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.

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 The Potential Misdiagnosis of Multifocal Motor Neuropathy as Amyotrophic Lateral Sclerosis—A Case Series

US Neurology ◽  
2018 ◽  
Vol 14 (2) ◽  
pp. 102 ◽  
Author(s):  
Victoria Lawson ◽  
Nathaniel M Robbins ◽  
◽  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Correct Diagnosis ◽  
Conduction Block ◽  
Case Series ◽  
Multifocal Motor Neuropathy ◽  
Immunoglobulin M ◽  
Motor Neuropathy ◽  
Ganglioside Gm1 ◽  
Neurological Conditions ◽  
Lateral Sclerosis

Multifocal motor neuropathy (MMN) is a rare neuropathy that is often treatable with immunomodulatory therapy if diagnosed early. However, accurate diagnosis is difficult due to a significant overlap of symptoms with other neurological conditions, such as amyotrophic lateral sclerosis (ALS). Evidence of immunoglobulin M (IgM) anti-ganglioside GM1 antibodies and electrodiagnostic findings of conduction block are useful diagnostic criteria for MMN but are not universal findings. This review explores the differential diagnosis of MMN and ALS and discusses three cases of MMN initially diagnosed as ALS, in which the correct diagnosis allowed effective treatment. These cases highlight the need for greater awareness of MMN among physicians.

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.

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.

Amyotrophic lateral sclerosis with sensitive findings

2001 ◽  
Vol 18 (3) ◽  
pp. 320-323
Author(s):  
Osvaldo JM Nascimento ◽  
Marco Orsini ◽  
Camila Pupe ◽  
Giseli Quintanilha ◽  
Mariana Pimentel De Mello ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cervical Spondylosis ◽  
Neurodegenerative Disorder ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Multifocal Motor Neuropathy ◽  
Final Diagnosis ◽  
Motor Neuropathy ◽  
Inflammatory Demyelinating Polyneuropathy ◽  
Lateral Sclerosis ◽  
Chronic Neuropathy

Introduction. Classical amyotrophic lateral sclerosis (ALS) is not hard to diagnose, but when it comes to atypical forms of motor neuron disease (MND) which account for about 20% in clinical setting, we may face some difficulties in differentiating clearly between atypical forms of ALS/MND and other non-ALS diseases, such as multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy and cervical spondylosis. Association between neuropathy and ALS has been reported rarely. Method. We report a patient who presented with clinical/electrophysiological features and investigations suggestive of chronic neuropathy but who later progressed with anterior horn and pyramidal signs and received a final diagnosis of ALS according to the original El Escorial criteria. Conclusion. Our findings support the hypothesis that ALS is a multisystem neurodegenerative disorder that may occasionally include neuropathy among its non-motor features.

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.

scholarly journals Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Philip Van Damme ◽  
Petra Tilkin ◽  
Katarina Jansson Mercer ◽  
Joke Terryn ◽  
Ann D’Hondt ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Amyotrophic Lateral Sclerosis ◽  
Growth Factor ◽  
Study Drug ◽  
Extension Study ◽  
Vascular Endothelial ◽  
Open Label ◽  
Open Label Extension ◽  
Endothelial Growth Factor ◽  
Lateral Sclerosis

Abstract We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.

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