004 Mechanisms of nerve dysfunction in inflammatory neuropathies

2018 ◽  
Vol 89 (6) ◽  
pp. A3.1-A3
Author(s):  
Nidhi Garg ◽  
Susanna B Park ◽  
James Howells ◽  
Con Yiannikas ◽  
Steve Vucic ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Conduction Block ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Treatment Approaches ◽  
Immune Mediated ◽  
Marked Variability ◽  
Nerve Enlargement ◽  
Axonal Excitability

IntroductionImmune-mediated neuropathies are a cause of disability and an immense cost to the healthcare system. They include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and the neuropathy associated with IgM antibodies against myelin-associated glycoprotein (MAG). CIDP is extremely heterogeneous with marked variability in treatment responsiveness. Patients with MMN often respond to treatment but progressive weakness and wasting typically ensues over time. No therapy has consistently proven effective in anti-MAG neuropathy. The present series of studies were undertaken to improve understanding of disease mechanisms in these neuropathies, a critical step before targeted treatment approaches can be developed.MethodsPatients fulfilling Peripheral Nerve Society criteria for CIDP or MMN and patients positive for anti-MAG IgM underwent comprehensive clinical assessments, neurophysiology, serological testing and structural assessments.ResultsThe patient cohort consisted of 80 patients (51 CIDP, 14 MMN, 15 MAG). 6% of CIDP patients tested positive for anti-neurofascin 155 (NF155) and 4% for anti-contactin 1 IgG4. Anti-NF155 neuropathy was characterised by diffuse nerve enlargement and an axonal excitability profile consistent with severe disruption of the paranodal seal. CIDP patients testing negative for IgG4 antibodies also demonstrated significant nerve enlargement compared with healthy subjects. Axonal excitability profiles differed in those with and without median nerve conduction block. MMN was characterised by patchy nerve enlargement, marked increases in super-excitability and enlarged motor unit size. In contrast, anti-MAG neuropathy patients demonstrated a proximal pattern of nerve enlargement and an axonal excitability profile characterised by reduced super-excitability consistent with increased juxta-paranodal fast potassium channel conductance.ConclusionPatterns of nerve enlargement and neurophysiological profiles differ in the immune-mediated neuropathies providing insights into molecular mechanisms. These results provide templates that can guide treatment approaches. The combination of directed autoantibody assays and measures of axonal function can be used to monitor disease progression and therapeutic response.

scholarly journals Treatment Approaches for Atypical CIDP

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepak Menon ◽  
Hans Dieter Katzberg ◽  
Vera Bril
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Immunosuppressive Agents ◽  
Conduction Block ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
First Line ◽  
Treatment Approaches ◽  
First Line Therapy ◽  
Myelin Associated Glycoprotein ◽  
Pure Motor

The variants of chronic inflammatory demyelinating polyneuropathy (CIDP) differ not just in their clinical, pathological and electrophysiological characteristics, but often in their indifferent response to conventional immunosuppressive agents which are effective in typical CIDP. High quality evidence is lacking as far as the management of these atypical variants is concerned. In this review, we summarize the treatment approaches to each of these CIDP variants based on existing data. Distal acquired demyelinating symmetric polyneuropathy (DADS) has the phenotype of a symmetric, demyelinating sensory, length-dependent polyneuropathy and is frequently associated with paraproteinemia and anti myelin associated glycoprotein (MAG) antibodies. While the management of idiopathic DADS (DADS-I) is the same as CIDP, DADS-M responds suboptimally and has a favorable response to rituximab. Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) manifests as a chronic progressive demyelinating mononeuropathy multiplex which can evolve to a confluent pattern indistinguishable from CIDP. Evidence favors treating MADSAM with conventional immunomodulatory therapy (IMT), but this disorder responds less favorably than CIDP. Some patients present with purely sensory symptoms, known as pure sensory CIDP or chronic inflammatory sensory polyradiculoneuropathy (CISP), the latter localizing to a pre-ganglionic pathology. Both respond well to first line IMT, particularly to intravenous immunoglobulin (IVIG), but patients relapse without maintenance therapy. Pure motor CIDP resembles multifocal motor neuropathy with conduction block (MMNCB), but the previously reported worsening status after steroid treatment was not reproduced in recent studies, and IVIG remains the first-line therapy. Some focal forms of CIDP defy exact classification, but respond well to first-line IMT including IVIG. Overall, atypical CIDP responds to treatment with first-line IMT, but has a suboptimal response compared to CIDP. There is evidence for effectiveness with agents such as rituximab, especially in DADS-M, and this medication can also be used in cases refractory to conventional IMTs. Rituximab is also effective in CIDP with IgG4 antibodies which has distinct clinical features and is mostly refractory to first-line IMT.

