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International audience; Background: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy.Methods: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years.Results: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system.Conclusions: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings.

Background Most data regarding the use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) comes from clinical series or regional databases that have a risk of recruitment bias. French health administrative data offers the significant advantage of being extensive in regards to both MS population coverage and DMT prescriptions. Objectives To describe patterns of DMTs usage at the level of the entire French population of MS patients from 2010 to 2015. Methods MS patients were identified during a 6-year study period via the French national health data system (covering 97% of the general population) and characteristics of patients who received at least one treatment were compared to those that never received treatment over the indicated period. A state sequence analysis was performed to study in a longitudinal way MS patients who started DMTs in 2010 and then to classify them into groups of similar therapeutic patterns. DMTs were categorized into first-line, second-line and off-label use, and included untreated periods for at least six months. Groups that were obtained were described and compared using a multinomial logistic regression. Results A total of 112,415 patients with MS were identified, of whom 54.0% received at least one DMT over the 6 years. The probability of being treated significantly decreased with age. Comorbidities and physical limitations appeared to be more frequent in not treated patients than in treated patients. Significant differences were also found between the two groups regarding the use of healthcare services (hospitalizations and visits to general practitioner, neurologist and nurse). Based on the 6-year therapeutic sequences, a four-cluster typology was obtained on the 4,474 patients who started a DMT in 2010. The first group which consisted of more than half of the patients (57.0%) mainly used first-line DMTs. The second group (13.1%) represented patients with second-line DMTs whereas the third group (7.3%) was comprised of off-label users and the last group (22.6%) was composed of MS patients who received no or minimal treatments. Classification into one of these groups was associated with patient's age, long-term disease status, pregnancy occurrence, estimated level of disability, levels of care (visits to a neurologist, nurse and/or physiotherapist and hospital/rehabilitation stays) and occurrence of death. Conclusions The exhaustive population-based dataset from the French national health data system gave the opportunity to provide a detailed description regarding the use of DMTs for MS at national level. The innovative method of state sequence analysis allowed obtaining four homogeneous groups of patients among thousands of longitudinal therapeutic sequences. The predominant place of first-line treatments was confirmed even if the type of first-line treatments has probably changed since 2015.

International audience; INTRODUCTION: Evaluating the quality of the care pathway for patients with chronic diseases, such as multiple sclerosis (MS), is an important issue. Process indicators are a recognized method for evaluating professional practices. However, these tools have been little developed in the field of MS, and few data are available. The aim of this study was to describe, retrospectively, with validated indicators, the quality of the care pathway in a population-based cohort of 700 patients with the first manifestations of the disease occurring between January 1, 2000 and December 31, 2001 and during the first 10 years of disease. METHOD: This assessment was based on 48 indicators specific to MS. The information required for the calculation of each indicator was collected from the source files of the 700 patients of the cohort. RESULTS: Data for the 10 years of follow-up were collected for 80% of the patients. In total, 36 indicators were calculated. These results reveal that there is room for improvement, particularly in terms of the initial assessment, access to ophthalmological evaluation, employment, obtaining an evaluation of the need for rehabilitation and access to such care. CONCLUSION: The results of this survey provide access to unprecedented new data in France, that professionals and patients can appropriate to improve the targeting of actions, to improve the quality of care further for patients with MS in France. We propose to continue this process by submitting, for discussion, a targeted list of updated indicators relating to changes in guidelines, and in issues concerning the quality of patient management.

Objectives To establish recommendations on immunization for patients with multiple sclerosis (MS). Background Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients. Methods The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975–June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain. Results Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs. Conclusion Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS.

