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Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3–4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis." The correction addresses errors in Table 1 of the article, specifically in the data for the second row under the column "Integrated safety analysis" and the sixth and seventh rows under the column "Post-approval cohort." The corrected data is provided in the notice. The original article has been corrected accordingly. [Extracted from the article]

Background Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH. Case reports Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases. Conclusion The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits are common in multiple sclerosis (MS) and affect patients at all stages of the disease, regardless of phenotype. Aims: This literature review focuses the cognitive deficits observed in secondary progressive MS (SPMS). It is mainly based on studies that compared the frequency and main characteristics of cognitive deficits in SPMS with other phenotypes. Methods: A bibliographic search was carried out using the PubMed database with the following keywords: multiple sclerosis, secondary-progressive, cognition. Results: Thirteen studies were initially selected that were published in English, reporting the neuropsychological data of a sample of at least 30 patients with SPMS, comparing them with patients with other phenotypes. Studies suggest that there is an association between the duration of the disease and the frequency and extent of the cognitive disorders. Studies also showed that the SP form is associated with an increased frequency of cognitive impairment and with an increased severity as compared to relapsing-remitting MS (RRMS). Compared to RRMS, progressive forms of MS are associated with more severe impairment in certain cognitive areas, such as episodic verbal memory, information processing speed, working memory, or verbal fluency. Two studies showed that cognitive performances decline overtime in SPMS. Conclusion: Cognitive disorders are more frequent and more severe in the SP form than in relapsing course of MS. The profile of cognitive impairment encountered in the SP form also appears to be different from those found in the other phenotypes. [ABSTRACT FROM AUTHOR]

In the assessment of basic medical knowledge, the composition of the reference panel between specialists and primary care (PC) physicians is a contentious issue. We assessed the effect of panel composition on the scores of undergraduate medical students in a script concordance test (SCT). The scale of an SCT on basic nephrology knowledge was set by a panel of nephrologists or a mixed panel of nephrologists and PC physicians. The results of the SCTs were compared with ANOVA for repeated measurements. Concordance was assessed with Bland and Altman plots. Forty-five students completed the SCT. Their scores differed according to panel composition: 65.6 ± 9.73/100 points for nephrologists, and 70.27 ± 8.82 for the mixed panel, p < 0.001. Concordance between the scores was low with a bias of −4.27 ± 2.19 and a 95% limit of agreement of −8.96 to −0.38. Panel composition led to a change in the ranking of 71% of students (mean 3.6 ± 2.6 places). The composition of the reference panel, either specialist or mixed, for SCT assessment of basic knowledge has an impact on test results and student rankings. [ABSTRACT FROM AUTHOR]

Cognition and health-related quality of life (HRQoL) are early involved in multiple sclerosis (MS). The aim of QUALICIS study was to monitor cognition and HRQoL prospectively in a cohort of clinically isolated syndrome (CIS) patients starting a treatment with subcutaneous beta-1b interferon as a first disease modifying treatment (DMT), and to assess their correlation with the clinical outcome 6 years later. Relapse history, EDSS and yearly standardized brain MRI data were also collected. 37 patients were included. Cognition and HRQoL remained stable over treatment period. At baseline, we found that SDMT was moderately correlated to T2 lesion load (r = − 0.47, p = 0.04). Baseline SDMT was predictive of HRQoL at year 2 (r = 0.53, p = 0.02). Regarding 6-year outcome, the most specific predictive factor of favorable outcome was achieving “No Evidence of Disease Activity” (NEDA) status at year 1. In this group, all the patients had a stable EDSS score and none switched to a second line therapy. In the “non-NEDA” group, 44% of patients experienced EDSS worsening and 38.9% switched to a second line therapy. The number of gadolinium enhancing lesions on baseline scan was the only predictive factor of poor outcome in this subgroup of patients (2 vs. 0.13, p = 0.03). Our results suggest that NEDA at 1 year could be used to predict long term outcome after initiation of DMT in CIS. For non-NEDA patients, monitoring SDMT and brain atrophy could be potentially relevant, but this should be confirmed on a larger sample. [ABSTRACT FROM AUTHOR]

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis is a progressive debilitating and lethal disorder, characterized by degeneration of motor neurons that warrant palliative care. Pain is frequent in patients with amyotrophic lateral sclerosis and significantly impacts on quality of life. Aim: To describe pain and assess the prevalence of pain with neuropathic characteristics in patients with amyotrophic lateral sclerosis. Design: Cross-sectional survey from March 2009 to October 2013. Setting/participants: Amyotrophic lateral sclerosis patients underwent multidisciplinary assessment and completed questionnaires measuring the severity and impact of pain and anxiety. The Douleur Neuropathique–4 questionnaire was used to look for pain with neuropathic characteristics. Results: Of 96 clinical evaluations, 93 were usable for analysis (age at onset: 62 ± 12.5 years; disease duration: 34 ± 33 months). The overall pain prevalence was 66%, with 9% experiencing pain with neuropathic characteristics. Pain was most often located in the neck and shoulders (38% of pain patients). Neck and shoulder pain was associated with neck (p = 0.04) and proximal upper limb muscular weakness (p = 0.02), respectively. Pain was not associated with disease duration, respiratory or nutritional parameters, but with higher anxiety scores (p = 0.01). Patients with neuropathic characteristics pain did not differ significantly from patients with or without pain, except that they had higher minimal pain intensity score (p < 0.05). Neuropathic characteristics pain was frequently spontaneous (rarely evoked) and described as numbness, burning, electric shock, tingling, and pins-and-needle. Conclusion: Even if amyotrophic lateral sclerosis is a disease of the motor system, pain is frequent and can rarely have neuropathic characteristics. Pain must be always sought and appropriately treated to limit quality of life impairment. [ABSTRACT FROM AUTHOR]

