Publications by authors named "Jean-Marc Léger"

73 Publications

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins.

Clin Neurophysiol 2020 04 6;131(4):921-927. Epub 2020 Feb 6.

Referral Centre for Neuromuscular Diseases and ALS, La Timone hospital, Marseille, France; Aix-Marseille University, Timone Neuroscience Institute, UMR CNRS 7289, 13005 Marseille, France. Electronic address:

Objective: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics.

Methods: The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies.

Results: All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%.

Conclusions: Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier.

Significance: Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a "demyelinating" neuropathy.
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http://dx.doi.org/10.1016/j.clinph.2020.01.013DOI Listing
April 2020

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies.

J Peripher Nerv Syst 2019 03 15;24(1):48-55. Epub 2019 Feb 15.

CSL Behring, Marburg, Germany, and King of Prussia, Pennsylvania.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].
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http://dx.doi.org/10.1111/jns.12302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594229PMC
March 2019

IqYmune® is an effective maintenance treatment for multifocal motor neuropathy: A randomised, double-blind, multi-center cross-over non-inferiority study vs Kiovig®-The LIME Study.

J Peripher Nerv Syst 2019 03 11;24(1):56-63. Epub 2018 Dec 11.

Maastricht University Medical Center, Maastricht, The Netherlands.

Intravenous immunoglobulin (IVIg) is the gold-standard for maintenance treatment of multifocal motor neuropathy (MMN). This phase III, randomised, double-blind, multi-centre, active-control, crossover study, aimed to evaluate the non-inferiority of IqYmune® relative to Kiovig®, primarily based on efficacy criteria. Twenty-two adult MMN patients, treated with any brand of IVIg (except Kiovig® or IqYmune®) at a stable maintenance dose within the range of 1 to 2 g/kg every 4 to 8 weeks, were randomised to receive either Kiovig® followed by IqYmune®, or IqYmune® followed by Kiovig®. Each product was administered for 24 weeks. The primary endpoint was the difference between IqYmune® and Kiovig® in mean assessments of modified Medical Research Council (MMRC) 10 sum score (strength of 5 upper-limb and 5 lower-limb muscle groups, on both sides, giving a score from 0 to 100) during the evaluation period (non-inferiority margin of Δ = 2). A linear mixed model analysis demonstrated the non-inferiority of IqYmune® relative to Kiovig®, independently of the covariates (value at baseline, treatment period, and treatment sequence). The estimated "IqYmune® - Kiovig®" difference was -0.01, with a 95% confidence interval (CI) -0.51 to 0.48. The number of adverse reactions (ARs) and the percentage of patients affected were similar for the two products: 39 ARs in 10 patients with IqYmune® vs 32 ARs in 11 patients with Kiovig®. No thromboembolic events nor haemolysis nor renal impairment were observed. In this first clinical trial comparing two IVIg brands for maintenance treatment of MMN, efficacy and tolerability of both brands were similar.
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http://dx.doi.org/10.1111/jns.12291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590491PMC
March 2019

Multifocal motor neuropathy.

Curr Opin Neurol 2018 10;31(5):559-564

National Referral Center for Neuromuscular Diseases, Institut Hospitalo-Universitaire (IHU) de Neurosciences, University Hospital Pitié Salpêtrière, Paris, France.

Purpose Of Review: Multifocal motor neuropathy (MMN) has specific clinical and electrophysiologic features but can be difficult to diagnose if cases are not typical. Intravenous immunoglobulin (IVIg) remains the core initial and long-term treatment. In this review, recent advances in the diagnosis, monitoring and treatment of MMN are discussed.

Recent Findings: The pathology of MMN likely depends on immune-mediated attack of the nodes of Ranvier and paranodal regions leading to conduction block. Antiganglioside antibodies are present in over 50% of patients. The sensitivity of antibody detection can be improved by testing for GM1/galactocerebroside (GM1/GalC) complexes. Complement activation plays a key role in the pathophysiology of MMN. Subcutaneous immunoglobulins are an efficacious alternative to IVIg for maintenance therapy in MMN. Complement inhibitor eculizumab may be a potential future treatment, but further studies are necessary.

Summary: The European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) guidelines for the diagnosis of MMN are currently widely used but probably need revision. Nerve ultrasound and plexus/nerve MRI can be helpful in diagnostic dilemmas. Monitoring of disease and response to treatment may improve using disease-specific evaluation scales such as MMN-Rasch-built overall disability scale. Further research into the pathophysiology of MMN is necessary to direct future treatment strategies.
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http://dx.doi.org/10.1097/WCO.0000000000000605DOI Listing
October 2018

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial.