International audience; BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Resume Objectif Etudier l’evolution de l’acuite visuelle et des parametres de la fonction visuelle des patients atteints de neuropathie optique inflammatoire (NOI) traites par corticotherapie orale a forte dose. Methode Neuf patients atteints de NOI traites par 1000 mg de methylprednisolone per os par jour pendant trois a cinq jours ont ete inclus dans cette etude retrospective descriptive monocentrique. Les visites de suivi ont ete effectuees aux 4 e (j4), 15 e (j15), 30 e (j30) et 90 e (j90) jours apres l’instauration du traitement. Le bilan initial (j0) et les visites comprenaient une mesure de l’acuite visuelle (AV) selon l’echelle de l’Early Treatment Diabetic Retinopathy Study, un test de la sensibilite au contraste (SC) et un champ visuel (CV) automatique 30,2 (indice Visual Field Index [VFI]). La tolerance subjective globale du traitement a ete evaluee sur une echelle de 0 a 10. Resultats Nous avons observe une amelioration de l’ensemble des parametres des j4. Entre j0 et j4, l’AV moyenne a progresse de 40,1 a 57,9 lettres, le VFI moyen de 40,9 % a 70,3 % et la SC globale moyenne de 7,7 a 11,3 dB. De j15 a j90, l’AV moyenne a progresse de 77 lettres a 80,3 lettres, le VFI moyen de 91,2 % a 97,9 % et la SC globale moyenne de 15,4 dB a 16,7 dB. Quatre patients ont qualifie la tolerance excellente (10), trois autres patients entre 8 et 9 et les deux derniers a 6. Conclusion Nous avons mis en evidence une amelioration rapide des parametres de la fonction visuelle des patients atteints de NOI apres corticotherapie orale a forte dose.

Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo’s concentric sclerosis, Schilder’s disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

Conditioned on the generating functions of offspring distribution, we study the asymp-totic behaviour of the probability of non-extinction of a critical multi-type Galton-Watson process in i.i.d. random environments by using limits theorems for products of positive random matrices. Under some certain assumptions, the survival probability is proportional to 1/ √ n.

The concept of induction followed by a long-term maintenance treatment has attracted much attention for the treatment of multiple sclerosis over the 30 past years. It was first demonstrated by the combination of induction therapy with mitoxantrone (six-monthly courses) followed by maintenance therapy with an immunomodulatory treatment such as an interferon-β or glatiramer acetate. Long-term observational studies confirmed that this therapeutic regimen provides a rapid reduction in disease activity and sustained disease control up to at least five years in 60% of patients. A better treatment response was observed in patients with early signs of aggressive disease, as shown in randomised studies (using six-monthly 12mg/m2 of mitoxantrone intravenously at a cumulative dose of 72mg/m2, followed by an interferon-β) as well as in long-term observational studies. But the safety profile of mitoxantrone make it more particularly suitable for young patients with frequent early relapses with incomplete recovery and multiple gadolinium-enhancing T1 lesions or spinal cord lesions on magnetic resonance imaging. More recently approved, the second candidate for an induction strategy is alemtuzumab: phases II and III randomised studies showed the superiority of alemtuzumab 12mg per day given intravenously for only five days and repeated for 3 days one year later, compared with interferon-β three times a week. Like with mitoxantrone, results supported the concept of long-term benefit after a short induction rather than escalation, in a subset of patients with early very active MS, with a sustained control of the disease for up to 7 years in 60% of patients in the phase III extension studies and in a long-term observational study. On the contrary, when alemtuzumab was first studied later in the disease course, results were disappointing. However, the risk of developing manageable but potentially severe systemic autoimmune diseases within the years following the last course of alemtuzumab make it, like mitoxantrone, more suitable for patients with early aggressive MS. More recently, cladribine an oral immunosuppressant, showed interesting results in a phase III study extension suggesting its potential induction effect, since after two cycles of treatment (5 days repeated 1 month later) at one year of interval, the remained low up to 4 years of follow-up, in the absence of any new treatment. However, today other immunosuppressive drugs have proved to be strongly and rapidly efficacious in treating highly active MS patients but through a mechanism of continuous immunosuppression (i.e., natalizumab and ocrelizumab). Indeed, disease activity can reappear rapidly after stopping these drugs, sometimes associated with a rebound of the inflammatory process, which is the contrary of a mechanism of induction that is associated with a remnant effect. Taking into account advantages and disadvantages of the different DMDs, which enriched the today therapeutic arsenal for MS, we propose in this paper some algorithms summarizing our reflexion about using an escalation strategy or an induction strategy according to disease course and activity.

