Epidemiology of myasthenia gravis in France: Incidence, prevalence, and comorbidities based on national healthcare insurance claims data.

BACKGROUND: The European literature has reported high variability in the incidence and prevalence rates of myasthenia gravis (MG), but no specific epidemiological data for France have been published. This study aimed to assess the incidence and prevalence rates of myasthenia gravis in France based on data extracted from the French National Health Insurance Claims Database (the SNIIRAM database). METHODS: We conducted a retrospective repeated cross-sectional population study from 2008 to 2018 using a representative sample of the French population (Échantillon généraliste des bénéficiaires) covered by health insurance. We calculated the incidence, prevalence, and sex ratio of MG and screened for comorbidities associated with MG (standardized to the general population). RESULTS: In total, 331 MG patients were identified between 2008 and 2018. The average incidence of MG in France was 50 per million person-years, while the mean prevalence was 465 per million people. The female-to-male ratio was 1.33. The Incidence of MG gradually increased from 40years of age for women and 60 for men. Thymoma was present for 5.1% of MG patients and a thymectomy was performed for 4.7%. Thyroid disease was the most prevalent autoimmune comorbidity, affecting approximately 8.5% of cases. MG patients had an increased cancer risk, with a standardized rate ratio of 2.38 (95% CI: 1.64-3.46). CONCLUSION: The incidence and prevalence rates of MG are significantly higher than those previously reported in the literature and the incidence increases with age. The excess risk of cancer raises concerns for MG patients, in particular, concerning the management of immunosuppressive drugs.

Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria.

BACKGROUND: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. METHODS: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. RESULTS: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. CONCLUSIONS: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

Rationale for off-label treatments use in primary progressive multiple sclerosis: A review of the literature.

BACKGROUND: Until recently, few therapeutic options, other than symptomatic treatment, were available for patients with primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only approved treatment in this indication, and only since 2017. However, many patients in France are receiving off-label treatments for PPMS, mainly rituximab, mycophenolate mofetil, methotrexate, cyclophosphamide, and azathioprine. OBJECTIVE: To evaluate published data concerning the efficacy of these five treatments frequently used as off-label disease-modifying therapies. METHODS: We reviewed and summarized the studies published in Pubmed since the inception of the database. RESULTS: Evidence from randomized controlled trials is lacking to support the use of these treatments as disease-modifying therapies in PPMS. CONCLUSION: The literature lacks dedicated studies to support the off-label use of these disease-modifying therapies in PPMS. However, some limited data are available in the literature suggesting that the use of rituximab and cyclophosphamide could potentially be of some interest in specific subpopulations.

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

[Functional stereotactic radiosurgery: Indications and perspectives]. / Radiochirurgie fonctionnelle : indications et perspectives.

Stereotactic radiosurgery (SRS) is a non-invasive technique that enables to create brain focal lesions with a high precision and localization. Thus, functional brain disorders can be treated by SRS in case of pharmacoresistance or inoperability. To date, treatment of trigeminal neuralgia is the most described and known indication. Other indications will be developed in the future like movement disorders, refractory epilepsy, obsessive compulsive disorder and severe depression. We present here a review of actual and future indications of functional brain SRS with their level of evidence. All these SRS treatments have to be strictly conducted by trained teams with an excellent collaboration between radiation physicists, medical physicists, neurosurgeons, neurologists, psychiatrists and probably neuroradiologists.

Dimethyl fumarate and teriflunomide for multiple sclerosis in a real-life setting: a French retrospective cohort study.

BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) and teriflunomide are approved oral disease-modifying treatments for relapsing-remitting multiple sclerosis (MS). Phase 3 trials established these agents to be effective and generally well tolerated, although comparative efficacy and discontinuation rates are still unknown. The aim of this study was to assess real-world efficacy and discontinuation of DMF and teriflunomide in patients with relapsing-remitting MS. METHODS: This retrospective observational cohort study was carried out in a French administrative region between March 2014 and July 2017. Patients who were followed by private or hospital neurologists were included. Efficacy and tolerance of the two treatments were assessed and compared by multivariate analysis, considering the duration of MS, annualized relapse rate and Expanded Disability Status Scale score at treatment initiation, treatment duration, type of prescriber and tobacco use. RESULTS: We identified 189 DMF- and 157 teriflunomide-treated patients who had been treated for 22 ± 10 months. After correction for confounders, DMF more efficiently reduced the annualized relapse rate after 2 years than teriflunomide (0.06 vs. 0.21; P = 0.03). DMF-treated patients had more clinical and biological adverse events, resulting in a higher rate of treatment discontinuation (28% vs. 12%, P = 0.03). CONCLUSION: In this retrospective cohort study, DMF demonstrated significantly better efficacy over 2 years than teriflunomide, but tolerance to teriflunomide was better.