Lancet Neurol 2018 08 9;17(8):689-698. Epub 2018 Jul 9.

Department of Neurology, Universitätsklinikum Düsseldorf and Center for Neurology and Neuropsychiatry LVR Klinikum, Heinrich-Heine-University, Düsseldorf, Germany.

Background: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids).

Methods: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182.

Findings: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo.

Interpretation: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission.

Funding: Novartis Pharma.
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http://dx.doi.org/10.1016/S1474-4422(18)30202-3DOI Listing
August 2018

N-hexane exposure: a cause of small fiber neuropathy.

J Peripher Nerv Syst 2018 Jun 26;23(2):143-146. Epub 2018 Mar 26.

National Referral Center for Neuromuscular Diseases, Institut Hospitalo-Universitaire (IHU) de Neurosciences, University Hospital Pitié Salpêtrière, Paris, France.

A 59-year-old woman presented with progressive paresthesias of all of her limbs for 4 years, associated with neuropathic pain, tingling in the tongue and allodynia, consistent with small fiber neuropathy (SFN). Several systemic symptoms and signs were found on clinical examination and laboratory work-up. Neurological investigations including neurophysiologic test and skin biopsy supported the diagnosis of SFN. Chronic exposure to N-hexane was then disclosed and suspected to be the cause of the disease. Following the discontinuation of chronic N-hexane exposure, the patient had a progressive improvement of all signs and symptoms, reinforcing the correlation between exposure to N-hexane, and development of SFN. Exposure to N-hexane may be considered as a novel reversible cause of SFN, which underlines the need to look for toxic etiologies in the diagnosis of SFN.
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http://dx.doi.org/10.1111/jns.12261DOI Listing
June 2018

Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.

J Neurol Neurosurg Psychiatry 2018 05 25;89(5):499-505. Epub 2017 Oct 25.

Department of Neurology, University Hospital Saint-Etienne, Saint-Etienne, France.

Objective: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres.

Methods: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres.

Results: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU.

Conclusion: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.
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http://dx.doi.org/10.1136/jnnp-2017-316715DOI Listing
May 2018

Muscle, neuromuscular junction and peripheral nerve diseases.

Authors:
Jean-Marc Léger

Curr Opin Neurol 2017 10;30(5):447-448

National Referral Center for Rare Neuromuscular Diseases, Hospital Pitié-Salpêtrière, University Pierre et Marie Curie (Paris VI), Paris, France.

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http://dx.doi.org/10.1097/WCO.0000000000000485DOI Listing
October 2017

Editorial: introducing the new Co-Editors-in-Chief of Current Opinion in Neurology.

Curr Opin Neurol 2017 06;30(3):207

aCenter for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA bCentre National de Référence Maladies Neuromusculaires, Institut Hospitalo-Universitaire de Neurosciences, CHU Pitié-Salpêtrière and University Pierre et Marie Curie (Paris VI), Paris, France.

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http://dx.doi.org/10.1097/WCO.0000000000000459DOI Listing
June 2017

[Guillain-Barré syndrome: current and future options for treatment].

Rev Prat 2017 02;67(2):123-125

Centre de référence Maladies neuromusculaires rares Paris-Est, IHU de neurosciences, CHU La Pitié-Salpêtrière et université Pierre-et-Marie-Curie (Paris-VI), Paris, France.

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February 2017

Too Often Forgotten: Passive Transfer of Antibodies.

Clin Infect Dis 2016 09 20;63(5):709-10. Epub 2016 May 20.

Department of Pharmacy, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, AP-HP, Paris, France.

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http://dx.doi.org/10.1093/cid/ciw337DOI Listing
September 2016

[Beware of immunoglobulin's passive transfer when interpreting serological analyses!].

Presse Med 2016 Jul-Aug;45(7-8 Pt 1):676-81. Epub 2016 Apr 28.