International audience; BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS. METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified. RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of

International audience; BACKGROUND: Launched in the US in 2012, Choosing Wisely® is a campaign promoted by the American Board of Internal Medicine (ABIM) Foundation with the goal of improving healthcare effectiveness by avoiding wasteful or unnecessary medical tests, treatments and procedures. It uses concise recommendations produced by national medical societies to start discussions between physicians and patients on the relevance of these services as part of a shared decision-making process. The Multiple Sclerosis Focus Group (Groupe de Reflexion Autour de la Sclérose en Plaques; GRESEP) undertook a pilot study to assess the relevance and feasibility of this approach in the management of multiple sclerosis (MS) in France.METHODS: Recommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility.RESULTS: Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS-related fatigue.CONCLUSION: This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely® model to MS by practitioners specializing in the disorder. However, the acceptability of these recommendations by other practitioners in other specialist fields as well as their impact on everyday clinical practices now need to be studied.

The question of pregnancy in patients with multiple sclerosis is regularly raised due to the prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of pregnancy on the disease. As with topics of previous works, the formal expert consensus method was used. The working group was composed of hospital-based and private practice neurologists. The reading group was composed of neurologists, anaesthetists and obstetricians. Each recommendation is presented with the relevant level of consensus.

Launched in the US in 2012, Choosing WiselyRecommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility.Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS-related fatigue.This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely

From 1991-2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath-1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath-1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath-1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath-1H and IFN-beta in the treatment of drug-naïve patients with early, active RR MS.

Resume Introduction Jusqu’a present, il etait habituel de traiter les poussees de sclerose en plaques (SEP) par fortes doses de methylprednisolone administrees en perfusion a l’hopital ou a domicile. La question de l’efficacite et de la tolerance des corticoides par voie orale est restee debattue pendant les deux dernieres decennies. Objectifs L’etude Corticotherapie orale dans le traitement des poussees de SEP (COPOUSEP) a ete pensee pour tester l’hypothese de non-inferiorite de la voie orale par rapport a la voie intraveineuse, tenant compte des avantages de la voie orale (simplification de la procedure, amelioration du confort des patients et economies evidentes). Le design de l’essai prenait en compte les limites des etudes anterieures. Resultats COPOUSEP est le premier essai randomise, en double insu, de non-inferiorite, incluant 200 patients en poussee depuis moins de 15 jours, a confirmer que la methylprednisolone 1 gramme par jour pendant 3 jours n’est pas moins efficace par voie orale que par voie intraveineuse sur la recuperation a 1 et 6 mois ainsi que sur les recidives dans les 6 mois, la tolerance etant similaire en dehors d’une insomnie plus frequente par voie orale. Discussion La simplification du traitement des poussees de SEP, grâce au recours a la voie orale, pourrait conduire a « banaliser » le diagnostic de poussee, mais elle doit etre validee par un neurologue ainsi que l’indication des corticoides. Afin d’encadrer cette pratique par une education therapeutique, le reseau SEP-Bretagne a redige des documents d’information destines aux patients et aux professionnels impliques, (neurologues et medecins generalistes) ciblant le role de chacun. Conclusion Le traitement des poussees de SEP (lorsqu’elles le justifient) peut desormais reposer sur l’administration d’un gramme de methylprednisolone par jour pendant 3 jours par voie orale, mais doit etre encadre par les neurologues et coordonne avec les medecins generalistes.

