Publications by authors named "Michel Clanet"

49 Publications

Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment.

Lancet Oncol 2021 Oct;22(10):e430-e434

Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France. Electronic address:

During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.
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http://dx.doi.org/10.1016/S1470-2045(21)00337-5DOI Listing
October 2021

Association of Central Hypersomnia and Fatigue in Patients With Multiple Sclerosis: A Polysomnographic Study.

Neurology 2021 07 30;97(1):e23-e33. Epub 2021 Apr 30.

From the Neurology Department (A.-L.D., B.S.), Saint Antoine Hospital, AP-HP; Sleep Disorders Unit and National Reference Center for Narcolepsy and Hypersomnia (A.-L.D., I.A.), Department of Biostatistics (S.T.d.M.), and Neurology Department (R.A., C.P., C.L.), Pitié-Salpêtrière University Hospital, APHP, Paris; Neurology Department (F.V., M.C.) and Neurophysiology Department (M.T.), Purpan Hospital, Toulouse; and Institut du Cerveau et de la Moelle Épinière (C.L., I.A., B.S.), Sorbonne Université, Hôpital de la Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, Paris, France.

Objective: To evaluate sleepiness and central hypersomnia in multiple sclerosis (MS)-associated fatigue, we performed long-term polysomnography in patients with MS and healthy controls.

Methods: Patients with MS and healthy controls completed questionnaires on sleep, fatigue, sleepiness, and depression. They underwent nocturnal polysomnography, multiple sleep latency tests, and bed rest 24-hour polysomnography. Patients were divided into 3 groups (fatigue and sleepiness, fatigue and no sleepiness, neither fatigue nor sleepiness).

Results: Among 44 patients with MS, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness. Compared to 24 controls, patients with fatigue and sleepiness had higher REM sleep percentages (median [interquartile range] 20.5% [19.6-24.7] vs 18.1% [12.6-20.6]), lower arousal indexes (12.7 [7.5-17.0] vs 22.4 [14.3-34.4]), and shorter daytime mean sleep latencies (8.6 [6.3-14.3] vs 16.6 [12.6-19.5] min). Restless leg syndrome, periodic leg movements, and sleep apnea had similar frequencies between groups. Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness (narcolepsy type 2, n = 2), in 2 (13%) patients with fatigue only, and in 3 (30%) patients with neither fatigue nor sleepiness. Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but had similar levels of fatigue, disability, depression, cognitive performance, and frequencies of the human leukocyte antigen DQB1*0602 genotype. The severity of fatigue increased with higher depression scores, higher sleepiness severity, and lower sleep efficacy.

Conclusion: Central hypersomnias are frequent in MS when fatigue and sleepiness are present. Screening them through polysomnography studies is recommended.
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http://dx.doi.org/10.1212/WNL.0000000000012120DOI Listing
July 2021

MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis.

Trials 2019 May 9;20(1):263. Epub 2019 May 9.

Department of Medicine (Neurology), University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.

Methods/design: This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.

Discussion: Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.

Trial Registration: Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.
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http://dx.doi.org/10.1186/s13063-019-3346-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507027PMC
May 2019

Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype.

Brain 2019 06;142(6):1573-1586

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21-62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.
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http://dx.doi.org/10.1093/brain/awz095DOI Listing
June 2019

Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France.

Mult Scler 2020 01 13;26(1):118-122. Epub 2018 Dec 13.

Department of Neurology, CHU de Toulouse, Toulouse, France.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.
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http://dx.doi.org/10.1177/1352458518815602DOI Listing
January 2020

Cervical dysplasia in a patient with multiple sclerosis treated with natalizumab.

Fundam Clin Pharmacol 2019 Feb 12;33(1):125-126. Epub 2018 Jul 12.

Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Pharmacopôle Midi-Pyrénées, INSERM, UMR 1027, CIC INSERM 1436, Toulouse, France.

