Immunotherapy in Peripheral Neuropathies

Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barré syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms.     

Current treatments of chronic immune‐mediated demyelinating polyneuropathies

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy are three demyelinating acquired neuropathies, with distinct responses to immunotherapy. In placebo‐controlled, double‐blind, randomized trials, intravenous immunoglobulin (IVIg) has been effective for CIDP and MMN, and plasmapheresis has been effective for CIDP. Corticosteroids have been beneficial in controlled trials for CIDP. Other agents, including cyclophosphamide, rituximab, azathioprine, cyclosporine, interferons, fludarabine, mycophenolate mofetil, and etanercept, have been reported to benefit some patients with inflammatory demyelinating neuropathies in case series and case reports. This review examines the use and toxicity associated with these immunotherapy medications in treating patients with chronic immune‐mediated demyelinating neuropathies. Muscle Nerve, 2009     

Anti-PMP22 antibodies in patients with inflammatory neuropathy

An experimental model of inflammatory radiculoneuropathy is induced by immunising rats with peripheral myelin protein 22 (PMP22). We have investigated whether PMP22 may be important in inducing human inflammatory neuropathy. We examined sera of patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), other neuropathies (ONP) and normal controls for IgM and IgG antibodies against PMP22 by ELISA (against synthetic PMP22 extracellular peptide fragments) and Western blot (against cauda equina). Antibodies were detected by both methods in 52% of patients with GBS, 35% with CIDP, 3% with ONP and no normal controls. We conclude that an immune response against PMP22 may play a role in the pathogenesis of the inflammatory neuropathies.     

INTRAMYELINIC EDEMA: AN ELEMENTARY PATHOLOGICAL LESION IN CIDP

Pathological abnormalities of sural nerve biopsies from patients affected by chronic inflammatory demyelinating polyneuropathy (CIDP) include segmental demyelination, inflammatory infiltrates, axonal degeneration, subperineurial edema and Schwann cell proliferation. There are few reports in the literature (Waddy '89, Sabatelli '96) describing edema of the myelin sheath as an additional pathological feature of CIDP. This peculiar abnormality is a prominent finding in several experimental toxic and compression neuropathies. In 1993 Tatum described Intramyelinic Edema in experimental allergic neuritis induced by systemic passive transfer of human IgM anti‐myelin‐associated glycoprotein, and suggested that this change may play a role in the pathogenesis of demyelination. In order to establish whether intramyelinic edema may represent an elementary pathological lesion in human peripheral neuropathies, we reviewed morphological data of sural nerve biopsies from 46 CIDP patients admitted to our Institute from 1988 to 2001 and we compared them with findings from patients affected by other neuropathies. IE was observed in 6 patients with CIDP, but in none of the 500 patients affected by neuropathies of different etiology. In two out of the six patients the neuropathy was associated with IgM‐paraprotein, without anti‐MAG activity. IE was a prominent feature in only one patient while in the remaining patients it was confined to sporadic fibers. In one patient with a mild form of CIDP, IE was the only pathological finding. In the remaining patients it was associated with segmental demyelination and axonal loss. Our findings show that although IE is observed in only a minority of CIDP patients (13% of our series), this pathological finding may be considered a specific abnormality of inflammatory demyelinating neuropathies. We suggest that axonal shrinkage, which is invariably associated with IE, may represent a mechanism of loss of function in CIDP, in addition to segmental demyelination and axonal loss.     

Diagnosis and management of immune-mediated neuropathies

Immune-mediate neuropathies, or inflammatory neuropathies are neuropathies due to the dysregulation of the immune system. The injury to peripheral nerves can be divided into two phases: an early stage of immune injury, and a later stage of structural damage. The overall effects are axonal degeneration or demyelination depending on the target of immunological attacks. According to time course, there are two major types: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Clinical manifestations of both diseases include progressive motor weakness and sensory disturbance with some variations among different patients. The major findings of nerve conduction studies on GBS patients are prolonged distal motor latencies and minimal F-wave latencies with variable reduction of nerve conduction velocities. In CIDP patients, slowed nerve conduction velocities are the usual findings in addition to prolongation of distal motor latencies and minimal F-wave latencies. Certain subtypes of immune-mediated neuropathies are associated with high titers of anti-gangliosdie antibodies. Patients with GBS and CIDP can benefit from immunotherapy. For GBS, plasma exchange and intravenous immunoglobulin (IVIG) are equally effective in reducing complications and neurological disability. Steroid of high dose is, however, harmful to GBS. Plasma exchange and IVIG can alleviate neurological deficits of CIDP with steroid to maintain the effects of plasma exchange and IVIG. In conclusion, careful clinical observations and judgment are the most important issue to manage patients with immune-mediated neuropathies.     