Background: Benign multiple sclerosis (BMS) is a controversial concept which is still debated. However identification of this kind of patients is crucial to prevent them from unnecessary exposure to aggressive and/or long term medical treatments. Objectives: To assess two definitions of ‘clinically definite benign multiple sclerosis’ (CDBMS) using long-term follow-up data, and to look for prognostic factors of CDBMS. Methods: In 874 patients with definite relapsing–remitting MS, followed up for at least 10 years, disability was assessed using the Disability Status Scale (DSS). CDBMS was defined by either DSS score≤2 (CDBMS1 group) or DSS score≤ 3 (CDBMS2 group) at 10 years. We estimated the proportion of patients who were still benign at 20 and 30 years after clinical onset. Results: CDBMS frequency estimates were 57.7% and 73.9% when using CDBMS1 and CDBMS2 definitions, respectively. In the CDBMS1 group, only 41.7% (105/252) of cases were still benign 10 years later, and 41.1% (23/56) after an additional decade, while there were 53.8% (162/301) and 59.5% (44/74) respectively in the CDBMS2 group. Conclusions: This 30-year observational study, which is one of the largest published series, indicates that favourable 10-year disability scores of DSS 2 or 3 fail to ensure a long-term benign course of multiple sclerosis. After every decade almost half of the CDBMS were no longer benign. CDBMS, as currently defined, is an unwarranted conceptual hodgepodge. Other criteria using new biomarkers (genetic, biologic or MRI) should be found to detect benign cases of MS.

Background: In multiple sclerosis (MS), the relapse rate declines during pregnancy and increases during the first three months post-partum before returning to the pre-pregnancy rate. It is unknown whether pregnancy impacts the risk of clinical conversion in those within the presymptomatic period. Objectives: We investigate the impact of pregnancy on developing a clinical event in women diagnosed with radiologically isolated syndrome (RIS). Methods: All women with RIS underwent clinical and radiological assessments as part of an observational, prospective, longitudinal study. Clinical and MRI outcomes were analyzed during and after pregnancy. Subjects who became pregnant were compared with an age-matched female RIS group who did not become pregnant during the same follow-up period. Results: A total of 60 women with RIS were followed for up to seven years. Among them, seven became pregnant and were compared with 53 age-matched control women with RIS who did not become pregnant during the observation period. A significantly shorter time of conversion to the first neurological event was observed in the pregnant group [15.3 months (10–18)] compared with the non-pregnant controls [35.7 months (8–76)], yielding an absolute difference of 20.4 months ( pConclusions: The risk for clinical conversion from RIS to a clinical event and new MRI disease activity seems to be influenced by pregnancy. Pregnancy related physiological changes could operate as early as the presymptomatic period in patients with MS.

To study the progression of visual acuity and visual function parameters in patients with optic neuritis (ON) treated with high-dose oral corticosteroid therapy.This retrospective descriptive monocentric study included nine patients with ON treated with orally administered methylprednisolone at 1000 mg per day for three to five days. The follow-up visits were performed on day 4 (D4), day 15 (D15), day 30 (D30) and day 90 (D90) after treatment was begun. The initial examination (D0) and the follow-up visits included a visual acuity (VA) assessment according to the Early Treatment Diabetic Retinopathy Study scale, a contrast sensitivity test and a 30.2 automated visual field (Visual Field Index [VFI]). The overall subjective tolerance of the treatment was assessed by patients on a scale from 0 to 10.We observed an improvement of all parameters from D4. From D0 to D4, the average VA increased from 40.1 letters to 57.9 letters, the average VFI from 40.9% to 70.3% and the overall average contrast sensitivity from 7.7 dB to 11.3 dB. From D15 to D90, the average VA increased from 77 letters to 80.3 letters, the average VFI from 91.2% to 97.9% and the overall average contrast sensitivity from 15.4 dB to 16.7 dB. Four patients rated tolerance at 10 (excellent), three between 8 and 9, and two at 6.We demonstrated rapid improvement of visual function parameters in patients with ON after high-dose oral corticosteroids.

