Effective treatment of experimental autoimmune neuritis with human immunoglobulin

High-dose intravenous immunoglobulin (IVIg) is an effective treatment for inflammatory demyelinating neuropathies, although the mechanism(s) of action remain incompletely understood. Experimental autoimmune neuritis (EAN) is an animal model of inflammatory demyelinating neuropathies; however, there have been conflicting reports regarding the efficacy of human IVIg in EAN. To obtain a model suitable for the study of the mechanism(s) of action of IVIg in Guillain-Barré syndrome, we investigated the effect of IVIg in EAN in the rat using clinical, electrophysiological and morphological measures. Human IVIg administered at the onset of signs of disease proved effective in preventing further progression of disease and shortening disease duration. This effectiveness was associated with significant differences in electrophysiological parameters including less prolongation of somatosensory evoked potential (S wave) latencies, better maintained S wave amplitudes, less reduction of distal motor nerve conduction velocity, and better maintained amplitudes of compound muscle action potentials of the dorsal foot muscles after stimulation at ankle and hip. Moreover, treatment with IVIg resulted in significantly lower histological grades in rat EAN. The current study provides evidence that human IVIg is effective in the treatment of EAN in the rat, indicating that this model may facilitate further investigation of the mechanism(s) of action of IVIg in inflammatory demyelinating neuropathies.     

Effective treatment of experimental autoimmune neuritis with Fc fragment of human immunoglobulin

IV immunoglobulin (IVIg) and its Fc fragment proved effective in preventing further progression of experimental autoimmune neuritis (EAN) in the rat induced by whole bovine peripheral nerve myelin and shortening disease duration. This effectiveness was associated with significant differences in electrophysiological parameters including less prolongation of somatosensory evoked potential (S wave) latencies, better maintained S wave amplitudes, less reduction of distal motor nerve conduction velocity, and better maintained amplitudes of compound muscle action potentials of dorsal foot muscles after stimulation at ankle and hip. Moreover, treatment with IVIg and Fc fragments resulted in less extensive inflammation and demyelination in nerve roots evidenced by significantly lower histological grades. The current study provides direct evidence for the first time that Fc fraction of IVIg is the effective component in the treatment of rat EAN.     

Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.

This review summarizes the current status of intravenous immunoglobulin (IVIg) in the treatment of autoimmune neuromuscular disorders and the possible mechanisms of action of the drug based on work in vivo, in vitro, and in animal models. Supply of idiotypic antibodies, suppression of antibody production, or acceleration of catabolism of immunoglobulin G (IgG) are relevant in explaining the efficacy of IVIg in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and antibody-mediated neuropathies. Suppression of pathogenic cytokines has putative relevance in inflammatory myopathies and demyelinating neuropathies. Inhibition of complement binding and prevention of membranolytic attack complex (MAC) formation are relevant in dermatomyositis (DM), Guillain-Barré syndrome (GBS), and MG. Modulation of Fc receptors or T-cell function is relevant in chronic inflammatory demyelinating polyneuropathy (CIDP), GBS, and inflammatory myopathies. The clinical efficacy of IVIg, based on controlled clinical trials conducted in patients with GBS, CIDP, multifocal motor neuropathy (MMN), DM, MG, LEMS, paraproteinemic IgM anti-myelin-associated glycoprotein (anti-MAG) demyelinating polyneuropathies, and inclusion body myositis is summarized and practical issues related to each disorder are addressed. The present role of IVIg therapy in other disorders based on small controlled or uncontrolled trials is also summarized. Finally, safety issues, risk factors, adverse reactions, spurious results or serological tests, and practical guidelines associated with the administration of IVIg in the treatment of neuromuscular disorders are presented.     

Intravenous immunoglobulin therapy for Guillain-Barré syndrome with IgG anti-GM1 antibody

To compare the effects of intravenous immunoglobulin (IVIg) therapy and plasmapheresis for the IgG anti-GM1-positive subtype of Guillain-Barré syndrome (GBS), clinical and electrophysiological recoveries were analyzed in 24 patients treated with IVIg (n = 10) or plasmapheresis (n = 14). At entry, there were no significant differences between the two patient groups in age, sex, clinical severity (Hughes grade), sum scores of distally evoked amplitudes of compound muscle action potentials (CMAPs), and frequency of Campylobacter jejuni infection. The patients treated with IVIg had significantly lower Hughes grade scores 1, 3, and 6 months after onset (P = 0.03), and a higher probability to regain independent locomotion at 6 months [P(logrank) = 0.044]. In the IVIg group, markedly rapid recovery (improvement by two or more Hughes grade scores within 4 weeks) was more frequent (6 of 10 vs. 3 of 14, P = 0. 03), and delayed recovery (unable to walk independently at 6 months) was less frequent (0 of 10 vs. 4 of 14, P = 0.06). CMAP sum score at 6 months tended to be greater for the IVIg group (P = 0.07). For the IgG anti-GM1-positive subgroup of GBS patients, IVIg therapy may be a more efficacious treatment than plasmapheresis.     