CIDP and Related Variants and Overlap Disorders

2019 ◽  
pp. 208-244
Author(s):  
Jeffrey A. Allen
Keyword(s):  
Monoclonal Gammopathy ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Clinical Manifestations ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Peripheral Nerve Disorder ◽  
Diagnostic Data ◽  
Immune Mediated ◽  
Inflammatory Demyelinating Polyneuropathy ◽  
History Of

This chapter begins with a history of chronic immunological neuropathies. It then looks in particular at chronic inflammatory demyelinating polyneuropathy (CIDP), which is an immune-mediated peripheral nerve disorder characterized by progressive or relapsing motor or sensory symptoms. It then considers the epidemiology, clinical manifestations, and electrophysiology of CIDP. The chapter examines diagnostic data and diagnostic criteria for CIDP. It then looks at other neuropathies with clinical and electrophysiologic features that are shared with CIDP. Particular attention is given to neuropathy associated with monoclonal gammopathy including IgM associated neuropathy and POEMS syndrome, polyneuropathies associated with specific autoantibodies including antibodies that target nodal and paranodal structures, and multifocal motor neuropathy. For each condition diagnostic data, pathophysiology and treatment are discussed.

Increased IP-10 production by blood–nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy

2018 ◽  
Vol 90 (4) ◽  
pp. 444-450 ◽  
Author(s):  
Fumitaka Shimizu ◽  
Mariko Oishi ◽  
Setsu Sawai ◽  
Minako Beppu ◽  
Sonoko Misawa ◽  
...  
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Conduction Block ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Vascular Endothelial ◽  
Interleukin 7 ◽  
Cytokines And Chemokines ◽  
Electrophysiological Studies ◽  
Endothelial Growth Factor ◽  
Lateral Sclerosis

ObjectiveDysfunction of the blood–nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN.MethodsWe determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system.ResultsThe induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor,vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups.ConclusionThe autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN.

scholarly journals How We Treat Autoimmune Small Fiber Polyneuropathy with Immunoglobulin Therapy

2018 ◽  
Vol 80 (5-6) ◽  
pp. 304-310 ◽  
Author(s):  
Jill R. Schofield ◽  
Kamal R. Chemali
Keyword(s):  
Intravenous Immunoglobulin ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Immunoglobulin Therapy ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Intravenous Immunoglobulin Therapy ◽  
Small Fiber ◽  
Immune Mediated ◽  
Inflammatory Demyelinating Polyneuropathy ◽  
Significant Efficacy

Intravenous immunoglobulin therapy is FDA approved for the immune-mediated peripheral nerve disorders Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. Immunoglobulin therapy has been used increasingly with significant efficacy in the treatment of patients with disabling autoimmune forms of dysautonomia, which are most often small fiber (autonomic and/or sensory) polyneuropathies. It is recognized by most who treat these disorders, however, that patients with autonomic dysfunction treated with intravenous immunoglobulin therapy develop aseptic meningitis or severe lingering headache more frequently than other patient populations when this therapy is dosed in the traditional fashion. We discuss our combined 27 years of experience with the use of immunoglobulin and other immune modulatory therapy in patients with autoimmune small fiber polyneuropathy.

scholarly journals Multifocal motor neuropathy: controversies and priorities

2019 ◽  
Vol 91 (2) ◽  
pp. 140-148 ◽  
Author(s):  
Wei Zhen Yeh ◽  
P James Dyck ◽  
Leonard H van den Berg ◽  
Matthew C Kiernan ◽  
Bruce V Taylor
Keyword(s):  
State Of The Art ◽  
Conduction Block ◽  
Node Of Ranvier ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Therapeutic Approaches ◽  
The Past ◽  
Immune Mediated ◽  
Recent Developments ◽  
Underlying Pathophysiology

Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy.

scholarly journals Motor Nerve Conduction Block Estimation in Demyelinating Neuropathies by Deconvolution

2022 ◽  
Vol 9 (1) ◽  
pp. 23
Author(s):  
Luca Mesin ◽  
Edoardo Lingua ◽  
Dario Cocito
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Motor Nerve ◽  
Conduction Block ◽  
Multifocal Motor Neuropathy ◽  
Motor Unit Potential ◽  
Motor Neuropathy ◽  
Clinical Methods ◽  
Compound Muscle Action Potentials ◽  
Previous State ◽  
Demyelinating Neuropathies

A deconvolution method is proposed for conduction block (CB) estimation based on two compound muscle action potentials (CMAPs) elicited by stimulating a nerve proximal and distal to the region in which the block is suspected. It estimates the time delay distributions by CMAPs deconvolution, from which CB is computed. The slow afterwave (SAW) is included to describe the motor unit potential, as it gives an important contribution in case of the large temporal dispersion (TD) often found in patients. The method is tested on experimental signals obtained from both healthy subjects and pathological patients, with either Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or Multifocal Motor Neuropathy (MMN). The new technique outperforms the clinical methods (based on amplitude and area of CMAPs) and a previous state-of-the-art deconvolution approach. It compensates phase cancellations, allowing to discriminate among CB and TD: estimated by the methods of amplitude, area and deconvolution, CB showed a correlation with TD equal to 39.3%, 29.5% and 8.2%, respectively. Moreover, a significant decrease of percentage reconstruction errors of the CMAPs with respect to the previous deconvolution approach is obtained (from a mean/median of 19.1%/16.7% to 11.7%/11.2%). Therefore, the new method is able to discriminate between CB and TD (overcoming the important limitation of clinical approaches) and can approximate patients’ CMAPs better than the previous deconvolution algorithm. Then, it appears to be promising for the diagnosis of demyelinating polyneuropathies, to be further tested in the future in a prospective clinical trial.

Intravenous immunoglobulin treatment in multifocal motor neuropathy and other chronic immune-mediated neuropathies

1997 ◽  
Vol 3 (2) ◽  
pp. 93-97 ◽  
Author(s):  
G. Comi ◽  
R. Nemni ◽  
S. Amadio ◽  
G. Galardi ◽  
L. Leocani
Keyword(s):  
Plasma Exchange ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Case Series ◽  
Multifocal Motor Neuropathy ◽  
Initial Therapy ◽  
Motor Neuropathy ◽  
Short Term ◽  
Term Efficacy ◽  
Immune Mediated

This review deals with the use of intravenous IVIg immunoglobulines in the treatment of chronic immune-mediated neuropathies: multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, neuropathies associated with monoclonal gammopathies. A particular attention is given to case series and trials which compare IVIg to other therapies, such as steroid treatment, immunosuppressors and plasma exchange. At present, clinical and instrumental data seem to indicate the short term efficacy of IVIg in multifocal motor neuropathies, especially as early treatment; further studies are need in order to prove its long term efficacy in this disease. Concerning chronic inflammatory demyelinating polyneuropathies, short term IVIg efficacy is comparable to that of plasma exchange and in the long term most patients need repeated treatments. Most patients respond to the initial therapy and the initial nonresponders usually improve with a second treatment modality.