We describe one report of a cervical dysplasia in a patient receiving natalizumab for multiple sclerosis. Other cases were identified in the WHO's global individual case safety report database, VigiBase . These data underline the importance of monitoring HPV infection in patients with MS treated with natalizumab.
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http://dx.doi.org/10.1111/fcp.12394DOI Listing
February 2019

Late-onset neutropenia and neurological relapse, during long-term rituximab therapy in myelin oligodendrocyte glycoprotein-antibody spectrum disorder.

Mult Scler 2018 10 9;24(12):1645-1647. Epub 2018 May 9.

Pole des Neurosciences, Unité de neurologie, Hôpital Pierre-Paul Riquet, CHU Purpan, Toulouse, France; INSERM UMR 1043, Université Toulouse III, Toulouse, France.

Late-onset neutropenia after rituximab therapy (LONART) is defined as a fall in the absolute neutrophil count below 500/mm at least 3 weeks after rituximab infusion, in the absence of any other explanation. LONART is rare during dysimmune conditions but can be life-threatening. We report on two patients with LONART and associated neurological relapse occurring in myelin oligodendrocyte glycoprotein (MOG)-antibody spectrum disorders. Rituximab was reintroduced in one patient, while the second patient was switched to tocilizumab. LONART can occur during anti-MOG spectrum disorders. Neurologists should be aware of this rare and treatable complication. Regular monitoring of blood cell counts is needed, and patients should be informed of the need to consult their physician if symptoms of infection appear.
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http://dx.doi.org/10.1177/1352458518765677DOI Listing
October 2018

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis.

Mult Scler 2018 02 20;24(2):96-120. Epub 2018 Jan 20.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions.

Objectives: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS.

Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.

Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus.

Conclusion: The present guideline will enable homogeneity of treatment decisions across Europe.
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http://dx.doi.org/10.1177/1352458517751049DOI Listing
February 2018

[Towards a national strategy on the diagnosis of neurocognitive disorders. A shared approach among the French National College of General Practitioners and specialists of neurocognitive disorders].

Presse Med 2018 Jan 26;47(1):75-83. Epub 2017 Dec 26.

Collège de médecine générale, 92200 Neuilly-Sur-Seine, France.

Neurocognitive disorders leading to progressive cognitive, functional and behavioural impairment are often undiagnosed or diagnosed lately. But tailored care and therapeutics help in implementing secondary and tertiary prevention dynamics aiming at preserving quality of life and delaying, anticipating or preventing behavioural crisis and severe stages of dementia. Moreover, the diagnosis of numerous diseases induces specific care and therapeutics, as well access to research and clinical trials. For the first time, the representatives of the National College of General Practitioners, the French Federation of Memory Centres, the French Federation of Gerontology and Geriatrics, the French Federation of Neurology, the French Society of Psychogeriatrics and the national plan on neurodegenerative diseases propose a graduated and tailored diagnosis strategy involving primary care and specialists of neurocognitive disorders. This strategy has been built in the context of the national plan on neurodegenerative diseases, the European Joint Action "Act on dementia", and has been consensually agreed after a seminar animated by the National College of General Practitioners in March 2017.
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http://dx.doi.org/10.1016/j.lpm.2017.10.029DOI Listing
January 2018

Geographical Heterogeneity of Multiple Sclerosis Prevalence in France.

PLoS One 2016 9;11(12):e0167556. Epub 2016 Dec 9.

Clinical and Evaluation department, Nancy University Hospital, Vandoeuvre-les-Nancy, France.

Introduction: Geographical variation in the prevalence of multiple sclerosis (MS) is controversial. Heterogeneity is important to acknowledge to adapt the provision of care within the healthcare system. We aimed to investigate differences in prevalence of MS in departments in the French territory.

Methods: We estimated MS prevalence on October 31, 2004 in 21 administrative departments in France (22% of the metropolitan departments) by using multiple data sources: the main French health insurance systems, neurologist networks devoted to MS and the Technical Information Agency of Hospitalization. We used a spatial Bayesian approach based on estimating the number of MS cases from 2005 and 2008 capture-recapture studies to analyze differences in prevalence.