Background: In multiple sclerosis (MS) studies, the most appropriate model for the distribution of the number of relapses was shown to be the negative binomial (NB) distribution. Objective: To determine whether the sample-size estimation (SSE) and the analysis of annualized relapse rates (ARRs) in randomized controlled trials (RCTs) were aligned and compare the SSE between normal and NB distributions. Methods: Systematic review of phase 3 and 4 RCTs for which the primary endpoint was ARR in relapsing remitting MS published since 2008 in pre-selected major medical journals. A PubMed search was performed on 30 November 2020. We checked whether the SSE and ARR analyses were congruent. We also performed standardized (fixed α/β, number of arms and overdispersion) SSEs using data collected from the studies. Results: Twenty articles (22 studies) were selected. NB distribution (or quasi-Poisson) was used for SSE in only 7/22 studies, whereas 21/22 used it for ARR analyses. SSE relying on NB regression necessitated a smaller sample size in 21/22 of our calculations. Conclusion: SSE was rarely performed using the most appropriate model. However, the use of an NB model is recommended to optimize the number of included patients and to be congruent with the final analysis. [ABSTRACT FROM AUTHOR]

Lumbar puncture (LP) is stressful and often painful. We evaluated the efficacy of a fixed 50% nitrous oxide–oxygen mixture (50%N2O-O2) versus placebo to reduce immediate procedural pain and anxiety during LP performed in an emergency setting. We conducted a randomized controlled trial involving adults who needed a cerebrospinal fluid analysis in an emergency department. Patients were randomly assigned to inhale either 50%N2O-O2 or medical air. The primary endpoint, assessed using a numerical scale, was the maximum pain felt by the patient during the procedure and the maximum anxiety and satisfaction as secondary outcomes. Eighty-eight patients were randomized and analyzed (ITT). The maximal pain was 5.0 ± 2.9 for patients receiving air and 4.2 ± 3.0 for patients receiving 50%N2O-O2 (effect-size = −0.27 [−0.69; 0.14], p = 0.20). LP-induced anxiety was 4.7 ± 2.8 vs. 3.7 ± 3.7 (p = 0.13), and the proportion of patients with significant anxiety (score ≥ 4/10) was 72.7% vs. 50.0% (p = 0.03). Overall satisfaction was higher among patients receiving 50%N2O-O2 (7.4 ± 2.4 vs. 8.9 ± 1.6, p < 0.001). No serious adverse events were attributable to 50%N2O-O2 inhalation. Although inhalation of 50%N2O-O2 failed to reduce LP-induced pain in an emergency setting, it tended to reduce anxiety and significantly increased patient satisfaction. [ABSTRACT FROM AUTHOR]

Background: Chikungunya virus (CHIKV) is responsible for major epidemics worldwide. Autochthonous cases were recently reported in several European countries. Acute infection is thought to be monophasic. However reports on chronic pain related to CHIKV infection have been made. In particular, the fact that many of these patients do not respond well to usual analgesics suggests that the nature of chronic pain may be not only nociceptive but also neuropathic. Neuropathic pain syndromes require specific treatment and the identification of neuropathic characteristics (NC) in a pain syndrome is a major step towards pain control. Methods: We carried out a cross-sectional study at the end of the major two-wave outbreak lasting 17 months in Réunion Island. We assessed pain in 106 patients seeking general practitioners with confirmed infection with the CHIK virus, and evaluated its impact on quality of life (QoL). Results: The mean intensity of pain on the visual-analogical scale (VAS) was 5.8 ± 2.1, and its mean duration was 89 ± 2 days. Fifty-six patients fulfilled the definition of chronic pain. Pain had NC in 18.9% according to the DN4 questionnaire. Conversely, about two thirds (65%) of patients with NC had chronic pain. The average pain intensity was similar between patients with or without NC (6.0 ± 1.7 vs 6.1 ± 2.0). However, the total score of the Short Form-McGill Pain Questionnaire (SF-MPQ)(15.5 ± 5.2 vs 11.6 ± 5.2; p < 0.01) and both the affective (18.8 ± 6.2 vs 13.4 ± 6.7; p < 0.01) and sensory subscores (34.3 ± 10.7 vs 25.0 ± 9.9; p < 0.01) were significantly higher in patients with NC. The mean pain interference in life activities calculated from the Brief Pain Inventory (BPI) was significantly higher in patients with chronic pain than in patients without it (6.8 ± 1.9 vs 5.9 ± 1.9, p < 0.05). This score was also significantly higher in patients with NC than in those without such a feature (7.2 ± 1.5 vs 6.1 ± 1.9, p < 0.05). Conclusions: There exists a specific chronic pain condition associated to CHIKV. Pain with NC seems to be associated with more aggressive clinical picture, more intense impact in QoL and more challenging pharmacological treatment. [ABSTRACT FROM AUTHOR]

Background: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. Objective: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. Methods: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. Results: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58–1.39), placebo = 0.97 (0.63–1.50) (p = 0.79)). Conclusion: POPARTMUS failed showing efficacy of a NOMAc–E2 combination in preventing post-partum relapses. [ABSTRACT FROM AUTHOR]

We compared SimoaTM and EllaTM immunoassays to assess serum neurofilament‐light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p < 0.0001) between both platforms. The EllaTM instrument overestimated values by 17%, but as the data were linear (p = 0.57), it was possible to apply a correction factor to EllaTM results. As for SimoaTM, serum neurofilament‐light chain levels measured by EllaTM were correlated with age and EDSS and were significantly higher in active multiple sclerosis, suggesting that these assays are equivalent and can be used in routine clinical practice. [ABSTRACT FROM AUTHOR]