Multifocal motor neuropathy

Neurology ◽  
1997 ◽  
Vol 49 (5) ◽  
pp. 1289-1292 ◽  
Author(s):  
Alan Pestronk ◽  
Rati Choksi
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
High Titer ◽  
Conduction Block ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Gm1 Ganglioside ◽  
Immune Disorder ◽  
Elisa Testing ◽  
Lipid Environment ◽  
Guillain Barré

IgM anti-GM1 antibodies occur with increased frequency in the serum of patients with multifocal motor neuropathy (MMN). We tested the ability of serum IgM from patients with MMN to bind to GM1 ganglioside covalently bound to secondary amino groups on ELISA plates (Co-GM1). The Co-GM1 technique detected high titer (>1,800), selective, serum IgM binding to GM1 ganglioside in 85% of our MMN patients (23/27), a significantly greater frequency compared with figures of 37% and 52% found using our previous testing methods. Selective IgM anti-GM1 antibodies showed disease specificity. The only other patients with selective, high-titer IgM anti-GM1 antibodies had either chronic motor neuropathy without conduction block or acute immune neuropathy in China. No patient from the amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré, or systemic immune disorder control groups had selective IgM anti-GM1 antibodies at titers greater than 1,800 detected using Co-GM1 ganglioside as ELISA antigen. Titers of IgM anti-GM1 antibodies in MMN(averaging 31,000 ± 15,000) were more than fourfold higher with Co-GM1 than with previous anti-GM1 assay methods, using conventional ELISA plates with GM-1 antigen alone (7,200 ± 4,400) or in a lipid environment(3,600 ± 1,300). We conclude that using ELISA testing with Co-GM1 antigen, serum anti-GM1 autoantibodies are a useful marker for MMN, because they are present in 85% of MMN patients and, at titers greater than 1,800, have strong specificity for immune-mediated motor neuropathies.

Analysis of anti-ganglioside antibodies by a line immunoassay in patients with chronic-inflammatory demyelinating polyneuropathies (CIDP)

2018 ◽  
Vol 56 (6) ◽  
pp. 919-926 ◽  
Author(s):  
Juliane Klehmet ◽  
Stefanie Märschenz ◽  
Klemens Ruprecht ◽  
Benjamin Wunderlich ◽  
Thomas Büttner ◽  
...  
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Neuromuscular Disorders ◽  
Multifocal Motor Neuropathy ◽  
Demyelinating Polyneuropathy ◽  
Motor Neuropathy ◽  
Immune Mediated ◽  
Younger Age ◽  
Ganglioside Antibodies ◽  
Clinical Variants ◽  
Elevated Frequency

Abstract Background: Unlike for acute immune-mediated neuropathies (IN), anti-ganglioside autoantibody (aGAAb) testing has been recommended for only a minority of chronic IN yet. Thus, we used a multiplex semi-quantitative line immunoassay (LIA) to search for aGAAb in chronic-inflammatory demyelinating polyneuropathy (CIDP) and its clinical variants. Methods: Anti-GAAb to 11 gangliosides and sulfatide (SF) were investigated by LIA in 61 patients with IN (27 typical CIDP, 12 distal-acquired demyelinating polyneuropathy, 6 multifocal-acquired demyelinating sensory/motor polyneuropathy, 10 sensory CIDP, 1 focal CIDP and 5 multifocal-motoric neuropathy), 40 with other neuromuscular disorders (OND) (15 non-immune polyneuropathies, 25 myasthenia gravis), 29 with multiple sclerosis (MS) and 54 healthy controls (HC). Results: In contrast to IgG, positive anti-GAAB IgM against at least one ganglioside/SF was found in 17/61 (27.9%) IN compared to 2/40 (5%) in OND, 2/29 MS (6.9%) and 4/54 (7.4%) in HC (p=0.001). There was a statistically higher prevalence of anti-sulfatide (aSF) IgM in IN compared to OND (p=0.008). Further, aGM1 IgM was more prevalent in IN compared to OND and HC (p=0.009) as well as GD1b in IN compared to HC (p<0.04). The prevalence of aGM1 IgM in CIDP was lower compared to in multifocal motor neuropathy (MMN) (12% vs. 60%, p=0.027). Patients showing aSF, aGM1 and aGM2 IgM were younger compared to aGAAb negatives (p<0.05). Patients with aSF IgM positivity presented more frequently typical CIDP and MMN phenotypes (p<0.05, respectively). Conclusions: The aGAAb LIA revealed an elevated frequency of at least one aGAAb IgM in CIDP/MMN patients. Anti-SF, aGM1 and aGM2 IgM were associated with younger age and anti-SF with IN phenotypes.

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