in the respective myelin genes. We have shown in a mouse model of one distinct hereditary demyelinating neuropathy (heterozygous P0-deficiency, P0+-) that an additional null mutation in the recombination activating gene-1 (RAG-1--) leads to a substantially milder disorder, indicating a disease modifying role of T-lymphocytes. In the present study, we addressed the role of lymphocytes in the mouse model by reconstituting bone marrow of P0+-/RAG-1-- mice with bone marrow from immunocompetent wild-type mice. We compared the pathology and nerve conduction in double mutant mice (P0+-/RAG-1-- on a C57BL/6 background) with that in double mutants after receiving a bone marrow transplant. We found that the milder demyelination seen in the lymphocyte-deficient P0+-/RAG-1-- mutants was reverted to the more severe pathology by reestablishing a competent immune system by bone marrow transfer. These data corroborate the concept that the immune system contributes substantially to the pathologic process in this mouse model and may open new avenues to ameliorate human hereditary neuropathies by exploiting immunosuppressive treatments.

Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy.

OBJECTIVE: To quantify the progression of diabetic polyradiculoneuropathy-a condition in which immune factors have been implicated-after immunotherapy. METHODS: The study evaluated 15 consecutive patients with this condition. All patients were older than 40. Four had type I diabetes and six were women. The duration of pre-existing diabetes varied from 2 to 20 years. The clinical presentation was dominated by painful progressive motor weakness, with or without exacerbation of sensory symptoms. The weakness involved all limbs, but was often asymmetric. RESULTS: Electrophysiological testing showed a predominantly axonal polyneuropathy, with more recent denervating polyradiculopathy. Analysis of CSF showed increased protein in 14 and oligoclonal bands in five. Quantitative autonomic tests showed abnormalities in all patients. Sural nerve biopsy was performed in 14 patients; all showed fibre loss and segmental demyelination, four had occasional onion bulbs, and 10 showed various inflammatory infiltrates. After immunomodulating therapy, there was no further deterioration and clinical improvement occurred in all patients. Sweat responses, cardiovascular reflexes, and sural nerve fibre density correlated best with functional outcome. There was no significant difference between plasmapheresis and intravenous gammaglobulin. CONCLUSION: Immunotherapy may improve this condition, but only certain variables correlate with rapid therapeutic response.