Background and purpose: Patients with a chronic illness, such as multiple sclerosis (MS), and their natural caregivers have a specific experience of healthcare and health services. These experiences need to be assessed to evaluate the quality of care. Our objective was to develop a French‐language questionnaire to evaluate the quality of care as experienced by MS patients and their natural caregivers. Methods: Eligible patients had been diagnosed with MS according to the McDonald criteria. Eligible caregivers were individuals designated by the patients. The MusiCare questionnaire was developed in two standard phases: (i) item generation, based on interviews with patients and caregivers; and (ii) validation, consisting of validity, reliability, external validity, reproducibility, and responsiveness measures. Results: In total, 1088 patients (n = 660) and caregivers (n = 488) were recruited. The initial 64‐item version of MusiCare was administered to a random subsample (n = 748). The validation process generated a 35‐item questionnaire. Internal consistency and scalability were satisfactory. Testing of the external validity revealed expected associations between MusiCare scores and sociodemographic and clinical data. The questionnaire showed good reproducibility and responsiveness. Conclusions: The availability of a reliable and validated French‐language self‐report questionnaire probing the experience of the quality of care for MS will allow the feedback of patients and caregivers to be incorporated into a continuous healthcare quality‐improvement strategy. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the safety and efficacy of ketamine‐magnesium combination to reduce attacks in a series of patients with refractory chronic cluster headache (rCCH). Background: Refractory chronic cluster headache (CCH) is a rare but highly debilitating condition that needs new treatment options. A previous publication reported that a single infusion of ketamine‐magnesium combination was effective in 2 patients with rCCH. Methods: The treatment was proposed to consecutive patients with rCCH seen in 2 French hospitals between November 2015 and February 2020 and who were resistant to at least 3 preventive treatments. They received a single ketamine infusion (0.5 mg/kg over 2 hours) combined with magnesium sulfate (3000 mg). The main outcome was a comparison of the number of daily attacks 2 weeks prior to the ketamine‐magnesium infusion and 1 week after (on days 7 and 8). The second outcome was the percentage of responders (patients with ≥50% reduction in the frequency of daily attacks). Safety was assessed by the recording of adverse events during infusion. Descriptive statistics are presented as mean ± standard deviation. Results: Seventeen patients (14 men), with an age of 35.2 ± 8.1 years, were included. They presented with CCH for 6.6 ± 4.3 years. The number of daily attacks decreased from 4.3 ± 2.4 before treatment to 1.3 ± 1.0 after treatment (difference: −3.1 (95% CI: −4.5 to −1.6), P <.001). Seventy six percent (13/17) were responders. Transient and mild sedation was reported by 7/17 patients (41.2%). Conclusions: The ketamine‐magnesium combination seems an effective and well‐tolerated therapy for rCCH. Placebo‐controlled studies should be conducted to further confirm these findings. [ABSTRACT FROM AUTHOR]

Le nivolumab est une immunothérapie recommandée dans le traitement du mélanome métastatique et des cancers bronchiques épidermoïdes. Depuis son autorisation de mise sur le marché plusieurs complications neurologiques ont été décrites. Nous rapportons une observation de polyradiculonévrite démyélinisante aiguë sous nivolumab. Il s’agit d’un patient de 58 ans présentant un cancer pulmonaire épidermoïde traité initialement par chirurgie et chimiothérapie. Face à une récidive locale et l’apparition d’une métastase osseuse, le nivolumab est débuté. Les premières cures sont bien tolérées. Mais quelques jours après la troisième cure, apparaît une diplopie binoculaire et un ptosis gauche. L’IRM encéphalique élimine une localisation secondaire. L’état clinique s’aggrave rapidement, avec l’apparition d’une dysarthrie et d’un déficit moteur proximal des quatre membres avec hyporéflexie. La ponction lombaire montre une dissociation albumino-cytologique sans synthèse intrathécale d’immunoglobuline. Les anticorps anti-gangliosides, anti-récepteurs de l’acétylcholine, anti- musk , et anti-onconeuronaux sont négatifs. L’ENMG est en faveur d’une polyradiculonévrite démyélinisante remplissant les critères EFNS/PNS 2010. Les stimulations répétitives à basses fréquences ne retrouvent pas de bloc pré- ou post-synaptique. Devant cette présentation nous évoquons un syndrome de Guillain-Barré (SGB). Malgré des perfusions d’immunoglobulines polyvalentes, l’état du patient s’aggrave, imposant une admission en réanimation. Il bénéficie alors de plasmaphérèses permettant une amélioration motrice progressive totale et la disparition des troubles de déglutition. Des complications infectieuses pulmonaires sévères dans un contexte de cancer métastatique conduisent cependant à une limitation des soins. Le patient décède en quelques semaines. Jusqu’à présent, plusieurs cas de myasthénie avaient été décrits mais un seul cas de SGB n’avait été recensé sous nivolumab. Son imputabilité est fortement probable avec une compatibilité clinique et chronologique. Les complications neurologiques du nivolumab sont rares mais souvent sévères. Les neurologues doivent être sensibilisés à ce risque face aux nouveaux traitements ciblés des cancers. [ABSTRACT FROM AUTHOR]