CHU de Rennes, laboratoire de virologie, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9 France. Electronic address:

Due to their extended indications, intravenous immunoglobulins (IVIg) are increasingly used in hospital setting. After injection, classical IVIg half-life reaches more than 3weeks. IVIg result from the pooling of many blood donations and contain all natural antibodies usually found in the general population. Administered antibodies are known to interfere with many diagnostic assays, particularly those used for infectious serology. It is not recommended to perform serological determination after IVIg infusion. It is recommended to keep a delay of at least 4months after IVIg infusion before doing any serological assay; failure to do so will result in misinterpretation of biological findings. Interpretation of any serological test after IVIg administration should be particularly cautious.
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http://dx.doi.org/10.1016/j.lpm.2016.03.009DOI Listing
February 2017

Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study.

J Peripher Nerv Syst 2016 Mar;21(1):10-4

Department of Neurology, National Referral Center for Rare Neuromuscular Diseases, University Hospital Pitié-Salpêtrière and University Paris VI, Paris, France.

The Rituximab vs. Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study showed no improvement using the inflammatory neuropathy cause and treatment sensory score (ISS) as primary outcome in patients with IgM anti-myelin-associated glycoprotein neuropathy (IgM anti-MAG neuropathy) treated with rituximab, when compared with placebo. However, some secondary outcomes seemed to improve in the per protocol analysis. Patients from one participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (interquartile range (IQR) 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in seven rituximab patients (group 1) and in eight placebo patients (group 2). In group 2, six of eight patients received immunotherapy during follow-up, while only two of seven did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. This study stresses the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy.
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http://dx.doi.org/10.1111/jns.12156DOI Listing
March 2016

Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study.

J Peripher Nerv Syst 2016 Mar;21(1):10-4

Department of Neurology, National Referral Center for Rare Neuromuscular Diseases, University Hospital Pitié-Salpêtrière and University Paris VI, Paris, France.

The Rituximab vs. Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study showed no improvement using the inflammatory neuropathy cause and treatment sensory score (ISS) as primary outcome in patients with IgM anti-myelin-associated glycoprotein neuropathy (IgM anti-MAG neuropathy) treated with rituximab, when compared with placebo. However, some secondary outcomes seemed to improve in the per protocol analysis. Patients from one participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (interquartile range (IQR) 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in seven rituximab patients (group 1) and in eight placebo patients (group 2). In group 2, six of eight patients received immunotherapy during follow-up, while only two of seven did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. This study stresses the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy.
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http://dx.doi.org/10.1111/jns.12156DOI Listing
March 2016

Immunotherapy in Peripheral Neuropathies.

Neurotherapeutics 2016 Jan;13(1):96-107

National Referral Center for Rare Neuromuscular Diseases, Institut Hospitalo-Universitaire de Neurosciences, University Hospital Pitié-Salpêtrière and University Pierre et Marie Curie (Paris VI), Paris, France.

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.
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http://dx.doi.org/10.1007/s13311-015-0401-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720673PMC
January 2016

Amyotrophic lateral sclerosis, channelopathies and peripheral neuropathies: current status and new perspectives.

Authors:
Jean-Marc Léger

Curr Opin Neurol 2015 Oct;28(5):453-4

National Referral Center for Rare Neuromuscular Diseases, Hospital Pitié-Salpêtrière and University Pierre et Marie Curie (Paris VI), Paris, France.

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http://dx.doi.org/10.1097/WCO.0000000000000247DOI Listing
October 2015

Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature.

J Autoimmun 2015 Dec 29;65:74-81. Epub 2015 Aug 29.

Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France. Electronic address:

In patients with infectious cryoglobulinemia vasculitis (CryoVas) in the absence of hepatitis C virus infection, data on presentation, therapeutic management and outcome are lacking. We conducted a nationwide survey that included patients with HCV-negative CryoVas. We describe here the presentation, therapeutic management and outcome of 18 patients with non-HCV infectious CryoVas and 27 additional patients identified form a systematic review of the literature. We included 18 patients, mean age 57.9±13.5 years. Infectious causes were viral infections in 8 patients [hepatitis B virus (HBV) in 4, and cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each], pyogenic bacterial infection in 6 patients, parasitic infection in 2 patients, and leprosy and candidiasis in one case each. Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. Most cases received specific anti-infectious therapy as first-line therapy, sometimes associated with corticosteroids, achieving sustained remission in the majority of cases. Refractory or relapsing patients, frequently related to HBV infection, showed a complete remission after rituximab in addition to antiviral therapy. In contrast, corticosteroids and/or immunosuppressive agents used in the absence of anti-infectious agents were frequently associated with refractory CryoVas. Viral and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas. Antimicrobial therapy is commonly associated with sustained remission. Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.
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http://dx.doi.org/10.1016/j.jaut.2015.08.008DOI Listing
December 2015

Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN.