Migraine prevalence in inflammatory bowel disease patients: A tertiary-care centre cross-sectional study.

BACKGROUND: Inflammatory bowel diseases (IBD) are systemic, chronic inflammatory conditions that predominately affect the gastrointestinal tract and can induce abdominal pain. Besides, many IBD patients complain about headaches in daily practice. The objective was to assess the prevalence of headaches, including migraines and pain with neuropathic characteristics (NC), in IBD patients compared to historical controls from the general population. METHODS: Overall, 203 consecutive tertiary-care centre patients completed validated self-administered questionnaires and benefitted from a clinical evaluation performed by an IBD physician at the same time. RESULTS: In our cohort, 75% of the patients experienced pain in the previous 3 months. Migraine prevalence was two-fold higher in IBD patients compared to the general population (41% vs. 21.3%, p < 0.001). Migraine was associated with a younger age, female gender and higher depression scores. Although migraine impact was very important for 30% of the patients (61/203), specific acute therapeutics were prescribed in only 22% of cases (18/83). Chronic pain with NC was more frequent than in the general population (11.3% vs. 6.9%, p = 0.012) and was strongly associated with the presence of extra-intestinal manifestations (p < 0.001). Abdominal pain concerned 19% of the patients during the previous week and was, as expected, associated with disease activity. CONCLUSIONS: Migraine prevalence is strongly increased in IBD patients followed in tertiary care. A systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics. Further studies are needed to confirm whether migraine should be classified as IBD extra-intestinal manifestations. SIGNIFICANCE: Migraine prevalence was two-fold higher in IBD patients compared to the general population, was generally poorly treated and a systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics.

Fixed 50:50 mixture of nitrous oxide and oxygen to reduce lumbar-puncture-induced pain: a randomized controlled trial.

BACKGROUND AND PURPOSE: Lumbar puncture (LP) has been frequently performed for more than a century. This procedure is still stressful and often painful. The aim of the study was to evaluate the efficacy of a fixed 50% nitrous oxide-oxygen mixture compared to placebo to reduce immediate procedural pain and anxiety during LP. METHODS: A randomized controlled trial was conducted involving adults who needed a cerebrospinal fluid analysis. Patients were randomly assigned to inhale either a fixed 50% nitrous oxide-oxygen mixture (50% N2 O-O2 ) or medical air (22% O2 -78% N2 ). Cutaneous application of a eutectic mixture of local anaesthetics was systematically done and all LPs were performed with pencil point 25G needles (20G introducer needle). The primary end-point was the maximal pain level felt by the patient during the procedure, the maximal anxiety level being a secondary outcome, both measured using a numerical rating scale (0-10). RESULTS: A total of 66 consecutive patients were randomized. The analysis was intention to treat. The maximal pain was 4.9 ± 2.7 for the 33 patients receiving air and 2.7 ± 2.7 for the 33 receiving 50% N2 O-O2 (P = 0.002). Similarly, the maximal LP-induced anxiety was 4.5 ± 3.1 vs. 2.6 ± 2.6 (P = 0.009), respectively. The number needed to treat to avoid one patient undergoing significant pain (pain score ≥ 4/10) was 2.75. Body mass index >25 kg/m2 was significantly associated with higher pain intensity (P = 0.03). No serious adverse events were attributable to 50% N2 O-O2 inhalation. CONCLUSIONS: Inhalation of a fixed 50% N2 O-O2 mixture is efficient to reduce LP-induced pain and anxiety.

Evaluation of quality of life and fatigue in radiologically isolated syndrome.

BACKGROUND: Radiologically isolated syndrome (RIS) is a new subtype entity described at the very left of the demyelinating disease spectrum, where spatial dissemination of T2-weighted lesions can be documented on MRI in subjects with no history of neurological symptoms. OBJECTIVES: This study was a longitudinal assessment of health-related quality of life (HRQOL) and fatigue in RIS patients. METHODS: Non-converted RIS patients were evaluated at the time of diagnosis, and at 1 and 2 years of follow-up; their scores were compared with scores in clinically isolated syndrome (CIS) patients and age-matched controls. RESULTS: Sociodemographic characteristics were comparable at baseline. There was no statistical difference between RIS and CIS groups in terms of cerebrospinal fluid (CSF) positivity or T2 lesion load. For HRQOL evaluations, RIS patients scored the same as controls, while CIS patients scored lower. Fatigue was detectable in both RIS and CIS patients compared with baseline and with controls. Mental HRQOL scores decreased significantly for RIS patients during follow-up. CONCLUSION: HRQOL impairment and fatigue were detectable during follow-up in both non-converted RIS and CIS patients.