Background: Atraumatic needles are proposed to lower complication rates after lumbar puncture (LP). Only a minority of physicians use such needles. Here we aimed to assess the impact of specific training in LP during clinical clerkship on the proportion of medical students using atraumatic needles. Methods: We performed a case-control study comparing medical students undergoing clinical clerkship and students undergoing specific LP training. The 176 students of a class underwent training in LP just before beginning their clinical rotations. This training consisted of 45 minutes of theoretical training and a 90-minute practical session with a dummy. Twenty students were selected from the class at random, and their competence was assessed with a multiple choice questionnaire (MCQ) and an objective structured clinical examination (OSCE), nine months after the specific training. These 20 cases were compared with 20 students randomly selected from a class of 180 students who had not undergone specific training in LP and were at the end of their clinical clerkship. Results: We found that 60% of the students with specific training and 25% of those with classic clinical training used an atraumatic needle during the OSCE (p = 0.025). The mean MCQ (/100) scores obtained were 57±15 and 60±15 for the specific and classic training groups, respectively (p = 0.35). Overall OSCE score was similar in the two groups (63.5±9.3 vs. 65.8±9.3; p = 0.20). Conclusion: Very few practicing physicians use atraumatic needles, which limits the teaching of their use to medical students. Specific training durably increases the use of appropriate needles. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease type 1A is the most common hereditary neuropathy. Affected individuals have a distal motor deficit, initially affecting the lower limbs and impairing walking performance. Isokinetic dynamometry can be used to objectively assess muscle strength of patients with neuromuscular disorders. No studies have evaluated the effect of muscle strength deficits of knee extensors and flexors on walking parameters for patients with Charcot-Marie-Tooth disease type 1A. The purpose of this study was to determine correlations between the isokinetic muscular strength of knee flexors and knee extensors and walk parameters for patients with Charcot-Marie-Tooth disease type 1A. isokinetic muscular strength of the knee was assessed on an isokinetic dynamometer (Cybex) and walking by instrumented walkway analysis (GaitRite).We included 33 patients (23 females, mean ± SD age 46.7 ± 13.3 yrs,mean ± SD body mass index 25.7 ± 4.6 kg/m² ). We found a correlation between walking speed and isokinetic muscular strength of knee extensors for the entire population and between walking speed and isokinetic muscular strength of knee extensors and knee flexors for patients younger than 50 yrs. Isokinetic dynamometry can provide objective measures of knee muscle strength, which is correlated with walking speed but not cadence or step/stride length of patients with Charcot-Marie-Tooth disease. [ABSTRACT FROM AUTHOR]

The article offers information on a study related to association of Neuraxial analgesia (NA) with increased risk of post-partum relapses in Multiple Sclerosis (MS). Topics discussed include high risk of post-partum relapses in women who experienced relapses in year before and during pregnancy; data collection from Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis study; and the results showing no association in post-partum relapses in MS and NA.

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.Trial Registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background This study investigated the effects of medication overuse and withdrawal on modulation of pain processing in women with migraine. Temporal summation of laser-evoked thermal pain was used to measure the effects of conditioned pain modulation. Methods 36 female participants (12 healthy volunteers, 12 with episodic migraine and 12 with medication overuse headache) were included in a two session protocol. Medication overuse headache subjects were also tested three weeks after medication overuse headache withdrawal. Mechanical and laser-evoked thermal pain thresholds were measured on the back of the non-dominant hand where, later, temporal summation of laser-evoked thermal pain to repetitive thermal stimuli was elicited for 30 min, at an intensity producing moderate pain. Between the 10th and 20th minutes, the contralateral foot was immersed into a water bath at a not painful (30℃) or painfully cold (8℃; conditioned pain modulation) temperature. Results Episodic migraine, medication overuse headache and medication overuse headache withdrawal were associated with an increase in extracephalic temporal summation of laser-evoked thermal pain as compared to healthy volunteer subjects, while there was no alteration of laser-evoked thermal and mechanical extracephalic pain thresholds in these subjects. Conditioned pain modulation was highly efficient in temporal summation of laser-evoked thermal pain in healthy volunteer subjects, with a solid post-effect (reduction of pain). Conditioned pain modulation was still present, but reduced, in episodic migraine. By contrast, conditioned pain modulation was normal in medication overuse headache and strongly reduced in medication overuse headache withdrawal. Furthermore, in medication overuse headache withdrawal, the post-effect was no longer a decrease, but a facilitation of pain. Conclusions These data show that a decrease in conditioned pain modulation does not underlie medication overuse headache in women. On the contrary, medication overuse reinstated conditioned pain modulation in female migraine patients. They also identify different phenotypes of pain modulation in migraine patients. Registration number N° 2008-A00471-54. [ABSTRACT FROM AUTHOR]

Background: The development of oral treatments for relapsing–remitting multiple sclerosis (RRMS) may alter patient satisfaction and quality of life (QoL). The aim of this survey was to evaluate treatment satisfaction and QoL in patients treated with fingolimod in everyday clinical practice in France. Methods: Neurologists treating MS in France were invited to participate in the survey by telephone. Each physician was expected to recruit up to six patients with RRMS currently being treated with fingolimod. Enrolled patients were asked to complete the Treatment Satisfaction Questionnaire for Medication (TSQM), the 3-level 5-dimension EuroQoL instrument, as well as specific questions on change in QoL since starting fingolimod. Factors associated with the TSQM score were evaluated using multiple logistic regression analysis. Results: Two hundred and fourteen patients were recruited by 54 neurologists. The mean age of the patients was 41.6±10.0 years, and 73.4% of them were women. During the hospitalization for initiation of fingolimod treatment, 70.1% of patients had received information on MS, 76.6% had received information on fingolimod, and 20.7% had participated in a therapeutic education program. The two variables with the strongest associations with high TSQM scores (≥75) were a positive perception of initial hospitalization (hazard ratio: 10.27) and receiving information on MS during hospitalization (hazard ratio: 5.70). The mean EQ-visual analog scale score was 71.6±16.8. The mean EQ-visual analog scale score was significantly higher in patients satisfied with their treatment (75.8±15.2) compared to those unsatisfied with treatment (66.6±17.2). The proportion of patients who reported an improvement in their capacity to plan for the future was higher in satisfied (72.6%) than in unsatisfied patients (49.5%). Conclusion: The majority of patients treated with fingolimod are satisfied with their treatment. Treatment satisfaction is associated with better self-rated QoL and an improvement of QoL since starting treatment. [ABSTRACT FROM AUTHOR]

