Serology results after COVID vaccine in multiple sclerosis patients treated with fingolimod.

INTRODUCTION: While it is recommended that patients with multiple sclerosis (MS) be vaccinated against COVID-19, it is unknown what the vaccine response is in MS patients treated with fingolimod, an agent which modulates the humoral response. We aimed to characterize the immune response to the COVID-19 vaccine in MS patients treated with fingolimod and to explore which factors influenced response. METHOD: We collected the following data from 59 MS patients treated with fingolimod and vaccinated against COVID-19: age, sex, duration of treatment, number of vaccine doses, date of last vaccination, type of vaccine, lymphocyte count, history of COVID-19, and serology to measure the vaccine response. We used Student's t-test and Chi2 test to see whether there was a relationship between these variables and seropositivity. A multivariate logistic regression model was used to identify factors influencing the serology result. A multivariate linear regression model was used to identify factors influencing the antibody titer. RESULTS: Twenty-eight participants (47%) developed a positive serology. Age (P<0.001) and the duration of treatment (P=0.002) were significantly related to seropositivity. Gender (P=0.73), number of vaccinations (P=0.78), lymphocyte count (P=0.46), and the time between the last vaccine dose and blood sampling (P=0.84) were not significant variables. Multivariate analysis using logistic regression (n=59) showed that age (P=0.003, RR = 2.28, 95%CI = 1.28, 4.07) and duration of treatment (P=0.04, RR=1.91, 95%CI=1.04, 3.50) were significantly and independently correlated with COVID serology. Multivariate linear regression analysis of the antibody titer (n=59) found the duration of treatment to be significant (P = 0.015), but not age (P = 0.53). After removing three outliers, age (P = 0.005, RR=6.82, 95%CI=1.66, 27.98) and duration of treatment (P = 0.008, RR=5.12, 95%CI=1.24, 21.03) were significantly correlated with the antibody titer. CONCLUSION: COVID-19 seropositivity was present in 47% of our sample of 59 MS patients on fingolimod. A strong relationship was found between antibody development, age, and duration of treatment, as well as between antibody titer and age and duration of treatment.

A decade of fingolimod in multiple sclerosis: Insights from a large real-world cohort study.

BACKGROUND AND OBJECTIVES: Ten years after its authorization, data about fingolimod use in real-world setting is still scarce. Here we describe the long-term evolution of fingolimod-treated relapsing-remitting MS (RRMS) patients and determine baseline characteristics associated with risk of relapses or disability. METHODS: We analyzed baseline characteristics and clinical evolution of 1227 patients with RRMS treated with fingolimod from 2010 to 2019 in 4 French MS referral centers. We used Cox models to determine risks factors of relapses and sustained EDSS worsening. RESULTS: Median follow-up duration was 50 months, and 63% of patients remained fingolimod-treated at the end of follow-up. Mean 5-years annualized relapse rate (ARR) decreased from 0.63 (0.60-0.67) to 0.26 (0.24-0.29, P<0.001), while the mean EDSS rose from 2.5 (2.4-2.6) to 3.0 (2.8-3.1, P<0.001). Female sex, lower age, higher EDSS and use of natalizumab were associated with relapse risk. Female sex was associated with sustained EDSS increase risk. CONCLUSIONS: Based on a large real-world cohort, our results confirm the durable reduction of the ARR described in pivot studies. Switching from moderate-efficacy DMT to fingolimod decreased the relapse risk. Switching patients from high-efficacy DMT increased risk of relapse, but the overall five-years ARR remained stable.

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.

Developing tools to evaluate quality of care management for patients living with multiple sclerosis: An original French initiative.

INTRODUCTION: Assessing the quality of care management for patients with a chronic disease such as multiple sclerosis (MS) is a major challenge for healthcare systems around the world. It needs to be carried out using tools that are recognized by professionals and patients alike, and should concern practices, systems, and scientific data. No such tools are currently available in Europe. The purpose of the present study was to develop indicators to contribute to assess the quality of care management for patients with MS in France. METHODS: An expert panel comprising 25 professionals from well known teams across France selected the indicators on the basis of consensus. In accordance with the Rand/UCLA Appropriateness Method, each expert had to agree with the recommendations, and there had to be agreement among the experts. RESULTS: The expert panel selected 48 indicators representing seven domains of care management for patients with MS: physical and rehabilitation medicine, disease progression, access to care, magnetic resonance imaging (MRI) management, relapse management, management of disease-modifying treatments, and management of the symptoms of disability progression. Some of these quality indicators (notably pertaining to MRI management) had not previously been identified in the literature. CONCLUSION: These indicators may allow professionals to comprehensively assess and compare their practices and cooperation, thereby contributing to improve the quality of care management for patients with MS in France.