International audience; BACKGROUND: In order to reduce the risk of progressive multifocal leucoencephalopathy when using natalizumab for more than 12 months, a 6-month drug holiday has been discussed. However, the consequences on short term disease activity have been poorly assessed. OBJECTIVE: The aim of this study was to assess clinical and radiological disease activity within 6 months after stopping natalizumab in very active relapsing remitting Multiple Sclerosis (RRMS) patients. METHODS: In 8 hospitals from Western France, we retrospectively collected clinical and MRI data from consecutive RRMS patients treated with natalizumab for at least 6 months, and who stopped the drug for various reasons except therapeutic failure. Patients didn't receive any other disease modifying treatment after discontinuing natalizumab. RESULTS: A total of 27 patients with very active RRMS before natalizumab start (mean annualized relapse rate of 2.3, MRI activity in 21 of 27 patients) were studied. Within 6 months after discontinuing natalizumab, 18 patients (67%) experienced clinical relapse and 3 additional patients had radiological activity, without clinical relapse. Four patients (15%) experienced a rebound activity, with severe relapse and 20 or more gadolinium enhancing lesions on MRI. CONCLUSION: Such observational data didn't support the concept of drug holiday when using natalizumab in very active RRMS.

Resume Introduction Nous rapportons une etude multicentrique observationnelle de 30 patients ayant presente une forme maligne inaugurale de sclerose en plaques (SEP) traites par mitoxantrone en premiere ligne. Methode Les patients ont ete selectionnes selon les criteres de forme maligne de SEP de Weinshenker (soit une poussee « catastrophique », soit une forme rapidement agressive) avec analyse retrospective de la severite clinique initiale et sur une periode d’un an apres l’instauration de mitoxantrone. Le nombre et le taux annuel de poussees (TAP) ont ete compares, ainsi que le score EDSS et l’activite IRM. Resultats La mitoxantrone a ete instauree 5,7 ± 3 mois apres les premiers symptomes de SEP, le nombre de poussees survenues avant traitement et l’annee suivant son instauration a ete respectivement de 87 et dix. Le TAP etait de 6,0 ± 2 avant traitement et de 0,3 ± 0,7 apres, soit une diminution de 95 %. Vingt-quatre patients (80 %) ont ete libres de poussees apres traitement avec un recul d’un an. Le score EDSS moyen etait a 4,8 a l’instauration du traitement et chutait a 2,9 a un an avec une amelioration chez 87 % des cas. En terme d’activite IRM, alors que 97 % des patients presentaient des lesions prenant le contraste avant traitement, seulement 17 % en presentaient apres. Conclusion La mitoxantrone a montre un impact clinique rapide dans les formes malignes inaugurales de SEP, son utilisation apres echec des corticoides merite d’etre consideree.

Resume Introduction Nous rapportons une etude observationnelle de 100 patients consecutifs ayant une SEP remittente agressive, traites par mitoxantrone (MITOX) selon les criteres de l’AMM obtenue en octobre 2003 (ELSEP ® ). Methode Cent patients ayant une SEP remittente agressive ont ete traites par MITOX 20 mg IV associee a 1 g de methylprednisolone IV par mois pendant 6 mois, suivie pour 57 d’entre eux par un traitement d’entretien par immunosuppresseur ou immunomodulateur. Les poussees et les scores EDSS ont ete recueillis prospectivement tous les 6 mois. L’activite IRM a ete evaluee avant et apres traitement par MITOX. Resultats Le suivi median etait de 3,8 ans. Avant MITOX, le taux annuel de poussees (TAP) etait de 3,2, l’EDSS moyen augmentait de 2,2 ± 1 points et 85 p. 100 des patients avaient une IRM active. A 1 an de suivi, le TAP etait reduit de 91 p. 100, 76 p. 100 des patients etaient indemnes de nouvelle poussee, l’EDSS moyen diminuait d’1,2 points (p 6 ), l’activite IRM etait reduite de 89 p. 100. Le benefice etait maintenu jusqu’a 5 ans sur les poussees et jusqu’a 4 ans sur le handicap. Conclusion Cet impact rapide et franc sur les marqueurs de l’inflammation suggere que la MITOX en cures mensuelles pendant 6 mois pourrait etre utilisee dans une strategie therapeutique plus globale en traitement d’induction.