The effect of IgG levels on the number of natural killer cells and their Fc receptors in chronic inflammatory demyelinating polyradiculoneuropathy

Background and purpose: High‐dose intravenous immunoglobulin (IVIg) is an established treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although Fc receptors on natural killer cells have been suggested as a target for IVIg, the pharmacological effects are not yet clarified. We hypothesize that IVIg therapy, dependent on the plasma IgG level, suppresses the cytotoxic capacity by a reduction in numbers of NK cells and their Fc receptor CD16. Patients and methods: Ten consecutive patients with CIDP in maintenance therapy with IVIg were studied before and immediately after the infusion of 0.7–2.0 g/kg IVIg. Peripheral blood mononuclear cell samples from these patients were analyzed immediately after isolation using flow cytometry and cytotoxicity assays. Results: We found that following IVIg treatment, the cytotoxic activity of NK cells in CIDP patients was suppressed, partly caused by a dose‐dependent decline in the number of circulating NK cells. In addition, a dose‐dependent blockage of CD16 occurred. Conclusions: The study implies that IVIg infusion induces a substantial decline in the number of peripheral NK cells and a suppression of NK‐cell‐mediated cytotoxicity. We propose that these impairments of the NK cells contribute to the therapeutic effect of IVIg in CIDP.     

多灶性运动神经病的临床表现及肌电图特征

目的 探讨多灶性运动神经病(multifocal motor neuropathy,MMN)的临床表现及肌电图(electromyography,EMG)特征.方法 选择2016 年6 月至2019 年12 月南京医科大学附属南京医院(南京市第一医院)收治的7 例MMN 患者,对其临床资料及神经电生理检查结果进行回顾性...     

Expression of chemokine receptors on peripheral blood mononuclear cells of patients with immune-mediated neuropathies treated with intravenous immunoglobulins

Intravenous immunoglobulin (IVIg) is an efficacious treatment for immune-mediated neuropathies like Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP), and multifocal motor neuropathy (MMN). In the pathogenesis of immune-mediated neuropathies chemokines and their receptors play a crucial role. Using flow cytometry we examined whether IVIg modulates chemokine expression repertoires of T cells and monocytes. The expression of inflammatory chemokine receptors CCR1, CCR2, CCR4, CCR5, CCR6 and CXCR3 was investigated on circulating T-cell subsets, and CCR1, CCR2 and CCR5 on circulating monocytes before and after IVIg treatment in patients with immune-mediated neuropathies (MMN, n  = 7; GBS, n  = 1; CIDP, n  = 2). Furthermore, the homing potential of T cells was analyzed by the expression of CCR7, a chemokine receptor known to be utilized by mature T cells to recirculate into secondary lymphoid organs. In contrast to studies in chronic heart failure, no differences in expression patterns before and after IVIg treatment of any of the investigated chemokine receptors were found. Furthermore, the proportion of CD45RO-positive CD4⁺ or CD8⁺ T-cell subsets was not changed by IVIg treatment. Thus, we concluded that modulation of the expression of chemokine receptors on circulating leukocytes by IVIg is not a mode of action in immune-mediated neuropathies.     

Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies

Immune-mediated neuropathies are a heterogeneous group of peripheral nerve disorders, which are classified by time course, clinical pattern, affected nerves and pathological features. Plasma exchange (PE) and intravenous immunoglobulins (IVIg) are mainstays in the treatment of immune-mediated neuropathies. Of all treatments currently used, IVIg has probably the widest application range in immune-mediated neuropathies and efficacy has been well documented in several randomized controlled trials for Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Beneficial effects of IVIg have also been proven for multifocal motor neuropathy (MMN). Likewise, PE is an established treatment for GBS and CIDP, whereas it is considered to be ineffective in MMN. Different mechanisms of action are sought to be responsible for the immunemodulatory effect of PE and IVIg in autoimmune disorders. Some of those might be important for immune-mediated neuropathies, while others are probably negligible. The aim of this review is to summarize the recent advances in elucidating disease-specific mechanisms of actions of PE and IVIg in the treatment of immune-mediated neuropathies.     