Increased frequencies of HPRT mutant T lymphocytes in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy: further evidence for a role of T cells in the etiopathogenesis of peripheral demyelinating diseases

We have used the HPRT mutant clonal assay to determine the frequency of mutant T lymphocytes (FMC), as a measure of recent T cell stimulation, in the blood of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We found that, compared to healthy controls, the FMC in patients with GBS (16) and CIDP (10) was significantly increased in the progressive phase of the neuropathy. FMC returned to normal values during recovery, suggesting a relationship between FMC and disease activity. No correlation was found between FMC values and motor deficit or severity of the neuropathy. The FMC of the GBS patients with a history of infection before onset of neurological symptoms or with insufficient respiration was not significantly different from the other GBS patients. Immunophenotypic analysis showed that the fraction of CD8⁺ HPRT mutant T cell clones was significantly increased in GBS patients (48%) compared to healthy controls (3%) or CIDP patients (4.5%). Our results are compatible with the notion that T cells are involved in the pathogenesis of demyelinating inflammatory neuropathies.     

Immunneuropathien

The Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune-mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune-mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits.     

Effector mechanisms of PNS demyelination in Gal-C induced-EAN

Myelin in PNS is multi-layered membranes formed by Schwann cells, and surrounds axon. Destruction of myelin sheath results in demyelination and disturbance of nerve conduction. In PNS, Charcot-Marie-Tooth disease, certain lipidoses, Guillain-Barré syndrome, lead poisoning, compression and some metabolic neuropathies can produce demyelination. In these diseases, GBS is thought to be resulted from abnormalities of immune mechanism. Recently, autoantibodies against Gal-C, P2 and GM1, and complement fixing antibodies against PNS myelin are found in some of GBS patient sera. Here, I present studies on effector mechanism of PNS demyelination using models produced by application of Galactocerebroside (Gal-C) antibodies to PNS. Mainly, three types of effector mechanisms are involved in Gal-C antibody-induced demyelination. In abundance of antibodies, complement-mediated demyelination is at work. When complements are absent, antibody dependent macrophage-mediated demyelination can be involved. Thirdly, myelin once damaged by oxidants and etc can be opsonized by antibodies and C3b, and phagocytized by macrophages. These processes may be operating in such diseases like GBS and CIDP.     

Simulating mild systematic and focal demyelinating neuropathies: membrane property abnormalities

This study provides numerical simulations of some of the abnormalities in the potentials and axonal excitability indices of human motor nerve fibers in simulated cases of internodal, paranodal and simultaneously of paranodal internodal demyelinations, each of them systematic or focal. A 70% reduction of the myelin lamellae (defining internodal demyelination), or of the paranodal seal resistance (defining paranodal demyelination), or simultaneously both of them (defining paranodal internodal demyelination) was uniform along the fiber length for the systematically demyelinated subtypes. These permutations were termed internodal systematic demyelination (ISD), paranodal systematic demyelination (PSD) and paranodal internodal systematic demyelination (PISD). In other tests, the same reductions of the myelin sheath parameters were used but restricted to only three (8th, 9th and 10th) consecutive internodes. Such fiber demyelinations were termed internodal focal demyelination (IFD), paranodal focal demyelination (PFD) and paranodal internodal focal demyelination (PIFD). The computations used our previous double cable model of the fibers. The axon model was comprised of 30 nodes and 29 internodes. The 70% reduction value was not sufficient to develop conduction block in all investigated demyelinations, which were regarded as mild. The membrane property abnormalities obtained in the ISD, PSD and PISD cases were quite different and abnormally greater than those in the IFD, PFD and PIFD cases. The changes in the excitability indices such as strength-duration time constants, rheobasic currents and recovery cycles in the focally demyelinated subtypes were so slight as to be essentially indistinguishable from normal values. Consequently, the excitability based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations. The membrane property changes simulated in the systematically demyelinated subtypes are in good accordance with the data from patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP). The excitability abnormalities obtained in each focally demyelinated subtype match those observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS). The results indicate that the model that was used is a rather promising tool in studying the membrane property abnormalities of hereditary, chronic and acquired demyelinating neuropathies, which up till now, have not been sufficiently well understood.     