Evaluation of the quality of the care pathway for patients with multiple sclerosis in France: Results of an original study of a cohort of 700 patients.

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.

Dronabinol use in France between 2004 and 2017.

OBJECTIVES: To investigate prescription practices for dronabinol, a pure extract of delta-9-tetrahydrocannabinol, prescribed for refractory chronic pain in France since 2004. DESIGN: A descriptive study based on answers to a questionnaire sent to dronabinol prescribers throughout metropolitan France between June and July 2017. MAIN OUTCOMES MEASURES: We assessed the type of prescribers including place of work (hospital, clinic or private practice) and their specialty. We also collected information about the patient profiles, diseases or symptoms initiating dronabinol prescription, its efficacy and side effects. RESULTS: We received completed questionnaires from 26 prescribers in 17 different areas throughout 12 regions. This represented a total of 191 patients of the 377 indexed since 1st January 2006: the sex ratio was 1:1, with an average age of 51 years for men and of 45 for women. The reason for dronabinol prescription was: multiple sclerosis (49.7%); central neuropathic pain from other causes (36.6%); peripheral neuropathic pain (8%); Parkinson's disease (2.9%); and other causes (around 1%). The duration of dronabinol treatment ranged from 1 month to 6 years and the dose from 2.5mg to 30mg per day (in one or several intakes). 59% of the patients declared experiencing a 30 to 50% reduction in pain. CONCLUSION: This first investigation into dronabinol in France underlines the need to further investigate prescription practices and efficacy so as to define conditions of good use and the place of dronabinol in pain management.

Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study.

BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

Classification and diagnostic criteria for demyelinating diseases of the central nervous system: Where do we stand today?

The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians' and patients' needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.

Clinical allergy. Managing generalized interferon-induced eruptions and the effectiveness of desensitization.

BACKGROUND: We evaluated the value of skin tests and the efficacy of a 12-step desensitization protocol to pegylated interferon (IFN) in patients with generalized drug eruptions due to IFNs. METHODS: A retrospective study (1998-2009) was followed by a cross-sectional clinical study conducted prospectively (2009-2011). All patients received a dermatological clinical examination and skin tests. Twelve-step IFN desensitization was proposed for patient with active hepatitis C and no alternative therapy. RESULTS: Twenty-six patients (13 males, mean age, 53.5 years) had generalized reactions to IFNs; 21 were treated with IFN-α and 5 with IFN-ß. Moreover, 21 patients had skin tests. Intradermal tests (IDTs) were positive after an average of 72 h. Cross-reactivity between peg-IFN-α2a and peg-IFN-α2b was observed in 5/10 cases in the prospective study. In 16 of 26 cases, IFN treatment was stopped. In 8 of 16 cases of diffuse eczematous drug eruption, treatment was continued. The corticosteroid and antihistamine were sufficient in 4/8 cases. In three other cases, topical tacrolimus was highly effective. In 3 of 16 cases in which treatment were stopped, patients underwent the early resumption of peg-IFN-α. These three patients had positive tests with peg-IFN-α2a and peg-IFN-α2b and successfully completed the tolerance induction protocol for peg-IFN-α2b. Tolerance induction involved a weekly dose of peg-IFN and a gradual increase in the recovery of an antiviral C. Clinical tolerance was excellent, and the patients' viral load C became negative. CONCLUSIONS: Our study demonstrates the benefit of allergy testing in cases of generalized drug reactions to IFN, cross-reactivities in a single class of IFNs and the importance of delayed IDT reading. We report for the first time the effectiveness of 12-step desensitization with peg-IFN.

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.

Cognitive rehabilitation in multiple sclerosis.