Intravenous immunoglobulin treatment in peripheral nerve disorders--indications, mechanisms of action and side-effects

This review summarizes observations of clinical use of high dose intravenous immunoglobulin G (IVIg) in regards to administration, kinetics, known or postulated mechanisms of action, and adverse reactions. Indications and value of IVIg for the treatment of various neuropathies with presumed autoimmune aetiology are examined. New knowledge that advances the understanding of the pathogenesis of the neuropathies and of the mechanisms of action of IVIg is discussed.     

Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barré syndrome

Intravenous immunoglobulin (IVIg) treatment ameliorates the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. We attempted to delineate the effect of IVIg on neuromuscular blocking antibodies in GBS. A total of seven GBS serum samples were examined for blocking antibodies and the effect of IVIg with a macro-patch-clamp technique in mouse hemidiaphragms. First, serum was tested before and after treatment with IVIg. Second, we investigated with coincubation experiments whether the IVIg was capable of neutralizing neuromuscular blocking antibodies in GBS serum or affinity-purified immunoglobulin G (IgG) fractions. Finally, the mechanism of the neutralizing effect was studied by the coincubation of active blocking GBS IgG with Fab and Fc fragments prepared from IVIg. All GBS sera (two adults and two children) and GBS IgG fractions (three adults) taken before treatment with IVIg blocked evoked quantal release by approximately 90%. Blocking activity was markedly reduced in sera obtained after treatment with IVIg. Coincubation of the pretreatment blocking serum with the posttreatment serum, or with the IVIg preparation used for treatment, reduced the blocking activity of the pretreatment GBS serum. When GBS IgG was coincubated with IVIg, the blocking activity of GBS IgG was diminished dose-dependently. Monovalent and divalent Fab fragments prepared from the IVIg were as effective as whole IVIg, but Fc fragments were ineffective. Therapeutic IVIg is capable of neutralizing neuromuscular blocking antibodies in GBS by a dose-dependent, antibody-mediated mechanism. This may, in part, explain its therapeutic efficacy.     

Efficacy and tolerability of different brands of intravenous immunoglobulin in the maintenance treatment of chronic immune‐mediated neuropathies

High‐dose intravenous immunoglobulin (IVIg) is effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Not all brands of IVIg are however licensed for these neuropathies. We reviewed six patients with CIDP and seven with MMN treated with maintenance therapy with IVIg from 2009 to 2013. In all patients, we measured the Medical Research Council (MRC) and Overall Neuropathy Limitation Scale (ONLS) scores before each infusion, registered the monthly dose and brand of IVIg, and recorded adverse events. Patients were treated for 25–60 months (mean 49 months) alternating different brands of IVIg including IgVena, Gammagard, Kiovig, and Flebogamma. Minor and transient side effects were equally observed with each brand. No difference in the MRC or ONLS scores was observed in relation to the brand of IVIg used. Chronic maintenance treatment with IVIg in patients with MMN and CIDP was not associated with a different tolerability or efficacy despite the use of different brands of IVIg.     

FTY720 ameliorates experimental autoimmune neuritis by inhibition of lymphocyte and monocyte infiltration into peripheral nerves

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system (PNS). T cells and macrophages are essential for the initiation and development of EAN. FTY720 acts as an agonist of sphingosine-1-phosphate receptors, resulting in inhibition of lymphocyte egress from secondary lymphoid tissues and thymocytes from thymus. This investigation describes the immunosuppressive effects of FTY720 in EAN, the animal model of autoimmune neuropathies. FTY720 (1 mg/kg body weight) completely suppressed paraparesis if administrated from the day of immunization. Furthermore, FTY720 greatly reduced the severity and duration of EAN even when administrated after the appearance of the first neurological sign. T cell, B cell, and macrophage infiltration and demyelination of sciatic nerves were significantly decreased in FTY720-treated EAN. Therefore, FTY720 might be a potential candidate for treatment of inflammatory neuropathies.     

Differentiation between axonal and demyelinating neuropathies: Identical segments recorded from proximal and distal muscles

The presence of significant slowing of motor nerve conduction velocity is considered one of the electrodiagnostic hallmarks of demyelinating neuropathies; however, slowing of conduction velocity may also accompany severe axonal loss. When compound muscle action potential (CMAP) amplitudes are markedly reduced, it is frequently difficult to determine if conduction velocity slowing is due to axonal loss with dropout of the fastest conducting fibers or demyelination. To evaluate the relationship between conduction velocity and axonal dropout, we compared conduction velocities through the same segment of nerve recording from distal and proximal peroneal muscles in patients with chronic neuropathies, in patients with motor neuron disease, and in control subjects. In controls and patients with motor neuron disease, conduction velocities were normal with no significant difference between proximal and distal sites. In patients with axonal neuropathies, conduction velocities were preferentially slowed when recording from distal muscles and relatively normal when recording from proximal sites. Patients with demyelinating neuropathies showed marked slowing of conduction at both sites. We conclude that comparing conduction velocity obtained from proximal versus distal muscle recordings provides a simple, reliable aid for differentiating between chronic axonal and demyelinating polyneuropathies, especially in cases with conduction velocity slowing and low CMAP amplitudes. © 1995 John Wiley & Sons, Inc.     