Introduction La pustulose sous-cornee de Sneddon-Wilkinson est une pustulose amicrobienne qui appartient a la famille des dermatoses neutrophiliques. Elle est souvent associee a une gammapathie monoclonale, parfois a des maladies auto-immunes et des cancers. Nous rapportons un cas de pustulose de Sneddon-Wilkinson avec manifestations neurologiques. Observations Un homme de 53 ans etait atteint depuis 2006 d’une pustulose aseptique recidivante des grands plis et du tronc. La biopsie cutanee retrouvait une pustule sous-cornee avec immunofluorescence directe negative en faveur d’une pustulose de Sneddon-Wilkinson. L’electrophorese des proteines seriques mettait en evidence une gammapathie biclonale IgG lambda et IgM lambda, et le myelogramme un syndrome lymphoproliferatif de bas grade. La pustulose recidivait des l’arret des dermocorticoides et le patient etait traite successivement sans efficacite par dapsone, phototherapie UVB, acitretine, colchicine, methotrexate. En 2011 puis en 2012, survenaient 2 episodes de syndrome cerebelleux. Le patient n’avait pas d’aphtose, de syndrome sec, de signes articulaires ou ophtalmologiques. L’IRM cerebrale trouvait des lesions en hypo-signal T1 et hyper-signal T2 des pedoncules cerebelleux, droit en 2011 et gauche en 2012, avec integrite des axes vasculaires, en faveur d’une origine inflammatoire. La ponction lombaire retrouvait une hyperproteinorachie a 0,51 g/L sans synthese intrathecale d’immunoglobulines. L’IRM medullaire n’apportait pas non plus d’argument pour une sclerose en plaques. Le reste du bilan, notamment immunologique, etait normal, et la recherche d’HLA-Cw1, B54, et B51 etait negative. Une corticotherapie par Solumedrol®, 3 bolus en 2011 puis 5 en 2012 relayes per os a 1 mg/kg/jour avec decroissance sur 20 mois permettait une recuperation neurologique complete. Les lesions pustuleuses recidivaient a la decroissance des corticoides et le methotrexate etait repris sans efficacite. Un traitement par anti-TNF etait envisage. Discussion Parmi les dermatoses neutrophiliques, seuls la maladie de Behcet et le syndrome de Sweet ont ete decrits en association a des atteintes neurologiques centrales. Le diagnostic de maladie de Behcet n’etait pas retenu chez notre patient. Le neuro-Sweet est exceptionnel et se manifeste souvent chez les porteurs HLA-Cw1 et B54 par des meningites, des encephalites ou des anomalies de signaux a l’IRM. L’originalite de notre cas est la survenue de manifestations neurologiques au cours d’une pustulose de Sneddon-Wilkinson, ce qui n’a jamais ete rapporte a notre connaissance. Conclusion Notre cas de pustulose sous-cornee de Sneddon-Wilkinson a la particularite d’etre associe a une atteinte neurologique centrale, ce qui incite a integrer cette affection au sein des maladies neutrophiliques avec atteinte systemique. L’examen neurologique des patients atteints de dermatoses neutrophiliques doit etre systematique, complete par une IRM en cas de point d’appel.