Results: The age- and sex-standardized prevalence of MS per 100,000 inhabitants ranged from 68.1 (95% credible interval 54.6, 84.4) in Hautes-Pyrénées (southwest France) to 296.5 (258.8, 338.9) in Moselle (northeast France). The greatest prevalence was in the northeast departments, and the other departments showed great variability.

Discussion: By combining multiple data sources into a spatial Bayesian model, we found heterogeneity in MS prevalence among the 21 departments of France, some with higher prevalence than anticipated from previous publications. No clear explanation related to health insurance coverage and hospital facilities can be advanced. Population migration, socioeconomic status of the population studied and environmental effects are suspected.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167556PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147922PMC
July 2017

Risk of relapse after natalizumab withdrawal: Results from the French TYSEDMUS cohort.

Neurol Neuroimmunol Neuroinflamm 2016 Dec 28;3(6):e297. Epub 2016 Oct 28.

Neurology Department (C.P., S.M., C.L.), Pitié-Salpêtrière Hospital, Paris; Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer (S.V., C.C.), and Neuro-epidemiology and Pharmaco-epidemiology (E.V.G.), Hospices Civils de Lyon, Lyon/Bron; Centre des Neurosciences de Lyon (S.V., C.C.), INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et Neuro-inflammation; Université de Lyon (S.V., C.C.); Observatoire Français de la Sclérose en Plaques (R.C., N.D., Z.U.), Bron; Neurology Department (B.S.), Saint Antoine Hospital, Paris; Agence Nationale de Sécurité des Médicaments (ANSM, formerly Agence Française de Sécurité Sanitaire des Produits de Santé-AFSSAPS) (A.C.), Saint-Denis; and Neurology Department (M.C.), Purpan Hospital, Toulouse, France.

Objective: To assess disease activity within 12 months after natalizumab (NZ) discontinuation in a large French postmarketing cohort.

Methods: In France, patients exposed at least once to NZ were included in the TYSEDMUS observational and multicenter cohort, part of the French NZ Risk Management Plan. Clinical disease activity during the year following NZ discontinuation was assessed in this cohort. Time to first relapse after NZ stop was analyzed using Kaplan-Meier method and potentially associated factors were studied using a multivariate Cox model.

Results: Out of the 4,055 patients with multiple sclerosis (MS) included in TYSEDMUS, 1,253 discontinued NZ and 715 of them had relevant data for our study. The probability of relapse within the year after NZ stop was estimated at 45% (95% confidence interval 0.41-0.49).

Conclusions: This large and systematic survey of patients with MS after NZ withdrawal allows quantifying the risk of increased disease activity following treatment discontinuation. This study provides large-scale, multicenter, systematic data after NZ cessation in real-life settings.
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http://dx.doi.org/10.1212/NXI.0000000000000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087255PMC
December 2016

Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients.

Neurology 2016 Nov 12;87(19):1985-1992. Epub 2016 Oct 12.

From Queen Mary University of London (G.G.), Barts and The London School of Medicine, UK; Mellen Center (J.A.C.), Cleveland Clinic, OH; Department of Clinical Neurosciences (A.J.C., D.A.S.C.), University of Cambridge, UK; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology and Center for Clinical Neuroscience (E.H.), First Medical Faculty, Charles University in Prague, Czech Republic; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; Sanofi Genzyme (D.H.M., S.L.L., M.A.P.), Cambridge, MA; and Evidence Scientific Solutions (S.M.K.), Philadelphia, PA (at the time the work was conducted).

Objective: To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.

Methods: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.

Results: Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.

Conclusions: In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.

Classification Of Evidence: This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
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http://dx.doi.org/10.1212/WNL.0000000000003319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109953PMC
November 2016

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

Mult Scler 2016 11 1;22(13):1719-1731. Epub 2016 Sep 1.