J Am Soc Nephrol 2016 Apr 10;27(4):1213-24. Epub 2015 Aug 10.

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 1155, Paris, France; Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Tenon Hospital, Paris, France; Sorbonne Universités, Tenon Hospital, Paris, France

Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m(2) Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m(2)with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death.
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http://dx.doi.org/10.1681/ASN.2015020114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814186PMC
April 2016

Long-term outcome of infliximab in severe chronic and refractory systemic sarcoidosis: a report of 16 cases.

Clin Exp Rheumatol 2015 Jul-Aug;33(4):509-15. Epub 2015 Jun 29.

1.Sorbonne Universités, UPMC Univ Paris, UMR7211 & Inflammation-Immunopathology-Biotherapy Dept. (DHU i2B); 2.INSERM, UMR_S959, Paris; 3.CNRS, FRE3632, Paris; 4.APHP, Groupe Hosp. Pitié Salpétrière, Dept. Internal Medicine & Clin.Immunol, Paris, France.

Objectives: Infliximab (IFX) appears to be effective in refractory sarcoidosis. However, data are lacking regarding its efficacy in severe sarcoidosis (i.e. with cardiac and/or neurological involvement).

Methods: Retrospective single-centre study including 16 unselected consecutive patients with biopsy proven, severe, and resistant sarcoidosis, who were treated by infliximab (3 or 5 mg /kg at 0, 2 and 6 weeks, then every 8 weeks) between 2005 and 2013.

Results: Following IFX therapy we observed an improvement in 92% of cases, with a marked decrease of the severity score [median score 6 (3-12) vs. 2 (1-8), p<0.0001] and trend toward steroid sparing effect [12.5 (0-40) vs. 8.5 mg/d (0-30), p=0.11] between baseline and the end of follow-up, respectively. Regarding the index organ response, we observed a remission of cardiac and central nervous system involvements in 4 out of 4 and 11 out 12 cases, respectively. Thirty-eight percent of patients experienced a relapse. After a median follow-up of 57 months (2 to 91), we observed 7 (44%) infectious complications, 1 paradoxical cutaneous granuloma and 1 leucoencephalopathy. Infectious complications were mostly observed in male [6/7 (86%), p=0.06], with a longer duration of steroids (108 vs. 39 months, p=0.11) and immunosuppressant use prior IFX (42 vs. 24 months, p=0.08) compared to their negative counterpart, respectively.

Conclusions: IFX was efficient in severe and refractory sarcoidosis. Infectious complications were frequent and occurred mainly in male patients with longer duration of steroids and immunosuppressant use prior to IFX.
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October 2015

Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.

J Peripher Nerv Syst 2015 Sep;20(3):269-76

Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar [Right/Left hands]: ICC 0.997/0.96; Vigori: ICC 0.95/0.98). Meaningful changes were comparable between the two instruments, being higher in GBS compared to CIDP patients. In MGUSP/MMN poor responsiveness was seen. Significant more patients preferred the Vigorimeter. In conclusion, validity, reliability, and responsiveness aspects were comparable between the Jamar dynamometer and Vigorimeter. However, based on patients' preference, the Vigorimeter is recommended in future studies in immune-mediated neuropathies.
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http://dx.doi.org/10.1111/jns.12126DOI Listing
September 2015

Outcome measures in MMN revisited: further improvement needed.

J Peripher Nerv Syst 2015 Sep;20(3):306-18

Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

The objectives of this study were to provide an overview of the outcome measures (OMs) applied in clinical trials in multifocal motor neuropathy (MMN) and to determine the responsiveness of a core set of selected OMs as part of the peripheral neuropathy outcome measures standardization (PeriNomS) study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous immunoglobulin (assessments: T0/T3/T12 months): 14 muscle pairs MRC (Medical Research Council) scale, the Neuropathy Impairment Scale motor-subset, a self-evaluation scale, grip strength, and MMN-RODS© (Rasch-built overall disability scale). All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (½ × SD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both the identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual SE (responder definition: MCID-SE ≥ 1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in one fourth to one third of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MMN.
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http://dx.doi.org/10.1111/jns.12124DOI Listing
September 2015

Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.

J Peripher Nerv Syst 2015 Sep;20(3):289-95

Department of Neurology, University Medical Centre Maastricht, Maastricht, The Netherlands.

