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1.  MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study 
Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.
To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.
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.
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.
MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.
PMCID: PMC5098693  PMID: 27589059
Multiple sclerosis; primary progressive multiple sclerosis; secondary progressive multiple sclerosis; high-dose biotin; MD1003; clinical trial; disability progression
2.  The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis 
PLoS ONE  2016;11(3):e0149685.
The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS.
Materials and Methods
We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed.
Among the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57–-0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12).
SLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.
PMCID: PMC4794160  PMID: 26983008
3.  Comparative efficacy of fingolimod vs natalizumab 
Neurology  2016;86(8):771-778.
To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis.
Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0–5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting).
The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation.
Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years.
Classification of evidence:
This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod.
PMCID: PMC4763805  PMID: 26826205
4.  Cutaneous and Mixed Nerve Silent Period Recordings in Symptomatic Paroxysmal Kinesigenic Dyskinesia 
The underlying neurophysiologic mechanism responsible for secondary paroxysmal kinesigenic dyskinesia (PKD) is still unclear. Here, we study the pathogenesis of PKD in two patients with a demyelinating lesion in the spinal cord.
Electromyogram recordings from affected arms of two patients with spinal cord lesions presenting PKD were compared with our laboratory standards. The cutaneous silent period (CuSP), mixed nerve silent period (MnSP) and coincidence period (CiP), defined as the common period between the CuSP and MnSP, were recorded.
A large decrease in the MnSP and disappearance of the CiP were observed in our patients, which was secondary to simultaneous extinction of the third portion of the MnSP, while the CuSP was normal. The MnSP and CiP were normal after recovery.
Our results demonstrate that the third portion of the MnSP and the CuSP do not correspond to the same physiologic process. These findings suggest that PKD patients have abnormal spinal interneuron integration.
PMCID: PMC4891988  PMID: 27330574
Cutaneous silent period; Dystonia; Mixed nerve silent period
5.  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;10(7):e0132033.
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.
Estimate survival in MS patients and compare mortality with that of the French general population.
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.
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]).
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.
PMCID: PMC4492994  PMID: 26148099
6.  Accuracy and cutoff values of delayed heart to mediastinum ratio with 123I-metaiodobenzylguanidine cardiac scintigraphy for Lewy body disease diagnoses 
BMC Neurology  2015;15:83.
Different studies have found diminished cardiac metaiodobenzylguanidine (MIBG) uptake in Lewy body (LB) related conditions (Parkinson’s disease (PD) and Lewy body dementia (LBD)). However, delayed heart/mediastinum (d-H/M) ratio diagnostic cutoff points are debated in parkinsonian syndromes.
We performed a monocentric retrospective analysis on 62 consecutive parkinsonian patients who underwent an 123I-MIBG scintigraphy, brain imaging and dopaminergic imaging using 123I-Ioflupane single photon emission computed tomography (SPECT) from 2009 to 2013. The optimal d-H/M ratio was determined from a Receiver Operating Characteristic (ROC) curve and the sensitivity (Se), specificity (Sp) and likelihood ratios (LR) were calculated. 42 patients were diagnosed with LB diseases (20 PD, 22 LBD) and 20 patients with other diseases.
123I-MIBG scintigraphy helped to distinguish PD (p < 0.001) and LBD (p = 0.03) from other diseases. The optimal d-H/M ratio was 1.48 (0.85 area under the ROC curve). Se and Sp were 83.3 %, and 85 % respectively with positive and negative LR of 5.5 and 0.2 respectively. Patients with LBD had a lower d-H/M ratio than patients with PD (result not statistically significant) and a cutoff point at 1.2 could help to differentiate the two diseases. We did not find any correlation between the d-H/M ratio and clinical or 123I-Ioflupane SPECT data.
According to our population, the d-H/M ratio at 1.48 led to the best performance diagnosis with good Se, Sp and accuracy. In addition, a d-H/M ratio cutoff at 1.2 could help to differentiate PD from LBD.