Following the publication practice guidelines for multiple sclerosis by a group of neurologists (multiple sclerosis study group [GRESEP]), the primary objective of this study was to compare the reality of practice to the guidelines according to the targeted clinical audit (TCA) method. The study was conducted at 17 neurology sites and was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA-EVOL). Two complementary surveys were done on the record keeping and the root causes of the deviations. The percentages of compliance ranged from 8 to 98% for the TCA-DIAG, and from 15 to 99% for the TCA-EVOL, with wide disparity between sites. The audits were able to identify causes of the flaws in traceability or accessibility. At the end of the study, despite its limitations, we think that the sharing of the results from different sites provided interesting approaches for the use of the assessment criteria defined by GRESEP in a complete audit cycle. This study is to our knowledge the first report of an experiment in which guidelines were created, and subsequently followed by the development of assessment criteria and then the performance of targeted clinical audits using them, all by the same participants.Clinical practice guidelines (CPGs) are intended to help practitioners and patients make informed treatment choices, but their integration into actual practice remains problematic. This study was done immediately following the publication of CPGs for multiple sclerosis (MS) by the multiple sclerosis study group [GRESEP]. The primary objective was to generate quality criteria, to test them within the same group, and to analyze the observed deviations.The study was conducted in the 17 voluntary departments that had participated in the development of the CPGs. The targeted clinical audit method was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA-EVOL). All the files were evaluated by a clinical research technician using digital format, which ensured thoroughness of the collection. Two complementary surveys were done on the record keeping and the potential causes of the deviations.The percentages of compliance to the criteria ranged from 8 to 98% (out of 240 files) for the TCA-DIAG, and from 15 to 99% (221 files) for the TCA-EVOL, with wide disparity between sites (interquartile distance ranges: TCA-DIAG between 0% and 55%; TCA-EVOL between 0% and 70%). The mean percentage of compliance with all the criteria as measured by the TCA-DIAG was 83.9% for the sites with digital files vs. 76.4% for those with only paper files (P0.01). For the TCA-EVOL, the difference was not significant. Explanations for the observed deviations were suggested (1 to 9 according to the participants).The quantified results could not be compared to other studies given the unique nature of the experiment. The importance of the traceability of practices in the patient files was discussed and assessed with regard to continuity and safety of care, as well as the medical-legal perspectives. Causes of lack of compliance were suggested (particularly the absence of reminders, the lack of means and/or time). Despite the limitations of the study, we think it is advisable that when a group becomes involved in the development of CPGs that they follow with the development of assessment criteria in order to evaluate the validity as well as their character as intermediate indicators of the quality of practices.

GUILLAIN-BARRE SYNDROME (GBS) is an acute peripheral neuropathy characterized by a symmetric, usually ascending paralysis due to an acute inflammatory demyelination. GBS is considered the prototype of postinfectious illness with immunopathologic features that include an inadequate immune response against persistent foreign epitopes which cross-react with self-epitopes of peripheral nerves. Regarding this hypothesis, progressive understanding of the immunopathological phenomena leading to the persistence of infective agents in host may provide a rationale for targeting immunotherapy in GBS. In the field of immune tolerance, recent studies have focused on the role of the Human Leukocyte Antigen–G (HLA-G) molecules, which belong to the non-classical HLA class Ib molecules. HLA-G proteins differ from classical HLA-Ia molecules by their low polymorphism, their restricted tissue distribution in tumors (1), and pulmonary (5) or muscle inflammation (6). Furthermore, they exert immunotolerant functions in feto-maternal tolerance, heart-graft acceptance, and tumor immunoevasion (1). Lastly, in a previous report, we evidenced HLA-G expression on monocyte-macrophages during human cytomegalovirus (HCMV) reactivation. We proposed this phenomenon as a new mechanism that could help HCMV eluding host defences and persisting in human body (4). Consequently, and because CMV infection is the most common viral disease causing GBS (2), we examined HLA-G expression on peripheral monocytes in a patient with a GBS induced by HCMV primary infection. A 41-year-old man presented with a bilateral ascending paresthesias and a progressive weakness in lower limbs. On admission, he was afebrile, presented with areflexia of the lower limbs, and had progressively developed a flaccid ascending tetraparesis. GBS was confirmed by elevated CSF protein concentration (0.6g/L) without cellular response and an absence of spinal cord compression on CT scan. Electrophysiological studies showed slow motor conduction, increased distal latencies, an abolition of F waves, and a normal sensory parameters. Acute HCMV infection was proved by high anti-CMV IgM and IgG antibodies, and positive blood PCR (3). Primary infection was demonstrated by an urea denaturation test showing predominance of low-avidity IgG produced early in infection. Tests for other viruses (HSV, HIV, HAV, HBV, and HCV) remained negative. Despite treatment by immunoglobulins and ganciclovir, the patient developed respiratory failure and required mechanical ventilation for 2 months. Recovery was slow, and he was discharged 3 months after admission. We evidenced HLA-G expression on some of the patient’s blood monocytes by allogeneic stimulation. Briefly, monocytes were isolated at the onset of the disease by Ficoll density gradient centrifugation and