This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.
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http://dx.doi.org/10.1111/jns.12118DOI Listing
September 2015

Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.

J Peripher Nerv Syst 2015 Sep;20(3):277-88

Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.
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http://dx.doi.org/10.1111/jns.12127DOI Listing
September 2015

The pathogenesis of multifocal motor neuropathy and an update on current management options.

Ther Adv Neurol Disord 2015 May;8(3):109-22

National Referral Center for rare Neuromuscular Diseases, Institut Hospitalo-Universitaire de Neurosciences, University Hospital Pitié-Salpêtrière and University Pierre et Marie Curie (Paris VI), Paris, France.

Multifocal motor neuropathy (MMN) is a rare and disabling disease. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis, although underlying mechanisms in MMN seem to be very specific, mainly because of the presence of IgM anti-GM1 serum antibodies and the dramatic response to intravenous immunoglobulins (IVIg). The origin of antiganglioside antibodies and the way in which they act at the molecular level remain unclear. Several studies have demonstrated the key role of complement activation in the underlying mechanisms of MMN, as well as in animal models of acute motor axonal neuropathy (AMAN). Deposition of the membrane attack complex may disrupt the architecture of the nodes of Ranvier and paranodal areas, causing local disruption of nodal sodium-channel clusters. In patients with MMN, muscle weakness is the consequence of conduction blocks (CB), which leads to secondary axonal degeneration, consequently the aim of the treatment is to reverse CB at early stages of the disease. High-dose immunoglobulin is to date the only therapy which has proven efficacy in MMN patients in providing transient improvement of muscle strength, but long-term follow-up studies show a progressive motor decline. Therefore, other therapies are needed to improve the conduction nerve properties in long-term design. The reduction of complement activation and more generally the gain in paranodal stabilization could be directions for future therapeutic strategies.
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http://dx.doi.org/10.1177/1756285615575269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409549PMC
May 2015

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

Cochrane Database Syst Rev 2015 Mar 4(3):CD003217. Epub 2015 Mar 4.

Department of Neurology, National Neuroscience Institute, 11 Jalan Tan, Tock Seng, Singapore, Singapore, 308433.

Background: Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin (IVIg) is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005, 2008 and 2011.

Objectives: To assess the effects of immunosuppressive agents for the treatment of multifocal motor neuropathy.

Search Methods: On 22 September 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE and LILACS for trials of MMN. We also searched two trials registers for ongoing studies.

Selection Criteria: We planned to include randomised controlled trials (RCTs) and quasi-RCTs. We considered prospective and retrospective case series and case reports in the Discussion.

Data Collection And Analysis: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently.

Main Results: Only one RCT of an immunosuppressive or immunomodulatory agent has been performed in MMN. This study randomised 28 participants and showed that mycophenolate mofetil, when used with IVIg, did not significantly improve strength, function or reduce the need for IVIg. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion.

Authors' Conclusions: According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for IVIg or improving muscle strength in MMN. Trials of other immunosuppressants should be undertaken.
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http://dx.doi.org/10.1002/14651858.CD003217.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781840PMC
March 2015

Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness.

Neurology 2014 Dec 5;83(23):2124-32. Epub 2014 Nov 5.

From the Department of Neurology (T.H.P.D., E.K.V., C.G.F., I.S.J.M.), University Medical Centre Maastricht; Department of Neurology (S.I.v.N., P.A.v.D.), Erasmus Medical Centre Rotterdam, the Netherlands; Department of Neurology (K.C.G.), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA; Department of Neurology (W.L.V.d.P., N.C.N., L.H.v.d.B.), Rudolf Magnus Institute of Neuroscience University Medical Centre Utrecht, the Netherlands; Department of Neurological Sciences (E.N.-O.), Milan University, Humanitas Clinical Institute, Rozzano, Milan, Italy; Department of Neurology (J.M.L.), Hôpital de la Salpêtrière, Paris, France; Department of Neurology (P.Y.K.V.d.B.), Catholique University of Louvain, Belgium; Department of Clinical Neurosciences (G.L.), 3rd Neurology Unit, Milan, Italy; Department of Neurology (V.B., H.K.), Toronto General Hospital, Canada; Department of Neurology (M.P.T.L.), Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Neurology (J.P.), Centre de Référence des Maladies Neuromusculaires et de la SLA, Hôpital de La Timone, Marseille, France; Department of Neurology (A.J.v.d.K.), Academic Medical Centre, Amsterdam, the Netherlands; Department of Neurology (A.F.H.), London Health Science Center, London, Canada; Department of Neurology (D.R.C.), Johns Hopkins School of Medicine, Baltimore, MD; and Department of Neurology (I.S.J.M.), Spaarne Hospital, Hoofddorp, the Netherlands.