Voluntary contraction and responses to submaximal cervical nerve root stimulation

Voluntary contraction of hand muscles increases compound muscle action potential (CMAP) amplitudes evoked by submaximal electrical percutaneous cervical stimulation (EPCS). This has been reported to be due to an intraspinal, presynaptic mechanism. We studied the effects of voluntary contraction on hypothenar CMAP amplitudes in 5 volunteers following electrical peripheral nerve stimulation at the wrist, EPCS, magnetic stimulation at the neck and the effects of a conditioning subthreshold cortical magnetic stimulus on CMAPs evoked by EPCS at rest. CMAP amplitudes increased with voluntary contraction of the target muscle, regardless of type or location of stimulus (P < 0.001). No increase in CMAP amplitude occurred when a conditioning transcranial stimulus was employed with EPCS (P = 0.35). Our findings indicate a peripheral rather than central mechanism underlies this effect of voluntary contraction. It is probably related to the recruitment order of motor axons, comparing voluntary activation with electrical or magnetic stimulation. © 1994 John Wiley & Sons, Inc.     

Does retrograde axonal atrophy really occur in carpal tunnel syndrome patients with normal forearm conduction velocity?

OBJECTIVE: The cause of decreased median forearm motor conduction velocity (FMCV) in carpal tunnel syndrome (CTS) is best ascribed to retrograde axonal atrophy (RAA); however, the relationships between the occurrence of RAA and electrophysiological or clinical severity remains controversial. We attempt to determine whether RAA really occurs in CTS patients with normal median FMCV and to investigate any relationships between RAA and severity of compression at the wrist. METHODS: Consecutive CTS patients were enrolled and age-matched volunteers served as controls. We performed conventional nerve conduction studies (NCS) and measured median and ulnar distal motor latencies (DML), FMCV, compound muscle action potential (CMAP) amplitudes, distal sensory latencies (DSL), and sensory nerve action potential (SNAP) amplitudes. Furthermore, palmar median stimulation was done to calculate the wrist-palm motor conduction velocity (W-P MCV). Patients included for analysis should have normal FMCV and needle examination. We compared each electrodiagnostic parameters between the patient group and controls. RESULTS: The mean+/-SD of the W-P MCV for patients and controls were 33.26+/-6.74 and 52.14+/-5.85 m/s and those of median FMCV were 55.26+/-3.56 and 57.82+/-3.9 m/s, respectively. There was a significant reduction in the W-P MCV (36.2%, P<0.00001), significant decrease in the median FMCV (4.43%, P<0.00001) and SNAP amplitudes, and an increase of the DML and DSL in the patient group (P<0.00001) compared to the controls; however, there were no differences in median and ulnar CMAP amplitudes, ulnar FMCV and DML between the controls and patients. CONCLUSIONS: RAA and relatively slowed median FMCV do occur in CTS patients with normal median FMCV, regardless of severity of clinical manifestations and electrophysiological abnormalities. SIGNIFICANCE: This article provides new information for research of the electrophysiological changes of the proximal nerve part at distal injury.     

Electrophysiologic correlations with clinical outcomes in CIDP

Data are lacking on correlations between changes in nerve conduction (NC) studies and treatment response in chronic inflammatory demyelinating polyneuropathy (CIDP). This report examined data from a randomized, double‐blind trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV‐C [Gamunex]; n = 59) versus placebo (n = 58) every 3 weeks for up to 24 weeks in CIDP. Motor NC results and clinical measures were assessed at baseline and endpoint/week 24. Improvement from baseline in adjusted inflammatory neuropathy cause and treatment score correlated with improvement in proximally evoked compound muscle action potential (CMAP) amplitudes (r = ?0.53; P < 0.001) of all nerves tested and with improvement in CMAP amplitude of the most severely affected motor nerve (r = ?0.36; P < 0.001). Correlations were observed between improvement in averaged CMAP amplitudes and dominant‐hand grip strength (r = 0.44; P < 0.001) and Medical Research Council sum score (r = 0.38; P < 0.001). Overall, the change in electrophysiologic measures of NC in CIDP correlated with clinical response to treatment. Muscle Nerve, 2010     