APHM, Hôpital de la Timone, CNRS, CRMBM UMR 7339, CNRS, Department of Neurology and Aix-Marseille Université, Marseille, France.

Background: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.

Objective: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.

Methods: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits.

Results: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo.

Conclusion: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.
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http://dx.doi.org/10.1177/1352458516667568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098693PMC
November 2016

Assessment of a program to encourage the multidisciplinary management of urinary disorders in multiple sclerosis.

Neurourol Urodyn 2017 03 29;36(3):706-709. Epub 2016 Mar 29.

Service de médecine physique et réadaptation, CHU Toulouse, France.

Aims: Urinary disorders (UD) secondary to multiple sclerosis (MS) are common and can be responsible for complications. Since 2004, we organized in our region their management through a neuro-urological activity and a care network that established and distributed an algorithm for screening and first line care. The objective was to assess the effects of this organization on the management of UD and its impact for patients.

Methods: Between January 2004 and December 2009, 328 patients were seen in neuro-urological consultation. The data of a group of 168 patients consulting during the deployment of our organization (before January 2007: group 1) were compared to those of 160 patients taken when the organization was well established (from January 2007: group 2). In parallel, the modification of the prescription rate of the first-line examination patients was evaluated.

Results: The two groups were significantly different concerning age, duration of MS, EDSS score (Group 1 vs. Group 2 respectively 51.6 ± 12.6 vs. 48 ± 11.8 years, P = 0.008; 19 ± 9.7 vs. 13.8 ± 10.5 years, P < 0.0001; 5.8 ±2.0 vs. 5.1 ± 2.1, P = 0.008). The occurrence of urinary complications in group 1 was more frequent than in group 2 (66.3% vs. 40%, P < 0.0001). The rate of first-line examinations rose from 1/16 patient seen in January 2006 to 9/12 patients in January 2008.

Conclusion: The multidisciplinary management of UD in MS led to patients being cared for sooner in the evolution of MS, with fewer complications and to an improvement in the rate of prescription of first-line examinations. Neurourol. Urodynam. 36:706-709, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/nau.23002DOI Listing
March 2017

Excess Mortality in Patients with Multiple Sclerosis Starts at 20 Years from Clinical Onset: Data from a Large-Scale French Observational Study.

PLoS One 2015 6;10(7):e0132033. Epub 2015 Jul 6.

Department of Neurology, CHU Rennes, WEst Neuroscience Network of Excellence (WENNE), Rennes, France.

Background: Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France.

Objectives: Estimate survival in MS patients and compare mortality with that of the French general population.

Methods: We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration.

Results: After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients (F/M sex ratio 2.5, mean age at onset 33.0 years, 85.5% relapsing onset). During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate (Standardized Mortality Ratio 1.48, 95% confidence interval [1.41-1.55]), but increased considerably after 20 years of disease (2.20 [2.10-2.31]).

Conclusions: This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492994PMC
April 2016

Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

Brain 2015 Feb 19;138(Pt 2):284-92. Epub 2014 Dec 19.

16 Département de Neurologie, CHU de Bordeaux, 33076 Bordeaux, France.

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.
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http://dx.doi.org/10.1093/brain/awu353DOI Listing
February 2015

Fingolimod treatment after natalizumab-related progressive multifocal leukoencephalopathy: three new cases.

Mult Scler 2015 Apr 10;21(5):671-2. Epub 2014 Oct 10.

Pole des neurosciences CHU Toulouse, France INSERM UMR 1043 et Université de Toulouse; UPS; France

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http://dx.doi.org/10.1177/1352458514549823DOI Listing
April 2015

A central nervous system B-cell lymphoma arising two years after initial diagnosis of CLIPPERS.

J Neurol Sci 2014 Sep 18;344(1-2):224-6. Epub 2014 Jun 18.

Pole des Neurosciences and INSERM UMR1043, Université Toulouse III, CHU Toulouse, Hôpital Purpan, Place du Docteur Baylac, 31059 Toulouse cedex 9, France.