Cognitive impairments are frequent in multiple sclerosis (MS). However, most studies about efficacy of cognitive rehabilitation interventions have been criticized in terms of methods and/or design. The aim of this study is to evaluate the efficacy of cognitive rehabilitation in MS patients with a cognitive intervention (ProCogSEP* program), compared to a control intervention (discussion program). Twenty MS patients have completed this simple blind study: 10 patients followed 13 sessions (2 hours) of the ProCog-SEP(1) program. Ten other patients followed 13 sessions (2 hours) of a discussion program (Control Group). All patients underwent neuropsychological assessment, before and after their program, in order to evaluate cognitive functions. Two neuropsychologists respectively assessed the patients and conducted the group sessions. Compared to its own baseline, ProCog-SEP Group show improvements in verbal memory [free recall (p = .02), learning (p = .002)], in visual memory [free (p = .05) and delayed recall (p = .007)], in working-memory (p = .03), in verbal fluency (p = .05) and in language (p = .01). Inter group analysis show a benefit of cognitive program mainly in verbal and visual memory, and in verbal fluencies. These results support the interest of a cognitive therapeutic management of MS patients.

Verbal episodic memory in 426 multiple sclerosis patients: impairment in encoding, retrieval or both?

Episodic memory is frequently impaired in multiple sclerosis (MS) patients but the exact nature of the disorder is controversial. It was initially thought to be due to a retrieval deficit but some studies have demonstrated an encoding deficit, which could be linked to a slowing of information processing speed or to a deficit in elaboration of strategies. The main objective of this study is to assess the prevalence and the nature of verbal episodic memory (VEM) impairment in MS patients. We retrieved memory performances of 426 patients [314 F-112 M; mean age: 46.1 years; median Expanded Disability Status Scale (EDSS) score: 3.1] from a neuropsychological data base. VEM was assessed using the 16 words RL-RI 16 test. 66% MS patients present at least one recall impaired in VEM (37.2% from 2 to 5 recall). 14.2% MS patients present an impairment in encoding phase. We observed that 5% of patients presented recognition difficulties. Correlations were observed between VEM performances and EDSS, and disease duration but no group effect (ANOVA) is observed between form of MS and VEM performances. These results confirm the high prevalence of VEM impairment in MS patients. Deficits affect mainly information retrieval in early stage MS patients and are then linked to encoding as disability increases. Storage disorders are infrequent, so cognitive rehabilitation with mental imaging could be effective in MS patients.

Paroxysmal hypothermia in two patients with multiple sclerosis.

BACKGROUND: Hypothermia is a rare condition in patients with multiple sclerosis (MS). Only 17 patients have been reported so far. CASE REPORT: We report 2 patients with a long history of MS who presented with severe acute hypothermia associated with thrombocytopenia and hepatic cytolysis. Both patients presented with an aggravation of their neurological status, psychomotor slowing and confusion. There was no clinical or biological sign of infection. Magnetic resonance imaging (1.5 T) revealed bilateral preoptic T(2)-weighted lesions for 1 patient. The neurological status of one patient was worse after the episode of hypothermia than before, which suggests that hypothermia could be a factor of poor prognosis concerning disease progression.

[Working memory in multiple sclerosis: a review]. / La mémoire de travail dans la sclérose en plaques: revue de la littérature.

INTRODUCTION: Impairment of working memory (WM) is frequently reported in multiple sclerosis (MS) patients. However, the various methodologies used, as well as the populations selected for study, hinder the interpretation of results. The aim of this study is to propose a review about WM in MS. METHOD: Twenty studies have presented results on WM with neuropsychological assessment. RESULTS: All studies conclude that WM is impaired in MS. Reduced processing speed would be central, with major impact on WM performance. According to Baddeley's model, difficulties may be located at the level of the central executive. MS patients would be sensitive to tasks with a high cognitive load. However, performances seem to become better when the processing speed is adapted. Explanatory models relating to this kind of impairment have been proposed from imaging studies. Compensation could mask deficits in WM at the early stage of the disease, but would become blurred with advancing illness and increasing load required for the task. CONCLUSIONS/PROSPECTS: In order to assess WM, adapted tools should be proposed to MS patients. Focus should be placed on processing speed. Further studies are needed, for instance to examine the dissociation of the processes operating within the central executive as described in Miyake's model. Imaging investigations have provided essential data helpful for understanding compensation mechanisms. These data should be useful for developing adapted remediation plans to compensate for the crippling impairment observed in everyday life.