Evaluation of the application of the European guidelines for the diagnosis and clinical care of amyotrophic lateral sclerosis (ALS) patients in six French ALS centres.

BACKGROUND AND PURPOSE: Our objective was to evaluate the extent to which the 2005 recommendations of the European Federation of Neurological Sciences (EFNS) on the multidisciplinary management of amyotrophic lateral sclerosis (ALS) are followed in clinical practice. METHODS: This was a multicentre observational study involving six French ALS referral centres receiving prevalent and incident cases. Recommendations were translated into ad hoc questions referring to key aspects of management, and their application was evaluated by a clinical research assistant who independently examined the medical charts (MCs). When necessary, an independent board-certified neurologist answered the questions based on examination of the MC and interview of the caring neurologist. Questions regarding diagnosis and communication were put to patients in a self-administered questionnaire. RESULTS: In all, 376 patients [176 incident, 200 prevalent cases; median age at diagnosis 62.8 years (interquartile range 55.7-72.3); sex ratio 1.37; 27.3% bulbar onset] were included. All the topics covered in the recommendations were evaluated: diagnostic delay (e.g. mean 13.6 months, associated with age and onset); breaking the news (e.g. criteria for communication quality were satisfactory in more than 90%); multidisciplinary and sustained support (e.g. clinic visits were scheduled every 2-3 months in 90%). Also considered were whether riluzole had been offered, symptom management, genetic testing, ventilation, communication defects, enteral nutrition, palliative and end-of-life care. Characteristics associated with poor compliance with some guidelines (schedule of visits, delayed riluzole initiation) were also identified. CONCLUSION: This is the first evaluation of the application of the EFNS recommendations for the management of ALS in a nationwide sample. The results allow us to highlight areas for improvement.

Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing-remitting, secondary progressive and primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Few studies have investigated the differences in cognitive skills between the three subtypes of multiple sclerosis (MS) and they confounded the course of the disease with the duration of the disease and the physical disability. Moreover, they were not population based. METHODS: This was a retrospective analysis of cognitive testing from the database of a French programme for MS care. The pattern and the frequency of cognitive impairment in secondary progressive (SP), primary progressive (PP) and late relapsing-remitting (LRR, disease duration of more than 10 years) MS were compared. RESULTS: A total of 101 patients with MS (41 LRRMS, 37 SPMS, 23 PPMS) were included. 63.0% had a significant cognitive impairment. After controlling for age, sex, Expanded Disability Status Scale, disease duration and education level, patients with SPMS were at least 2-fold more frequently impaired than patients with LLRMS in information processing speed (P = 0.005), executive functions (P = 0.04), verbal fluency (P = 0.02), verbal episodic memory (P = 0.04), working memory (P = 0.02) and visuospatial construction (P = 0.01). The number of patients with at least one or two deficient cognitive domain(s) was higher in the SPMS group than in the LRRMS group (P = 0.002 and P < 0.001). Patients with PPMS were more frequently impaired in verbal fluency (P = 0.046) than patients with LRRMS and they more often presented at least one impaired cognitive domain (P = 0.03). SPMS and PPMS groups differed only for visuospatial construction (P = 0.02). CONCLUSION: In this population-based study, patients with a progressive subtype of MS were more frequently and more severely impaired than patients with RRMS, even after more than 10 years of disease.

A novel autosomal dominant leukodystrophy with specific MRI pattern.

Etiologic diagnosis of adulthood leukodystrophy is challenging in neurologic practice. We describe here the clinico-radiological features of a novel autosomal dominant leukodystrophy in a single family. Clinical and MRI features were recorded in a three generation family. Exome sequencing was performed in two affected relatives and one healthy member. Four total relatives (3 women and 1 man, mean age at onset: 45, range 32-59) were followed: 2 for migraine and 2 for cognitive loss. MRI features were homogeneous in the four affected relatives: extensive and symmetrical white matter hyperintensities on T2-weighted images, with a posterior predominance, involvement of the middle cerebellar peduncles, corpus callosum and the posterior limb of the internal capsules. An extensive metabolic screening was negative. In addition, sequencing of pathogenic genes involved in dominant leukodystrophies (NOTCH3, LMNB1, GFAP, CSF1R) was negative. No mutation has been identified yet with exome sequencing. This report is peculiar because of dominant inheritance, adult onset, highly homogeneous white matter hyperintensities on T2-weighted MR images, predominant in the middle cerebellar peduncles and posterior part of internal capsule and absence of mutation of the genes involved in dominant leukodystrophies.

Two cases of bilateral amiodarone-associated optic neuropathy.