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http://dx.doi.org/10.1016/j.jns.2014.06.015DOI Listing
September 2014

Defining the clinical course of multiple sclerosis: the 2013 revisions.

Neurology 2014 Jul 28;83(3):278-86. Epub 2014 May 28.

From the Corinne Goldsmith Dickenson Center for Multiple Sclerosis (F.D.L., A.E.M.), Icahn School of Medicine at Mount Sinai, New York, NY; Scientific and Clinical Review Associates, LLC (S.C.R.), Salisbury, CT; The Mellen Center for MS Treatment and Research (J.A.C., R.J.F., R.A.R.), Cleveland Clinic, OH; the Department of Biostatistics (G.R.C.), University of Alabama at Birmingham; the Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, Copenhagen University Hospital Rigshospitalet, Denmark; University College London Institute of Neurology (A.J.T.), UK; the Department of Neurology (J.S.W., J.A.L.), University of Texas Health Sciences Center, Houston; the Department of Neurology (L.J.B.), New York University Langone Medical Center, New York; the Division of Neurology (B. Banwell), The Children's Hospital of Philadelphia, PA; the Departments of Radiology and Nuclear Medicine (F.B.) and Neurology (C.H.P.), VU Medical Center, Amsterdam, the Netherlands; Research Programs Department (B. Bebo), National Multiple Sclerosis Society, New York, NY; the Department of Neurology (P.A.C.), The Johns Hopkins Hospital, Baltimore, MD; Fédération de Neurologie (M.C.), CHU Hôpital Purpan, Toulouse, France; the Department of Neurology (G.C.), Scientific Institute San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Canada; the Department of Neurology (A.D.G.), University of Rochester Medical Center, NY; the Departments of Neurology, Radiology and Neuroscience (M.I.), Mount Sinai School of Medicine, New York, NY; the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; the Department of Neurology (B.C.K.), Heinrich-Heine-University, Düsseldorf, Germany; the Department of Neurology (C.L.), Salpêtrière Hospital, UPMC, Paris, France; the Department of Neurology-Neuroimmunology (X.M.), Cemcat, Hospital Universitari Vall d'Hebron, Barcelona, Spain; the Division of

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.
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http://dx.doi.org/10.1212/WNL.0000000000000560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117366PMC
July 2014

Risk evaluation and monitoring in multiple sclerosis therapeutics.

Mult Scler 2014 Sep 30;20(10):1306-11. Epub 2013 Nov 30.

Scientific and Clinical Review Associates LLC, USA.

Background: Risk for multiple sclerosis (MS) disease-modifying therapies (DMT) must be assessed on an ongoing basis. Early concerns regarding the first-approved DMTs for MS have been mitigated, but recently licensed therapies have been linked to possibly greater risks.

Objectives: The objective of this review is to discuss risk assessment in MS therapeutics based on an international workshop and comprehensive literature search and recommend strategies for risk assessment/monitoring.

Results: Assessment and perception of therapeutic risks vary between patients, doctors and regulators. Acceptability of risk depends on the magnitude of risk and the demonstrated clinical benefits of any agent. Safety signals must be distinguishable from chance occurrences in a clinical trial and in long-term use of medications. Post-marketing research is crucial for assessing longer-term safety in large patient cohorts. Reporting of adverse events is becoming more proactive, allowing more rapid identification of risks. Communication about therapeutic risks and their relationship to clinical benefit must involve patients in shared decision making.

Conclusions: It is difficult to produce a general risk-assessment algorithm for all MS therapies. Specific algorithms are required for each DMT in every treated-patient population. New and evolving risks must be evaluated and communicated rapidly to allow patients and physicians to be well informed and able to share treatment decisions.
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http://dx.doi.org/10.1177/1352458513513207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232326PMC
September 2014

Christian Confavreux (1949 - 2013).

Mult Scler 2013 Dec;19(14):1811-2

Department of Neurology, Mayo Clinic, Rochester, USA.