Introduction: In young patients with mononeuropathy who lack family history and precipitating factors, hereditary neuropathy with liability to pressure palsy (HNPP) may be a possibility. Our objective is to propose neurophysiological criteria for HNPP in patients <30 years of age.Methods: We conducted a national multicenter retrospective clinical and neurophysiological study in patients under 30 with genetically confirmed HNPP.Results: All of the 51 patients included in the study had at least 1 demyelinating pattern in 2 asymptomatic nerves, and 3 abnormalities were found in almost 90%, including slowed motor nerve conduction velocity across the elbow in at least 1 ulnar nerve (97.5%), increased distal motor latency (DML) in at least 1 fibular nerve (95.8%), and increased DML in both median nerves (89%). Age influenced DML slightly only in the fibular nerve.Discussion: Dissemination of nerve involvement in HNPP incites to perform a complete nerve conduction study. including bilateral ulnar, fibular, and median nerves. Muscle Nerve 57: 217-221, 2018. [ABSTRACT FROM AUTHOR]

Background: Studies of cancer prevalence have produced conflicting results concerning the relative risk of overall and specific sub-types of cancer in patients with multiple sclerosis (MS). Contemporary controls and information on tobacco use and alcohol consumption are generally missing from previous studies. Objectives: To evaluate lifetime cancer prevalence in a large cohort of MS patients relative to appropriate controls. Methods: We conducted a case-control study, using a postal survey of a cohort of MS patients. Of the 1574 questionnaires sent, 1107 could be used for statistical analysis. Data from 1568 controls were prospectively collected using the same self-administered survey among consecutive out-patients in a single neurology department. Propensity scores matched on age, gender, and history of smoking and alcohol consumption were calculated. Results: Among the MS patients, 7.32% had ever presented with a cancer, whereas 12,63% of the controls had, leading to a bootstrap matched odds ratio (OR) of 0.63; 95% CI 0.57–0.70. Although only exploratory, the use of DMT (immunomodulators or immunosupressants) did not appear to increase this risk (p = 0.42). The disease course also did not affect cancer prevalence. Conclusion: MS was associated with a reduced overall cancer risk. [ABSTRACT FROM AUTHOR]

Background Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown. Methods In this study, 48 patients with relapsing-remitting MS were included in a 3-year open-label, single group, multicenter, clinical trial ( NCT01392872 ). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition, fatigue, anxiety and depression scores at baseline, 6 months, 12 months, 18 months and 36 months after starting natalizumab therapy. Results Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6 months after the beginning of natalizumab therapy, with medium effect-size (58.6 ± 16.2 vs 69.8 ± 18.9, p < 0.001, Cohen's d = 0.63). This improvement was maintained over time for up to 3 years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p < 0.001 for every dimensions). The variation of global HRQoL after 3 years was negatively correlated with the variation of fatigue score ( r = − 0.44, p = 0.015). Furthermore, a higher fatigue score at baseline was correlated with improvement in global HRQoL 3 years afterwards ( r = 0.34, p = 0.041), independently of age, educational level, disease duration and disability at baseline (β = 2.45, p = 0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. Conclusion Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline. [ABSTRACT FROM AUTHOR]

Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay.Methods: Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 – ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively.Results: At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5–2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors.Conclusion: At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression. [ABSTRACT FROM AUTHOR]

Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).Methods: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively.Results: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment.Interpretation: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. Objective: To compare CPM to methylprednisolone (MP) in SPMS. Methods: Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area—MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. Results: Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31–1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14–4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17–0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. Conclusion: Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. Trial Registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The number and indications of lumbar punctures (LPs) performed nowadays are unknown. The primary aim of this work was to report the number of LPs performed in each of the departments of 2 French university hospitals, their indications and the prevalence of atraumatic spinal needles used. Methods: We carried out a retrospective study of all the LPs performed in 2014. The clinical department in which the intervention was performed and the final diagnosis was made from the Medical Information Department. The type of needles (cutting or atraumatic) used during the study period was also available. Results: In 2014, 6,594 LPs were performed. Overall, 80% were performed for diagnostic purposes. Twenty percent of these LPs were performed in the Neurology Department and were usually carried out at routine check-ups. Overall, atraumatic needles were used in 8.0% of cases. Overall, 1.4 LPs per 100 hospital stays were performed and 0.8 LP for 100 Emergency department admis-sions. Conclusion: LP is a routine procedure for many clinicians and although neurologists perform the largest number of LPs, they are doing only one fifth of all procedures. Atraumatic needles are underused. [ABSTRACT FROM AUTHOR]

Memantine, an uncompetitive antagonist of N-methyl- d -aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients. Aims The purpose of the “EMERITE” (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS). Methods The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18–60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial. Results Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p = 0.88). Adjusted mean score difference (memantine minus placebo), was − 0.40 (95% confidence interval: -5.5; + 4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine. Conclusions No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected. [ABSTRACT FROM AUTHOR]