PMCID: PMC4448316  PMID: 25971430
Sympathetic innervation; Parkinson's disease; parkinsonism; MIBG; Myocardium; Lewy body dementia; Diagnosis
7.  Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis 
Beecham, Ashley H | Patsopoulos, Nikolaos A | Xifara, Dionysia K | Davis, Mary F | Kemppinen, Anu | Cotsapas, Chris | Shahi, Tejas S | Spencer, Chris | Booth, David | Goris, An | Oturai, Annette | Saarela, Janna | Fontaine, Bertrand | Hemmer, Bernhard | Martin, Claes | Zipp, Frauke | D’alfonso, Sandra | Martinelli-Boneschi, Filippo | Taylor, Bruce | Harbo, Hanne F | Kockum, Ingrid | Hillert, Jan | Olsson, Tomas | Ban, Maria | Oksenberg, Jorge R | Hintzen, Rogier | Barcellos, Lisa F | Agliardi, Cristina | Alfredsson, Lars | Alizadeh, Mehdi | Anderson, Carl | Andrews, Robert | Søndergaard, Helle Bach | Baker, Amie | Band, Gavin | Baranzini, Sergio E | Barizzone, Nadia | Barrett, Jeffrey | Bellenguez, Céline | Bergamaschi, Laura | Bernardinelli, Luisa | Berthele, Achim | Biberacher, Viola | Binder, Thomas M C | Blackburn, Hannah | Bomfim, Izaura L | Brambilla, Paola | Broadley, Simon | Brochet, Bruno | Brundin, Lou | Buck, Dorothea | Butzkueven, Helmut | Caillier, Stacy J | Camu, William | Carpentier, Wassila | Cavalla, Paola | Celius, Elisabeth G | Coman, Irène | Comi, Giancarlo | Corrado, Lucia | Cosemans, Leentje | Cournu-Rebeix, Isabelle | Cree, Bruce A C | Cusi, Daniele | Damotte, Vincent | Defer, Gilles | Delgado, Silvia R | Deloukas, Panos | di Sapio, Alessia | Dilthey, Alexander T | Donnelly, Peter | Dubois, Bénédicte | Duddy, Martin | Edkins, Sarah | Elovaara, Irina | Esposito, Federica | Evangelou, Nikos | Fiddes, Barnaby | Field, Judith | Franke, Andre | Freeman, Colin | Frohlich, Irene Y | Galimberti, Daniela | Gieger, Christian | Gourraud, Pierre-Antoine | Graetz, Christiane | Graham, Andrew | Grummel, Verena | Guaschino, Clara | Hadjixenofontos, Athena | Hakonarson, Hakon | Halfpenny, Christopher | Hall, Gillian | Hall, Per | Hamsten, Anders | Harley, James | Harrower, Timothy | Hawkins, Clive | Hellenthal, Garrett | Hillier, Charles | Hobart, Jeremy | Hoshi, Muni | Hunt, Sarah E | Jagodic, Maja | Jelčić, Ilijas | Jochim, Angela | Kendall, Brian | Kermode, Allan | Kilpatrick, Trevor | Koivisto, Keijo | Konidari, Ioanna | Korn, Thomas | Kronsbein, Helena | Langford, Cordelia | Larsson, Malin | Lathrop, Mark | Lebrun-Frenay, Christine | Lechner-Scott, Jeannette | Lee, Michelle H | Leone, Maurizio A | Leppä, Virpi | Liberatore, Giuseppe | Lie, Benedicte A | Lill, Christina M | Lindén, Magdalena | Link, Jenny | Luessi, Felix | Lycke, Jan | Macciardi, Fabio | Männistö, Satu | Manrique, Clara P | Martin, Roland | Martinelli, Vittorio | Mason, Deborah | Mazibrada, Gordon | McCabe, Cristin | Mero, Inger-Lise | Mescheriakova, Julia | Moutsianas, Loukas | Myhr, Kjell-Morten | Nagels, Guy | Nicholas, Richard | Nilsson, Petra | Piehl, Fredrik | Pirinen, Matti | Price, Siân E | Quach, Hong | Reunanen, Mauri | Robberecht, Wim | Robertson, Neil P | Rodegher, Mariaemma | Rog, David | Salvetti, Marco | Schnetz-Boutaud, Nathalie C | Sellebjerg, Finn | Selter, Rebecca C | Schaefer, Catherine | Shaunak, Sandip | Shen, Ling | Shields, Simon | Siffrin, Volker | Slee, Mark | Sorensen, Per Soelberg | Sorosina, Melissa | Sospedra, Mireia | Spurkland, Anne | Strange, Amy | Sundqvist, Emilie | Thijs, Vincent | Thorpe, John | Ticca, Anna | Tienari, Pentti | van Duijn, Cornelia | Visser, Elizabeth M | Vucic, Steve | Westerlind, Helga | Wiley, James S | Wilkins, Alastair | Wilson, James F | Winkelmann, Juliane | Zajicek, John | Zindler, Eva | Haines, Jonathan L | Pericak-Vance, Margaret A | Ivinson, Adrian J | Stewart, Graeme | Hafler, David | Hauser, Stephen L | Compston, Alastair | McVean, Gil | De Jager, Philip | Sawcer, Stephen | McCauley, Jacob L
Nature genetics  2013;45(11):1353-1360.