Autoimmune neuropathies: diagnosis, treatment, and recent topics

Here, we have reviewed the clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies of autoimmune neuropathies such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and IgM paraproteinemic neuropathy. Antiganglioside antibodies are frequently present in the serum samples obtained during the acutephase of GBS and Miller Fisher syndrome (MFS), a subtype of GBS. Recently, we found that some patients with GBS and MFS have serum antibodies against antigenic epitopes formed by 2 different gangliosides (ganglioside complex). The antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe disability and a requirement for mechanical ventilation. Anti-GM1/GalNAc-GD1a antibodies are found to be associated with pure motor GBS with frequent conduction blocks. In GBS, corticosteroids given alone do not significantly hasten the recovery or affect the long-term treatment outcome. Intravenous immunoglobulin therapy (IVIg) or plasma exchange (PE) is equally effective. Combined treatment with corticosteroids and IVIg may be a promising therapy for GBS. On the basis of the EFNS/PNS guidelines, we describe the treatment of chronic autoimmune neuropathies such as CIDP, MMN, and IgM paraproteinemic neuropathy. In treating CIDP, corticosteroids, IVIg, and plasma exchange are equally effective. In MMN, IVIg is the first-choice therapy; corticosteroids and PE are ineffective or even detrimental. IgM paraproteinemic neuropathies are known to be intractable, and these patients often have anti-myelin-associated glycoprotein antibodies and may respond to immunosuppressive and immunomodulatory therapies. However, the potential therapeutic benefits should be balanced against their possible side effects and usual slow disease progression.     

HLA-DR Schwann cell reactivity in peripheral neuropathies of different origins

HLA-DR antigens have been found on Schwann cells in peripheral neuropathies of different origins but not in normal control cases. Class II antigen reactivity was more intense in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and hereditary motor and sensory neuropathy type 1 (HMSN), but was also observed in toxic or metabolic neuropathies. The expression of HLA-DR antigen on Schwann cells does not appear to be related to the inflammatory or autoimmune origin of the disease.     

Inflammatory neuropathies

Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP.     

Expression of integrins in experimental autoimmune neuritis and guillain-barré syndrome

Integrins are a subclass of adhesion molecules that mediate cell–cell and cell–extracellular matrix interactions. Integrins influence transendothelial migration of lymphocytes and monocytes and are suitable targets for experimental immunotherapy. They are critically involved in the pathogenesis of autoimmune neuritis and abnormally expressed in human neuropathies. Also, the role of integrins in myelination, neurite outgrowth, and nerve regeneration suggests that they could be involved in the recovery phase of immune-mediated neuropathies. We investigated by immunohistochemistry the expression of a number of integrin subunits during the course of experimental autoimmune neuritis (EAN). Results were compared with the human immune neuropathy Guillain-Barré syndrome (GBS) and extended in vitro. Inflammation and demyelination in both EAN and GBS induced the down-regulation of β4 integrin in Schwann cells (SCs), whereas loss of α2 was noted only in EAN. When axonal loss was present, SCs displayed α5integrin, in both EAN and GBS. In vitro, basal lamina and inflammatory cytokines modulated the expression of β4 in SCs, but they did not influence α2 and α5 expression. Finally, integrins were differentially expressed in blood vessels during EAN. In conclusion, the spatiotemporal changes in integrin expression may be used to characterize, stage, and better understand the pathogenesis and evolution of inflammation during GBS and EAN. This may help to establish useful, novel therapy for immune-mediated neuropathies.     

Class II antigen expression in peripheral neuropathies.

The expression of class II antigen was studied in sural nerve biopsies from patients with peripheral neuropathies. These included patients with chronic demyelinating polyradiculoneuropathy (CIDP), non-immune mediated neuropathies of diverse etiologies and controls without evidence of neuropathy. The major finding in CIDP was a marked increase in class II expression on Schwann cells. Endoneurial Schwann cell staining to the same degree as in CIDP was seen in diabetic symmetric proximal motor neuropathy, neuropathies associated with monoclonal gammopathies and hereditary sensory and autonomic neuropathy type 1. In the control nerves and the other non-immune mediated neuropathies class II expression was mainly restricted to endothelial and perineurial cells. Increased endoneurial expression of class II antigen was found to correlate with elevated cerebrospinal fluid (CSF) protein levels but not with other clinical variables or demyelination as defined by electrophysiologic criteria or teased fiber analysis. The increased expression of class II antigen on Schwann cells may be indicative of a breakdown in immunological tolerance but should not be used as a diagnostic marker for dysimmune neuropathies due to overlap with non-immune mediated neuropathies.     

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.     