Summary Seizures are common clinical manifestations in anti- N -methyl- d -aspartate receptor (anti-NMDA-R) encephalitis, among other neurological and psychiatric symptoms. During the course of the disease, some specific EEG patterns have been described: generalized rhythmic delta activity (GRDA) and extreme delta brush (EDB). In comatose patients, the association of these EEG abnormalities with subtle motor manifestations can suggest ongoing non-convulsive status epilepticus (NCSE). We report the case of a 28-year-old woman admitted for a clinical presentation typical of anti-NMDA-R encephalitis, which was confirmed by CSF analysis. She was rapidly intubated because of severe dysautonomia and disturbed consciousness. Clinical examination revealed subtle paroxysmal and intermittent myoclonic and tonic movements, correlated on video-EEG with GRDA and/or EDB. NCSE was then suspected, but electroclinical manifestations persisted despite many anti-epileptic drugs combinations, or reappeared when barbiturate anesthesia was decreased. In order to confirm or dismiss the diagnosis, intracranial pressure (ICP) and surface video-EEG monitoring were performed simultaneously and revealed no ICP increase, thus being strongly against a diagnosis of seizures. Sedation was progressively weaned, and clinical condition as well as EEG appearance progressively improved. Literature review revealed 11 similar cases, including 2 with focal NCSE. Of the nine other cases, NCSE diagnosis was finally excluded in 5 cases. NCSE diagnosis in association with anti-NMDA-R encephalitis is sometimes very difficult and its occurrence might be overestimated. Video-EEG is highly recommended and more invasive techniques may sometimes be necessary. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is a life-threatening disease without any validated treatment strategy. Recent retrospective studies suggested the efficacy of B cell depletion without any distinction between first-line or rescue therapy. To assess whether rituximab as first-line therapy in NMO could efficiently control the occurrence of relapses. A retrospective analysis of NMO patients from NOMADMUS network found 32 patients receiving rituximab as first-line therapy. Main measures were number of relapse-free patients, changes in the annualized relapse rate (ARR), and changes in the EDSS. Tolerance was reported. At baseline, NMO patients were 45 ± 12.1 years old, with a sex ratio of 5.4, and 87.5 % of them had AQP4 antibodies. The median disease duration was 6.5 months (1-410), the mean EDSS was 5.8 ± 2.4 and the mean ARR was 3.8 ± 4.3. After rituximab with a mean follow-up of 28.7 ± 21 months, twenty-seven patients (84.3 %) were relapse free. Patients presented a 97 % decrease of ARR ( p = 0.00001). EDSS decreased significantly to 3.9 ± 2.6 ( p = 0.01). No relevant side effect was noted. New retrospective data are presented on RTX use in NMOSD. When used as first-line therapy RTX is highly effective and well tolerated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Homozygous mutations in BIN1 have been associated with severe autosomal recessive centronuclear myopathies. However, Böhm et al. now report heterozygous BIN1 mutations in patients with mild autosomal dominant centronuclear myopathies. BIN1 mutations act via distinct pathomechanisms to cause either severe recessive or mild dominant forms of disease.Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the clinical significance of serum soluble IL-2R (sIL-2R) in inflammatory myopathies. Methods. Serum sIL-2R and CK levels were determined in 27 patients with IM during periods of disease exacerbation and inactive disease and were compared to 20 healthy controls and 23 controls with noninflammatory elevated CK. The performance of sIL-2R and CK tests for assessing disease activity was compared. Results. sIL-2R levels were increased in patients with IM. Significantly higher sIL-2R levels were detected in patients with disease exacerbation than in patients with inactive disease. In patients with IM, the sIL-2R levels correlated with the CK levels. Based on ROC analysis, diagnostic accuracy of sIL-2R and CK tests for disease activity was similar. However, when the CK threshold was defined by the upper limit of the normal, the specificity for the CK test dropped to 58%. Conclusion. Serum sIL-2R level could be useful to distinguish disease exacerbation from damage in IM, especially in patients with persistent elevated CK levels when a clinical muscular worsening is noted. For discrimination of the disease activity, CK testing requires the use of a different threshold than the upper limit of the normal. [ABSTRACT FROM AUTHOR]

We conducted a postal survey to assess the prevalence and characteristics of neuropathic pain and migraine in a cohort of multiple sclerosis (MS) patients. Of the 1300 questionnaires sent, 673 could be used for statistical analysis. Among the respondents, the overall pain prevalence in the previous month was 79%, with 51% experiencing pain with neuropathic characteristics (NCs) and 46% migraine. MS patients with both migraine and NC pain (32% of the respondents) reported more severe pain and had lower health-related quality of life than MS patients with either migraine or NC pain. Pain intensity in MS patients with migraine was moderate (6.0±0.1). Migraine was mostly episodic, but headaches were occurring on ⩾15days per month in 15% of those with migraine. MS patients with migraine were younger and had shorter disease durations than those with NC pain. NC pain was most often located in the extremities, back and head, and was frequently described as tingling and pins-and-needles. The intensity of NC pain was low to moderate (4.9±0.1), but positively correlated with the number of painful body sites. Nonetheless, patients with NC pain were more disabled (with a higher Expanded Disability Status Scale and pain interference index) than patients with migraine. Migraine, but not NC pain, was associated with age, disease duration, relapsing-remitting course, and interferon-beta treatment. This suggests that NC pain and migraine are mediated by different mechanisms. Therefore, pain mechanisms that specifically operate in MS patients need to be characterized to design optimal treatments for these individuals. [ABSTRACT FROM AUTHOR]

Enteroviruses (EVs) are a major cause of aseptic meningitis, and RNA detection using molecular assay is the gold standard diagnostic test. The aim of this study was to assess the impact of an EV positive diagnosis on the clinical management of patients admitted for meningitis over the course of two observational study periods (2005 and 2008–09) in the same clinical departments. We further investigated in multivariate analysis various factors possibly associated with hospital length of stay (LOS) in all age groups (infants, children, and adults). The results showed an overall improvement in the management of patients (n = 142) between the study periods, resulting in a significantly shorter hospital LOS for adults and children, and a shorter duration of antibiotic use for adults and infants. In multivariate analysis, we observed that the time from molecular test results to discharge of patients and the median duration of antibiotic treatment were associated with an increase in LOS in all age groups. In addition, among adults, the turnaround time of the molecular assay was significantly correlated with LOS. The use of CT scan in children and hospital admission outside the peak of EV prevalence in infants tended to increase LOS. In conclusion, the shorter length of stay of patients with meningitis in this study was due to various factors including the rapidity of the EV molecular test (particularly in adults), greater physician responsiveness after a positive result (in adults and children), and greater experience on the part of physicians in handling EV meningitis, as evidenced by the shorter duration of antibiotic use in adults and infants. [ABSTRACT FROM AUTHOR]