Background: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. Methods: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. Results: Mean age at onset was 34.5 years (range 4–66) with a mean disease duration of 10 ± 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score ≥4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity ≤1/10. Conclusions: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

In an observational multicenter study, we analyzed retrospectively 30 patients with malignant form of multiple sclerosis (MS) treated with mitoxantrone the year following the first neurological event.The 30 patients were selected according to Weinshenker criteria of malignant MS (either a "catastrophic" relapse or a quickly aggressive form). We compared clinical and MRI findings the year before with the year following mitoxantrone onset treatment: annualized relapse rates (ARR), EDSS score and percentage of patients with gadolinium enhancing lesions on MRI.A total of 87 relapses were observed in the 5.7 months before and 10 during the year following onset of mitoxantrone treatment. The ARR decreased by 95% (6.0+/-2 before and 0.3+/-0.7 after). Twenty-four patients (80%) were relapse-free one year after onset of mitoxantrone treatment. The EDSS score improved in 87% of MS patients and the mean EDSS decreased by 1.9. Ninety-seven percent had at least gadolinium enhancing lesions before the start of mitoxantrone treatment as compared to 17% after.In our experience, mitoxantrone had a rapid and strong impact on the malignant forms of MS with a short disease duration. In this MS subgroup, mitoxantrone should be considered as an early treatment option.

In France no data have been published about comparing survival in multiple sclerosis (MS) patients with the general French population. We estimated survival probabilities in MS patients from a major centre for MS in West France. We also compared MS survival with the general population and assessed prognostic parameters. All patients with MS onset after January 1976 and classified as dead or alive on 1 January 2004 were included. One thousand eight-hundred and seventy-nine patients (sex ratio W: M 2.3; relapsing/progressive onset 77.4%/22.6%) fulfilled these criteria, disease duration ranged from one to 28 years. By 2004, 68 patients died (51 due to MS) and the 15 and 25-year survival probabilities were 96% and 88%. Male gender, progressive course (either primary or secondary), polysymptomatic onset, and increased annual relapse rate during the first two years of MS were related to a worse prognosis. After a mean follow-up duration of 12.7 years since clinical onset, MS increased the number of deaths compared with the general population. However taking into account disability status, we found that less disabled MS patients had a better survival and highly disabled patients a worse survival (eight-fold increase of mortality) compared with the French population. Multiple Sclerosis 2007; 13: 865—874. http://msj.sagepub.com

Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Isolated aspergillosis of the sphenoid sinus is a rare condition that is frequently diagnosed at a late stage because of its nonspecific and varying symptomatology. We report the case of a 75-year-old diabetic woman with a long history of retroorbital pain before she developed a subacute cavernous sinus syndrome. Neuroimaging including CT scan and MRI suggested a malignant tumor involving the sphenoid sinus but the diagnosis of aspergillosis was made intraoperatively and by histopathological examination. Soon after surgical drainage of the sphenoid sinus and systemic anti-fungal drug therapy, both retroorbital pain and cavernous sinus syndrome had completely resolved. This case emphasizes the fact that invasive isolated sphenoid sinus aspergillosis must be considered in the list of lesions causing sinus cavernous syndrome.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI)=0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukaemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.

A case history illustrating the use of hypnosis in the retrieval of memory loss due to post-traumatic retrograde amnesia is described. This information was subsequently accepted as admissible in court proceedings. This report has implications for the process of the laying down of memory, and adds support to the retrieval failure hypothesis and the catalogue model of memory formation, with virtually instantaneous encoding of memory. It is also potentially of importance in that it provides a precedent for the acceptance by courts of law of previously amnesic information retrieved by means of hypnosis.