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http://dx.doi.org/10.1177/1352458513512239DOI Listing
December 2013

Urinary complications and risk factors in symptomatic multiple sclerosis patients. Study of a cohort of 328 patients.

Neurourol Urodyn 2015 Jan 23;34(1):32-6. Epub 2013 Sep 23.

Service de médecine physique et réadaptation, CHU, Toulouse, France.

Aims: Lower urinary tract dysfunctions (LUTD) are very common in Multiple Sclerosis (MS), have a significant social impact, while the organic impact is discussed. We studied urinary complications and their risk factors in our cohort of MS patients, in order to improve the management of LUTD in MS.

Methods: Between 2004 and 2009, all patients affected by MS and managed for LUTD were included in a retrospective study. We studied the epidemiological data (age, gender), the clinical data (duration of MS, EDSS score, progression of MS) and the paraclinical data (urinary creatinine clearance, urine culture, urinary tract ultrasonography and in some cases urodynamic assessment and cystography). We then identified the urinary complications and their risk factors.

Results: Three hundred twenty eight patients, mean age 49.9 ± 12.3 years, with a MS for 14.3 ± 10 years on average and with a median EDSS score equal to 6 (1-9), were managed for LUTD. One hundred seventy eight (54%) patients developed one or more urinary complications. We identified duration of MS greater than 8.5 years and an EDSS above 7 as risk factors.

Conclusion: Urinary complications are common in symptomatic MS, these results imply screening and specialized care to limit the impact on the quality of life but also to prevent urinary complications.
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http://dx.doi.org/10.1002/nau.22495DOI Listing
January 2015

A case report of simultaneous PML-IRIS during corticosteroids tapering in a patient with an anti-synthetase syndrome.

F1000Res 2013 23;2:283. Epub 2013 Dec 23.

INSERM UMR 1043, Centre de Physiopathologie, Toulouse-Purpan, France ; Université Toulouse III, Toulouse F-31000, France ; Department of Neurology, Toulouse University Hospital, Toulouse, France.

We report a case of simultaneous progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) during corticosteroid tapering in a patient with an anti-synthetase syndrome. We describe the challenges associated with the diagnosis and the management of this emerging inflammatory neurological condition in this immunocompromised patient with a severe rheumatic disease. We highlight that, in the setting of IRIS, the low-level of the JC virus viral load requires a sensitive PCR assay before excluding PML.
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http://dx.doi.org/10.12688/f1000research.2-283.v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968897PMC
April 2014

Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification.

Neurology 2013 Jan 19;80(2):181-7. Epub 2012 Dec 19.

Inserm U1079, University Hospital and Faculty of Medicine, Rouen.

Objectives: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene.

Methods: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes.

Results: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1.

Conclusion: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology.
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http://dx.doi.org/10.1212/WNL.0b013e31827ccf34DOI Listing
January 2013

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.

Brain 2012 Oct;135(Pt 10):2980-93

INSERM, UMR_S975 - CRICM, F-75013 Paris, France.

Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.
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http://dx.doi.org/10.1093/brain/aws240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470714PMC
October 2012

Prospective evaluation of laparoscopic assisted cystectomy and ileal conduit in advanced multiple sclerosis.

Urology 2012 Oct 29;80(4):852-7. Epub 2012 Aug 29.

Département d'Urologie, Transplantation Rénale et Andrologie, CHU Rangueil, Toulouse, France.

Objective: To assess the morbidity, mortality, and impact on quality of life and renal function after laparoscopic cystectomy and ileal conduit in patients with multiple sclerosis with lower urinary tract symptom refractory to conservative management.

Materials And Methods: A prospective study was conducted between February 2004 and December 2010 on 44 consecutive patients with multiple sclerosis who underwent laparoscopic cystectomy and ileal conduit for lower urinary tract symptom. Median Expanded Disability Status Scale score was 8 (6.5-8.5). Mean duration of multiple sclerosis was 19.3 ± 7.9 years. The quality of life was determined using the validated Qualiveen questionnaire preoperatively and at minimum 6 months after the surgery.