BackgroundExogenous 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).MethodsMS 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.FindingsDuring 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).InterpretationAn 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. [ABSTRACT FROM AUTHOR]

Background: Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS). Methods: Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%. Results: Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MSrelated impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/ 22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups. Conclusion: These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation. [ABSTRACT FROM AUTHOR]

Prior to the era of disease-modifying therapies (DMT), multiple sclerosis (MS) was linked to reduced rates of cancer. Early use of immunosuppressors (IS) in MS justifies the follow-up of patients to evaluate a possible increase in the incidence of cancer in these patients. We performed a descriptive study of MS patients with a documented oncological event. Among the 22,563 MS patients in the EDMUS databases, patients with a history of cancer were identified, and cancer risk in a multiple sclerosis cohort (CARIMS) was evaluated. Four groups were defined: (A) MS patients without cancer receiving DMT or not, (B) MS patients with cancer but without any history of DMT, (C) MS patients with cancer who received an immunomodulator (IM), and/or (D) MS patients treated with an IS. A total of 9,269 patients (44.1%) had a history of DMT (52% IM; 18% IS; 30% both); 253 patients with MS and cancer were identified, 182 had a history of DMT. The mean duration of DMT was longer for group D (A: 3.6 years vs. D: 4.9 years; P < 0.01). There was no increased risk of cancer among patients treated exclusively with IM. IS treatment ( P = 0.043) and the duration of exposure ( P < 0.001) significantly increased the risk of cancer, especially skin cancer, as observed in other autoimmune diseases. This result could influence the attitude of the medical profession with respect to the benefit to risk ratio when proposing DMT to MS patients. [ABSTRACT FROM AUTHOR]

We carried out a retrospective multicentre study to assess the safety of home parenteral nutrition (HPN) in patients with ALS. We reviewed the case records of patients from French ALS centres treated with HPN by central venous catheter (CVC) using an implantable port between January 2005 and October 2009. Seventy-three patients received HPN for a total of 11,908 catheter days. Twenty-seven patients experienced a total of 37 CVC related complications resulting in an incidence rate of 3.11 CVC complications/1000 catheter days, including 1.93 septic complications and 1.09 mechanical complications/1000 catheter days. Metabolic complications were frequent but without serious consequences on mortality. The use of the catheter for intravenous therapies in addition to HPN was identified as a septicaemia's risk factor (relative risk (RR) == 2.54, confidence interval (CI) 1.56--4.14, p == 0.04). In conclusion, HPN is an alternative procedure to PEG in advanced ALS patients. The incidence of complications appears to be comparable to data from the literature on HPN in other diseases. A prospective study comparing HPN and radiologic inserted gastrostomy (RIG) would allow comparison of the relative risk-benefit and survival of these procedures. The relation of CVC and RIG placement timing and the complications'' occurrence should also be investigated. [ABSTRACT FROM AUTHOR]

Objectives: Many patients with amyotrophic lateral sclerosis (ALS) develop progressive difficulty swallowing secretions, leading to drooling. Although external beam radiation is considered to be an effective and well-tolerated treatment, the optimum schedule in terms of dose, target, radiation type, and number of fractions is unknown. The aim of this observational study was to define the most effective schedule for salivary gland irradiation and to compare electron and photon radiotherapy. Methods: Sixteen patients with ALS (12 females and 4 males) with drooling, enrolled for external radiation of salivary glands between 2002 and 2007, were included. Patients received different treatment protocols according to the decision of their radiotherapist. Efficacy and safety were assessed at 1 and 6 months after treatment by a neurologist and a radiotherapist using a 4-point Likert patient improvement scale, as follows: 0 (no change), 1 (slight improvement), 2 (good improvement), and 3 (very good improvement). Results: Radiotherapy for drooling was shown to be safe and effective in ALS patients with duration of effect expected up to 6 months. Eighty percent of patients felt improved at 1 month and 43% at 6 months after external radiation. Patients with sustained improvement at 6 months were treated with electron therapy (>8 MeV; p = 0.02). Conclusions: Electron-based radiotherapy, delivered as five 4Gy fractions to a total dose of 20 Gy, encompassing the whole of the submandibular gland and sparing the upper part of the parotid gland, can be proposed as a safe and effective schedule for the treatment of sialorrhea in patients with ALS. [ABSTRACT FROM AUTHOR]

Detection of enterovirus (EV) in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) has been reported on post mortem central nervous system tissues. In cases of persistent infection, it is very likely that the EV genome might be detected in the cerebrospinal fluid (CSF). A study was conducted in seven French amyotrophic lateral sclerosis (ALS) centres between 1997 and 2002. A total of 242 ALS patients and 354 age- and sex-matched controls (non-ALS patients) were enrolled. A sensitive RT-PCR method was performed on the CSF to assess the presence of EV RNA; 14.5% of ALS patients were positive compared to 7.6% of controls (χ2 value, 5.31; p = 0.02). Although EV infection has a seasonal pattern, we observed no seasonality in positive detection of the EV genome among ALS patients. There was no significant relationship among ALS patients between the initial clinical form or survival and the result of the RT-PCR. These findings suggest a relationship between the presence of EV sequences in CSF and ALS. Our study is consistent with the hypothesis that persistent EV infection can be one of the multiple factors involved in the development of ALS. [ABSTRACT FROM AUTHOR]