Electrophysiological testing in chronic inflammatory demyelinating polyneuropathy patients treated with subcutaneous immunoglobulin: The Polyneuropathy And Treatment with Hizentra (PATH) study

ObjectiveTo assess electrophysiology parameters that can reflect patients' clinical status and show changes in nerve function with treatment, in a study of subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy.MethodsNerve conduction studies (latency, conduction velocity, conduction block and compound muscle action potential [CMAP] on upper limb median, ulnar, and lower limb peroneal motor nerves) were conducted in the placebo-controlled PATH (Polyneuropathy And Treatment with Hizentra) study of two doses of maintenance subcutaneous immunoglobulin (SCIG) IgPro20 in CIDP.ResultsAveraged proximal latency substantially increased with placebo (+1.1 ms) indicating electrophysiologic deterioration but remained stable with IgPro20 (0.2 g/kg bodyweight [bw]: +0.1 ms; 0.4 g/kg bw: −0.1 ms). Distal latencies were also more prolonged with placebo versus IgPro20. Averaged motor nerve conduction velocity substantially decreased with placebo (−1.6 m/s) versus increasing in both IgPro20 groups (+0.2 m/s and +1.0 m/s, respectively). Conduction block and CMAP amplitudes did not change substantially.ConclusionThese findings support the effectiveness of maintenance IgPro20, as nerve function changed in the direction of increasing nerve dysfunction with placebo but remained stable with ongoing IgPro20 therapy.SignificanceElectrophysiology testing can support assessment of clinical status in CIDP to determine treatment efficacy.     

Chronic inflammatory demyelinating polyneuropathy in a patient with hyperIgEaemia

We herein report the case of a 46 year old man with chronic inflammatory demyelinating polyneuropathy (CIDP) with hyperIgEaemia. The patient presented with bilateral weakness, generalized hyporeflexia, and mild paresthesia of the fingers of both hands. Nerve conduction studies revealed multiple sites of motor conduction block in the absence of sensory abnormalities. Muscle strength increased, as did compound muscle action potential (CMAP) amplitude immediately after the intravenous infusion of immunoglobulin (IVIg). Serum IgE levels also fluctuated in parallel with his relapsing-remitting clinical course. We propose that pure motor CIDP may be immune mediated and suggest that IgE-mediated allergy may be one potential cause of this condition.     

CD16+CD57- natural killer cells in multifocal motor neuropathy

We analyzed the CD16+CD57- lymphocyte subset, which is considered to have strong natural killer (NK) cell activity, in peripheral blood from patients with chronic immune-mediated neuropathies and patients with other neurological diseases. We found that the ratio of CD16+CD57- NK cells to total lymphocytes was increased in 4 of 6 patients with multifocal motor neuropathy (MMN) with persistent conduction block. Since the CD16 molecule is an Fc receptor for immunoglobulin G (IgG), high-dose intravenous immunoglobulin (IVIg) may interfere with CD16+CD57- NK cells via Fc receptor blockade. In addition, cyclophosphamide (Cy) is often used to suppress NK cells. Therefore, our findings may partly account for the effectiveness of IVIg or Cy, which is the current treatment of choice for MMN.     

Polymorphism of transient axonal glycoprotein-1 in chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by immune-mediated peripheral demyelination. Although corticosteroid, intravenous immunoglobulin (IVIg), and plasma exchange have been established as the most effective therapeutics, sub-populations of patients show little or no response to either of these therapies. We identified the clinical, electrophysiological, and genetic features related to IVIg responsiveness in CIDP by conducting a multi-center study. Muscle atrophy and decreased compound muscle action potential (CMAP) were pronounced in IVIg non-responders, that is, features suggesting axonal dysfunction in peripheral nerves indicated IVIg unresponsiveness in CIDP. We then performed an association analysis using single nucleotide polymorphisms (SNPs) and haplotype studies between the IVIg responders and non-responders. We assessed SNPs of candidate genes that are particularly related to the function of Ranvier's node, paranode, or juxtaparanode. Two separate SNPs, corresponding to transient axonal glycoprotein-1 (TAG-1) and C-type lectin domain family 10, member A (CLEC10A), showed significant differences between responders and non-responders. Haplotype analysis of a series of expanded SNPs, from TAG-1 or CLEC10A, showed that only TAG-1 included a significant haplotype within one linkage disequilibrium block that accommodates IVIg responsiveness. Diplotype analysis of TAG-1 also supported this observation. In conclusion, SNPs in TAG-1, which is a key molecule for axon-Schwann cell interactions and is distributed at the juxtaparanode, are related to the IVIg responsiveness of CIDP patients.