Objectives: We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP).

Methods: One hundred thirty-seven patients (GBS: 55, CIDP: 59, IgM-MGUSP: 23) with a new diagnosis or clinical relapse assessed both scales. Patients with GBS/CIDP were examined at 0, 1, 3, 6, and 12 months; patients with IgM-MGUSP at 0, 3, and 12. We subjected all data to Rasch analyses, and calculated for each patient the magnitude of change on both scales using the minimal clinically important difference (MCID) related to the individual standard errors (SEs). A responder was defined as having an MCID-SE ≥1.96. Individual scores on both measures were correlated with the EuroQoL thermometer (heuristic responsiveness).

Results: The I-RODS showed a significantly higher proportion of meaningful improvement compared with the INCAT-ONLS findings in GBS/CIDP. For IgM-MGUSP, the lack of responsiveness during the 1-year study did not allow a clear separation. Heuristic responsiveness was consistently higher with the I-RODS.

Conclusion: The I-RODS more often captures clinically meaningful changes over time, with a greater magnitude of change, compared with the INCAT-ONLS disability scale in patients with GBS and CIDP. The I-RODS offers promise for being a more sensitive measure and its use is therefore suggested in future trials involving patients with GBS and CIDP.
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http://dx.doi.org/10.1212/WNL.0000000000001044DOI Listing
December 2014

[Amyotrophic lateral sclerosis: new concept and strategies for a heteregeneous entity].

Presse Med 2014 May;43(5):536-7

Centre national de référence maladies neuromusculaires rares, IHU de neurosciences, CHU Pitié-Salpêtrière et université Pierre-et-Marie-Curie, 75005 Paris, France.

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http://dx.doi.org/10.1016/j.lpm.2014.04.004DOI Listing
May 2014

Predictors of early relapse in patients with non-infectious mixed cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey.

Autoimmun Rev 2014 Jun 10;13(6):630-4. Epub 2014 Jan 10.

Department of Internal Medicine, Reference Center for Autoimmune Diseases, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris 6, UMR 7211, F-75005 Paris, France; INSERM, UMR S 959, F-75013 Paris, France; CNRS, UMR 7211, F-75005 Paris, France; Departement Hospitalo-Universitaire I2B, Univ Paris 06, UMR 7211, F-75005, Paris, France; AP-HP, Groupe Hoitalier Pitié-Salpérière, Departement of Internal Médicine, 75013, Paris, France. Electronic address:

Objective: Although in most patients induction therapy leads to complete or partial remission, relapses in patients with non-infectious mixed cryoglobulinemia vasculitis (CryoVas) remain a major problem. We aimed to identify predictors of early relapses occurring within the first 12months of treatment in such patients.

Methods: Patients included in the French CryoVas survey exhibiting complete/partial clinical remission and followed-up for at least 12months after induction therapy (n=145) were analyzed for predictors of early relapses.

Results: Forty out of 145 patients (28%) experienced early relapse. Relapses occurred after a median time of 9.5months after induction therapy (3-12) and involved skin (75%), joints and peripheral nerve (28% each), kidneys (25%) and gastrointestinal tract (5%). Baseline factors associated with an early relapse were purpura [HR 3.35 (1.02-10.97), P=0.046], cutaneous necrosis [HR 4.46 (1.58-12.57), P=0.005] and articular involvement [HR 2.20 (1.00-4.78), P=0.048]. The only factor negatively associated with an early relapse during follow-up was the achievement of complete immunological response [HR 0.07 (0.01-0.51), P=0.009]. The use of corticosteroids plus rituximab or cyclophosphamide tended to be associated negatively with early relapse [HR 0.43 (0.17-1.08), P=0.07].

Conclusion: In patients with non-infectious CryoVas, main predictors of early relapses after initial remission are purpura, articular involvement, and cutaneous necrosis. The absence of complete immunological response during follow-up was associated with early relapse. These findings may help in adapting future treatment strategies.
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http://dx.doi.org/10.1016/j.autrev.2013.11.006DOI Listing
June 2014