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
PMCID: PMC3832895  PMID: 24076602
8.  Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence 
About 15 million strokes occur each year worldwide. As the number one cause of morbidity and acquired disability, stroke is a major drain on public health-care funding, due to long hospital stays followed by ongoing support in the community or nursing-home care. Although during the last 10 years we have witnessed a remarkable progress in the understanding of the pathophysiology of ischemic stroke, reperfusion induced by recombinant tissue-type plasminogen activator (tPA—Actilyse) remains the only approved acute treatment by the health authorities. The objective of the present review is to provide an overview of our present knowledge about the impact of tPA on the neurovascular unit during acute ischemic stroke.
PMCID: PMC3210341  PMID: 21878948
acute stroke; clinical trials; excitotoxicity; interventional neuroradiology; neurovascular unit; thrombolysis
9.  Inflammatory-like presentation of CADASIL: a diagnostic challenge 
BMC Neurology  2012;12:78.
CADASIL is an autosomal dominant genetic leukoencephalopathy linked to mutations in the Notch3 gene. In rare cases, widespread brain lesions on T2 MRI mimicking multiple sclerosis are observed. From a national registry of 268 patients with adult-onset leukodystrophy, we identified two patients with an atypical presentation of CADASIL without co-occurrence of another systemic disease.
Case presentations
Patient 1 experienced progressive gait disability and patient 2 relapsing optic neuritis and sensory-motor deficit in the leg. Both patients responded to corticotherapy and patient 2 was also responsive to glatiramer acetate. No oligoclonal bands were found in the CSF, and MRI showed myelitis and lesions with gadolinium enhancement in brain (patient 1) or incomplete CADASIL phenotype (patient 2).
In rare cases, an inflammatory-like process can occur in CADASIL. In these patients, immunomodulatory treatments, including corticosteroids, could be effective.
PMCID: PMC3488471  PMID: 22905984
CADASIL; Multiple sclerosis; Leukoencephalopathy; Notch3; Cerebral vasculitis
10.  Stroke in hereditary hemorrhagic telangiectasia patients. New evidence for repeated screening and early treatment of pulmonary vascular malformations: two case reports 
BMC Neurology  2011;11:84.
Paradoxical embolism due to pulmonary arteriovenous malformations is the main mechanism of brain infarction in patients with hereditary hemorrhagic telangiectasia. International Guidelines have recently been published to clarify the performance of screening tests and the effectiveness of treatment for pulmonary arteriovenous malformations.
Case Presentation
We present two cases of hereditary hemorrhagic telangiectasia patients of our hospital who experienced an acute stroke secondary to paradoxical embolism.
These two cases show that the guidelines must be followed to prevent the occurrence of ischemic stroke in patients with hereditary hemorrhagic telangiectasia, and that although they may be adequate in most cases, there are some patients who need a more personalized approach.
PMCID: PMC3148967  PMID: 21740592

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