INTRODUCTION: The widespread use of amiodarone is limited by its toxicity, notably to the optic nerve. We report two cases of bilateral optic nerve neuropathy due to amiodarone, and provide a detailed description of the disease. OBSERVATIONS: The first case was a 59-year-old man complaining from insidious monocular loss of vision within ten months of initiating amiodarone. Funduscopy and optical coherence tomography showed bilateral optic disc edema. The second case was a 72-year-old man presenting with a decrease in visual acuity in his left eye for a month. Funduscopy showed a left optic nerve edema, and fluorescein angiography showed bilateral papillitis. In both cases, the clinical presentation was not suggestive of ischemic neuropathy, because of the preservation of visual acuity and the insidious onset. In addition, both cardiovascular and inflammatory work-up were normal. An amiodarone-associated neuropathy was suspected, and amiodarone was discontinued with the approval of the cardiologist, with complete regression of the papilledema and a stabilization of visual symptoms. DISCUSSION: Differentiating between amiodarone-associated optic neuropathy and anterior ischemic optic neuropathy may be complicated by the cardiovascular background of such patients. The major criterion is the absence of a severe decrease in visual acuity; other criteria are the normality of cardiovascular and inflammatory work-up, and the improvement or the absence of worsening of symptoms after discontinuation of amiodarone. CONCLUSION: Amiodarone-associated neuropathy remains a diagnosis of exclusion, and requires amiodarone discontinuation, which can only be done with the approval of a cardiologist, and sometimes requires replacement therapy.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

Rates of progression of weight and forced vital capacity as relevant measurement to adapt amyotrophic lateral sclerosis management for patient Result of a French multicentre cohort survey.

OBJECTIVES: To compare survival, to describe the progression of anthropometry, pulmonary capacity and functioning in ALS (Amyotrophic Lateral Sclerosis) and to identify the most relevant variables to adapt ALS management for patients. METHODS: A cohort study was performed in French ALS centres between January 2003 and July 2005. Eligible patients were treated by Riluzole and had a slow vital capacity (SVC) or a forced vital capacity (FVC) at least equal to 60%. Demographic, medical and ALS characteristics were registered. Manual Muscular Testing (MMT) and ALS Functional Rating Scale (ALSFRS) were performed. Kaplan Meier method was used to analyse survival. ALS progression was measured by the percentage weight, FVC, SVC, MMT and ALSFRS loss and was analysed as longitudinal data using mixed model. RESULTS: Three hundred and eighty three patients were included. The median survival since ALS diagnosis was 2.34 years (95%CI 2.10-2.65). Mixed model analyses revealed a more significant worsening progression of weight and FVC loss for bulbar onset. The drop of ALSFRS and SVC is similar whatever the ALS forms. CONCLUSIONS: Rates of progression of weight and FVC should be regularly watched over to support neurologists to adapt ALS management for patients.

Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.

PURPOSE: This retrospective study evaluated the effectiveness of salivary gland radiotherapy for reducing sialorrhea in patients with amyotrophic lateral sclerosis (ALS). PATIENTS AND METHODS: From August 2001 to February 2008, 21 patients with amyotrophic lateral sclerosis (six men, 15 women; mean age 61.2 years, range 39-81) received external beam radiotherapy for sialorrhea (evaluation by the ALS Functional Rating Scale). All patients had previously received pharmacological treatments with unsatisfactory results or side effects. The mean dose was 19.1Gy (range 3-48), delivered in five fractions (range 1-16) on 17 days (range 1-77). Eight patients received 3D-conformal and 13 received 2D-conformal radiotherapy. Clinical target volumes included the parotids and submandibular glands (18 patients), submandibular glands and one parotid (one patient), or parotids (two patients). Thirteen patients were treated with 5.5-6MV photons and eight were treated with 6-15MeV electrons. A satisfactory salivary response was defined as complete or partial improvement. The median follow up was 10.4 months (range 0.4-26). One patient was lost to follow up. RESULTS: A positive response was observed in 65% of patients during a mean of 7 months (range 1-23). Four patients (20%) treated with photons and no patients treated with electrons experienced acute toxicity. Half (50%) the patients treated with photons and 87.5% of patients treated with electrons responded positively (P=0.09). Positive responses were more common with a high total dose (≥16Gy; 78.6%) than a low total dose (<16Gy; 33%; P=0.07). No differences were observed in tolerance (P=0.27). Age and sex did not impact the response. CONCLUSION: Salivary gland radiotherapy effectively reduced sialorrhea in patients with amyotrophic lateral sclerosis. An adequate compromise between toxicity and efficiency was achieved with 3D-conformal radiotherapy delivered with electrons to parotids and submandibular glands in a total dose of 16Gy or more (mean: 20Gy in five fractions).