In clinically isolated syndrome (CIS), the detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is critical for space dissemination validation when magnetic resonance imaging (MRI) diagnostic criteria are not fulfilled. However, lumbar puncture for CSF collection is considered relatively invasive. Previous studies have demonstrated applicability of OCB detection in tears to the diagnosis of multiple sclerosis (MS). The objective of the present study was to assess concordance between OCB detection in tears and in CSF. We have prospectively included patients with CIS and compared results of CSF and tear OCB detection by isoelectric focusing (IEF). Tears were collected using a Schirmer strip. We included 82 patients. For 69 of them, samples were analysable. OCBs were detected in CSF for 63.8% and in tears for 42% of patients. All patients with tear OCBs had CSF OCBs. We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with CIS. This would circumvent the practice of invasive lumbar punctures currently used in MS diagnosis. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease which targets motor neurons of the cortex, brainstem and spinal cord. About 5–10% of all amyotrophic lateral sclerosis cases are familial (FALS), and 15–20% of FALS cases are caused by mutations in the zinc-copper superoxide dismutase gene ( SOD1). We identified a large family from France with ten members affected with ALS. Linkage was established to the SOD1 locus on chromosome 21 and genomic and cDNA sequencing was performed for the SOD1 gene. This revealed an activated pseudoexon between exons 4 and 5 that was present in two tested members of the family. Translation of this 43 base pair exon results in the introduction of seven amino acids before a stop codon is present, leading to a prematurely truncated SOD1 protein product of 125 amino acids. Sequencing intron 4 in a patient revealed a heterozygous change 304 bp before exon 5 (c.358 – 304C > G), but only 5 bp after the cryptic exon, thus causing this alternative splice product. This mutation segregated in all affected individuals of the family. This adds an additional genetic mechanism for developing SOD1-linked ALS and is one which can be more readily targeted by gene therapy. [ABSTRACT FROM AUTHOR]

Background Prior to the era of immunomodulating or immunosuppressive (IS) treatments Multiple Sclerosis (MS) was linked to reduced rates of cancer. Method A descriptive study of MS patients with a documented oncological event was performed. From 1 January 1995 to 30 June 2006, we collected and studied the profile of 7418 MS patients gathered from nine French MS centers. We evaluated the incidence of cancer in a Cancer Risk In MS Cohort. Results Thirty one patients (1.75%) with confirmed MS had a history of cancer: mean age at MS diagnosis of 37.9 years and a mean age at cancer diagnosis of 46.4 years. The most frequent cancers were breast (34.5%), gynecological (12.5%), skin (10.2%), acute leukemia and lymphoma (5.9%), digestive (8.8%), kidney and bladder (5.1%), lung (3.4%) and central nervous system (3%). Calculated standardized incidence rates were 0.29 (0.17–0.45) for men and 0.53 (0.42–0.66) for women. The incidence of cancer in this MS population was lower than that expected for the general population. Matched to age, gender and histology, cancers in MS were associated with a young age and exposure to IS treatments. When considering all patients, treated patients had a 3-fold higher risk of developing cancer, if they had a history of IS (P = 0.0035). For treated patients, the cancer sites were more likely the breast, the urinary tract, the digestive system and the skin. Conclusion Our data suggest that MS patients do not have an increased risk of cancer. Rather for several types of cancer a significantly reduced risk was observed, except for breast cancer in women treated with IS. The relative increased risk of breast cancer in MS women under IS treatment warrants further attention. [ABSTRACT FROM AUTHOR]

• The severity of axonal loss in Charcot-Marie-Tooth (CMT) disease type 1A may be associated with loss of function and health-related quality of life. • Despite severe impairment in electrophysiological parameters and significant distal amyotrophy, we found relative conservation of autonomy for activities of daily living, health-related quality of life and manual function. • Electrophysiological follow-up seems to be of little relevance to follow health-related quality of life in CMT and manual function related to functional objectives for everyday physical medical and rehabilitation. Charcot-Marie-Tooth (CMT) disease type 1A (CMT1A) is the most common hereditary neuropathy. Several studies have assessed the relation between axonal loss and grip strength; however, the functional impact on dexterity and health-related quality of life (HRQoL) is unknown. We hypothesized that the severity of axonal loss will be correlated with loss of function and HRQoL. The purpose of this study was to evaluate the relation between severity of electroneuromyography impairment and its impact on function and HRQoL in adults with CMT1A. Grip and lateral pinch strength were evaluated with specific dynamometers: the Jamar and the Pinch Gauge. Dexterity was explored with the Sollerman, Jebsen, and Nine-hole Peg tests. The CMT impact on well-being was assessed by the validated Medical Outcomes Study Short Form 36 (SF-36), Beck Depression Inventory, and Fatigue Severity Scale, and disease severity by the CMT neuropathy score and Inflammatory Neuropathy Cause and Treatment sensory sum score. Finally, axonal loss and demyelination process was assessed by electroneuromyography. We included 33 participants with CMT1A (23 females, mean [SD] age 47.0 [4.7] years). We found lack of correlation between severe electroneuromyography impairment (frequency of abnormal results >80%), significant distal amyotrophy (70%) and quality of life (mean [SD] scores for physical and mental SF-36 36.4 [10.0] and 48.4 [11.5]), autonomy for activities of daily living, and hand function that remains relatively preserved. We found a correlation between lateral pinch and dexterity according to the Sollerman test (r = 0.52, p < 0.05) but a lack of correlation among the other parameters. Electrophysiological follow-up seems to be of little relevance to follow HRQoL in individuals with CMT1A and manual function related to functional objectives for everyday physical medicine and rehabilitation practice. The manual function is complex and requires an overall, quantitative, qualitative and multidisciplinary assessment. Each tool (Pinch Gauge, Jamar, Sollerman, Jebsen, Nine-hole Peg) measures a specific element of manual function and is necessary when performing a grip function analysis. [ABSTRACT FROM AUTHOR]

Radicular involvement in Horton’s disease is rare. In all but one of the eight documented cases, C5 nerve roots were affected. We report a new case with C5 involvement. Cervical radiculopathy could be due to arteritis of radicular vessels. Preferential involvement of C5 nerve roots may depend on the vascularization of cervical roots but could be due to the inability to diagnose upper cervical involvement (C1-C3). Outcome is favourable in all cases with corticosteroids. [Copyright &y& Elsevier]