Results: No conversion to open surgery was required. Postoperative morbidity rate was 18.2%; minor (Clavien ≤ 2) and major (Clavien ≥ 3) complications occurred in 13.6% and 6.8%, respectively. Mean follow-up was 44.5 ± 20.6 months. Complications noted were asymptomatic ureteroileal stenosis (n = 6) and pyelonephritis (n = 3). Neurological status and Expanded Disability Status Scale score remained stable throughout. Renal function remained unchanged. Limitations, constraints, and specific urinary impact index subscores of the Qualiveen were significantly improved at 6 months time.

Conclusion: Laparoscopic cystectomy and ileal conduit for lower urinary tract symptom in advanced multiple sclerosis is a safe procedure with low complications. Neurological status and renal function remain stable and quality of life improves and continues to remain improved during long-term follow-up, suggesting this to be an attractive option in patients with advanced multiple sclerosis with lower urinary tract symptom refractory to conservative treatment.
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http://dx.doi.org/10.1016/j.urology.2012.06.039DOI Listing
October 2012

Long-term outcomes of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive series of 12 patients.

Arch Neurol 2012 Jul;69(7):847-55

Department of Neurology, Centre Hospitalier Universitaire, Nimes, France.

Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease.

Objective: To describe the disease course of CLIPPERS.

Design: A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS.

Setting: Academic research.

Patients: Twelve patients with CLIPPERS.

Main Outcome Measures: The therapeutic management of CLIPPERS was evaluated.

Results: Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy.

Conclusions: CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.
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http://dx.doi.org/10.1001/archneurol.2012.122DOI Listing
July 2012

Increased risk of multiple sclerosis relapse after in vitro fertilisation.

J Neurol Neurosurg Psychiatry 2012 Aug 11;83(8):796-802. Epub 2012 Jun 11.

Service de Neurologie, Centre Hospitalier Universitaire de Nantes, Hôpital Laennec, Nantes Cedex, France.

Background: Exogenous sexual steroids together with pregnancy have been shown to influence the risk of relapses in multiple sclerosis (MS). Treatments used during assisted reproductive techniques may consequently influence the short term evolution of MS by modifying the hormonal status of the patient. The objective of this study was to determine if there was an increased risk of developing exacerbations in women with MS after in vitro fertilisation (IVF).

Methods: MS and IVF data were either automatically extracted from 13 French university hospital databases or obtained from referring neurologists. After matching databases, patient clinical files were systematically reviewed to collect information about MS and the treatments used for IVF. The association between IVF and the occurrence of MS relapses was analysed in detail using univariate and multivariate statistical tests.

Findings: During the 11 year study period, 32 women with MS had undergone 70 IVF treatments, 48 using gonadotrophin releasing hormone (GnRH) agonists and 19 using GnRH antagonists. A significant increase in the annualised relapse rate (ARR) was observed during the 3 month period following IVF (mean ARR 1.60, median ARR 0) compared with the same period just before IVF (mean ARR 0.80, median ARR 0) and to a control period 1 year before IVF (mean ARR 0.68, median ARR 0). The significant increase in relapses was associated with the use of GnRH agonists (Wilcoxon paired test, p=0.025) as well as IVF failure (Wilcoxon paired test, p=0.019).

Interpretation: An increased relapse rate was observed in this study after IVF in patients with MS and may be partly related both to IVF failure and the use of GnRH agonists.
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http://dx.doi.org/10.1136/jnnp-2012-302235DOI Listing
August 2012

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Lancet Neurol 2011 Aug;10(8):745-58

University Hospital, Basel, Switzerland.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.
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http://dx.doi.org/10.1016/S1474-4422(11)70149-1DOI Listing
August 2011

Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.

Ann Neurol 2011 Feb;69(2):292-302

Department of Neurology, Free University, Amsterdam, the Netherlands.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.
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http://dx.doi.org/10.1002/ana.22366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084507PMC
February 2011
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