Distribution of sodium channels in chronically demyelinated spinal cord axons: immuno-ultrastructural localization and electrophysiological observations

The immuno-ultrastructural localization of voltage-sensitive sodium channels was demonstrated within a central demyelinating lesion induced in the rat spinal cord by ethidium bromide/irradiation using polyclonal antibody 7493. Antibody 7493 has previously been shown to immunostain intensely axon membrane at nodes of Ranvier, and also perinodal astrocyte processes. At 25–35 days post injection/irradiation, the central portion of the demyelinating lesion is populated with chronically demyelinated axons and there is an absence of glial processes. Sodum channel immunoreactivity was not observed on the chronically demyelinated axolemma within this central portion of the lesion. Within the peripheral portion of the lesion demyelinated axons were occasionally abutted by astrocyte and Schwann cell processes. At these focal sites of apposition, the axon membrane displayed intense sodium channel immunoreactivity, while the abutting astrocyte and Schwann cell processes did not exhibit immunostaining. Also in the periphery of the lesion, some axons become ensheathed and myelinated by oligodendrocytes and Schwann cells. The axon membrane of circumferentially ensheathed axons displayed antibody 7493 immunostaining, and this immunoreactivity persisted on the axolemma until the ensheathing cytoplasmic processes compacted into myelin. Internodal axon membrane beneath the myelin sheath did not display sodium channel immunoreactivity, though (putative) developing nodal axon membrane adjacent to terminal paranodal loops exhibited robust sodium channel staining. Electrophysiological recordings within the ethidium bromide/irradiation lesion demonstrated that at least some axons conducted action potentials within the lesion, while others exhibited conduction block. These results indicate that there is a reorganization of sodium channels within the axon membrane of chronically demyelinated central axons.     

Chronic inflammatory demyelinating polyneuropathy and other immune-mediated demyelinating neuropathies

The identification of specific disorders caused by immune-mediated attack on Schwann cells and myelin have both improved and confused our understanding and classification of chronic inflammatory and immune-mediated neuropathies. Some investigators consider all neuropathies that respond to immunosuppressive treatment as chronic inflammatory demyelinating polyneuropathy (CIDP), regardless of whether there is evidence for demyelination. Other investigators rely on a very strict definition of CIDP and do not include variations. The goal of this article is to clarify the spectrum of these disorders and provide a logical classification scheme that has clinical utility and yet allows for new information that might distinguish new variations. Therapeutic strategies are also discussed.     

Electrodiagnosis of demyelinating neuropathies

The inflammatory demyelinating neuropathies constitute a significant proportion of the acquired polyneuropathies. Major progress in finding the causes and in the treatment of these neuropathies has been made over the last decade. Early recognition is of paramount importance, because timely and appropriate treatment can largely reduce morbidity and disability. Electrodiagnosis plays a key role in the detection and characterization of the inflammatory demyelinating neuropathies. Electrodiagnostic criteria for primary demyelination have therefore been developed. They are empirically based on changes of nerve conduction parameters in populations of patients with a confirmed clinical and laboratory diagnosis of inflammatory demyelinating neuropathy. The challenge consists of defining criteria sets that are highly specific but also as sensitive as possible. Most of the hereditary demyelinating neuropathies are part of Charcot-Marie-Tooth disease type 1. The pattern of nerve conduction abnormalities usually provides valuable clues for the distinction from chronic inflammatory demyelinating neuropathies.     

Investigation of serum response to PMP22, connexin 32 and P(0) in inflammatory neuropathies.

We investigated serological immune responses against three major peripheral nerve myelin constituents in patients with immune-mediated neuropathies. Connexin 32 (Cx32), myelin protein zero (MPZ, P(0)) and peripheral myelin protein 22 (PMP22) were produced in Chinese hamster ovary (CHO)-K1 cells. From a panel of 25 Guillain-Barré syndrome (GBS) and 24 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, only two patients showed reactivity towards Cx32 and P(0).     

IgG monoclonal paraproteinaemia and peripheral neuropathy.

Five patients with peripheral neuropathy and benign IgG monoclonal paraproteinemia are reported, all of whom had a sensorimotor neuropathy with a remitting and relapsing course. The serum paraprotein level did not correlate with the patient's clinical status. Electrophsyiological studies showed marked slowing of conduction velocity and conduction block in four of the patients and mild slowing in the other. Sural nerve biopsies demonstrated a demyelinating neuropathy with inflammatory cell infiltrates in each of the five patients. Three of the patients had evidence of myelin/Schwann cell reactivity on immunofluorescence studies and in all nerves dense expression of major histocompatability complex class I and II molecules was evident within the endoneurium, on invading mononuclear cells, endothelial cells and Schwann cells. All the patients responded to treatment, plasmapheresis being particularly effective. Four patients have achieved prolonged remissions after all treatment had ceased. These five cases of peripheral neuropathy and IgG paraproteinaemia were identical in their clinical, electrophysiological and pathological features to patients with chronic inflammatory demyelinating polyneuropathy.