[Hypothalamic involvement in multiple sclerosis]. / Atteintes hypothalamiques dans la sclérose en plaques.

Hypothalamic involvement is a rare condition in patients with multiple sclerosis (MS). We report two patients with a long history of MS who presented with severe acute hypothermia with associated thrombocytopenia and elevated transaminase levels. Several cases of hypothermia or hyperthermia in patients with MS have been reported in the literature. They could be linked with hypothalamic lesions, in particular in the pre-optic area. However, other anatomical locations seem to be involved in thermoregulation and can be affected by MS. Besides, some cases of syndrome of inappropriate antidiuretic hormone secretion have been reported in patients with MS. Finally, some sleep disorders, particularly hypersomnia or narcolepsy, could be related to hypothalamic lesions, through the fall in hypocretin-1 in the cerebrospinal fluid. Hypocretin-1 is a neuropeptide that is secreted by some hypothalamic cells. It plays a role in the sleep-awake rhythm. We report one patient with narcolepsy and cataplexy before the first symptoms of MS appeared. Hypothalamic signs are rare in MS. However, several series of autopsies have shown a high frequency of demyelinating lesions in the hypothalamic area. Among these lesions, the proportion of active lesions seems elevated. Yet only few of them have a clinical or biological translation such as thermoregulation dysfunction, sleep disorders or natremia abnormalities. Thus, it seems unlikely that inflammatory hypothalamic lesions alone, even when bilateral, could be the explanation of these signs. A sufficient number of inflammatory demyelinating lesions, which we can observe in patients with a long history of MS and an already severe disability, is probably necessary to develop such a rare symptomatology. Hypothalamic signs might be a factor of poor prognosis for the disease course and progression of the disability.

High-risk syndrome for neuromyelitis optica: a descriptive and comparative study.

BACKGROUND: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies. OBJECTIVE: To describe HRS patients and compare them with NMO patients. METHODS: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database. RESULTS: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup. CONCLUSION: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.

[Left mesiotemporal lesions and anterograde memory impairement: a case of neurosyphilis]. / Lésions mésiotemporales gauches et amnésie antérograde: un cas de neurosyphilis.

INTRODUCTION: Neurosyphilis has become uncommun in the developed countries. OBSERVATION: We report a case of neurosyphilis with limbic presentation, left mesiotemporal lesions on MRI and severe anterograde amnesia. DISCUSSION: Pathogeneses of MRI findings are unknown. We suggest the implication of arteritis wich affects small vessels, parenchymatous and excitotoxic lesions. The absence of mesiotemporal lesion in immunodeficient patients, the limbic systematization of pathology underlines the involvement of probably auto-immune process. Neurosyphilis should always be considered in the differential diagnosis of limbic encephalitis in order to initiate treatment and to prevent cognitives sequelaes. At last, partial status epilepticus should be diagnosed and excitotoxicity lesions prevents with antiepileptic treatment.

[Cognitive rehabilitation in multiple sclerosis: a review of the literature]. / Remédiation cognitive dans la sclérose en plaques: revue de la litérature.

INTRODUCTION: Cognitive impairment is now well-known in multiple sclerosis (MS). However, few rehabilitation interventions are proposed or really efficient. OBJECTIVES: To present a review of cognitive rehabilitation intervention research conducted in people with multiple sclerosis (MS), regarding different findings about episodic memory, working memory, attention and executive function disorders in MS. DATA SOURCES: A search of Medline (yield 20 papers) and of PsychInfo (yield 1 article), using combinations of the following terms: cognitive rehabilitation, multiple sclerosis, cognitive therapy, neuropsychological rehabilitation, in the title or in the abstract, from 1960 to March 2010, excluding animal studies. RESULTS: Episodic memory rehabilitation studies appear to be promising. Programs on working memory, attention and executive functions are in the very early phases. CONCLUSIONS: Results are encouraging and allow specific recommendations for future research about: (1) inclusion criteria, often not defined, (2) a specific baseline adapted to the program of rehabilitation, (3) a control measure regarding program efficiency and (4) a role for the psychologist (presence and advice during the program).