Frequent detection of IFN-gamma -producing memory effector and effector T cells in patients with progressive multifocal leukoencephalopathy.

Introduction: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Methods: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. Results: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). Discussion: The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis.

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. Exposure: HET or MET at treatment initiation. Main Outcomes and Measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). Conclusions and Relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up.

BACKGROUND AND OBJECTIVES: Spinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort. METHODS: We retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model. RESULTS: A total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor-α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]). DISCUSSION: Regarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure: Diagnosis of RIS. Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab.

OBJECTIVES: The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses. METHODS: NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations. RESULTS: Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses. CONCLUSIONS: These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%.

Untreated patients with multiple sclerosis: A study of French expert centers.

BACKGROUND AND PURPOSE: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. METHODS: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. RESULTS: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. CONCLUSION: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

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

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols.

Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology.

Argan Oil-Mediated Attenuation of Organelle Dysfunction, Oxidative Stress and Cell Death Induced by 7-Ketocholesterol in Murine Oligodendrocytes 158N.

Argan oil is widely used in Morocco in traditional medicine. Its ability to treat cardiovascular diseases is well-established. However, nothing is known about its effects on neurodegenerative diseases, which are often associated with increased oxidative stress leading to lipid peroxidation and the formation of 7-ketocholesterol (7KC) resulting from cholesterol auto-oxidation. As 7KC induces oxidative stress, inflammation and cell death, it is important to identify compounds able to impair its harmful effects. These compounds may be either natural or synthetic molecules or mixtures of molecules such as oils. In this context: (i) the lipid profiles of dietary argan oils from Berkane and Agadir (Morocco) in fatty acids, phytosterols, tocopherols and polyphenols were determined by different chromatographic techniques; and (ii) their anti-oxidant and cytoprotective effects in 158N murine oligodendrocytes cultured with 7KC (25-50 µM; 24 h) without and with argan oil (0.1% v/v) or α-tocopherol (400 µM, positive control) were evaluated with complementary techniques of cellular and molecular biology. Among the unsaturated fatty acids present in argan oils, oleate (C18:1 n-9) and linoleate (C18:1 n-6) were the most abundant; the highest quantities of saturated fatty acids were palmitate (C16:0) and stearate (C18:0). Several phytosterols were found, mainly schottenol and spinasterol (specific to argan oil), cycloartenol, ß-amyrin and citrostadienol. α- and γ-tocopherols were also present. Tyrosol and protocatechic acid were the only polyphenols detected. Argan and extra virgin olive oils have many compounds in common, principally oleate and linoleate, and tocopherols. Kit Radicaux Libres (KRL) and ferric reducing antioxidant power (FRAP) tests showed that argan and extra virgin olive oils have anti-oxidant properties. Argan oils were able to attenuate the cytotoxic effects of 7KC on 158N cells: loss of cell adhesion, cell growth inhibition, increased plasma membrane permeability, mitochondrial, peroxisomal and lysosomal dysfunction, and the induction of oxiapoptophagy (OXIdation + APOPTOsis + autoPHAGY). Altogether, our data obtained in 158N oligodendrocytes provide evidence that argan oil is able to counteract the toxic effects of 7KC on nerve cells, thus suggesting that some of its compounds could prevent or mitigate neurodegenerative diseases to the extent that they are able to cross the blood-brain barrier.

Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy.

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

Mitochondrial dysfunctions in 7-ketocholesterol-treated 158N oligodendrocytes without or with α-tocopherol: Impacts on the cellular profil of tricarboxylic cycle-associated organic acids, long chain saturated and unsaturated fatty acids, oxysterols, cholesterol and cholesterol precursors.

In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). α-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis. In presence of 7KC, the amount of adherent 158N cells was decreased and oxidative stress was enhanced. An increase of caspase-3 and PARP degradation (evidences of apoptosis), and an increased LC3-II/LC3-I ratio (criterion of autophagy), were detected. These events were associated with a decrease of the mitochondrial membrane potential (ΔΨm) and by a decrease of oxidative phosphorylation revealed by reduced NAD+ and ATP. The cellular lactate was higher while pyruvate, citrate, fumarate, succinate (tricarboxylic acid (TCA) cycle intermediates) were significantly reduced in exposed cells, suggesting that an impairment of mitochondrial respiratory functions could lead to an increase of lactate production and to a reduced amount of ATP and acetyl-CoA available for the anabolic pathways. The concentration of sterol precursors lathosterol, lanosterol and desmosterol were significantly reduced together with satured and unsatured long chain fatty acids (C16:0 - C18:0, structural elements of membrane phospholipids). Such reductions were milder with α-tocopherol. It is likely that the cell death induced by 7KC is associated with mitochondrial dysfunctions, including alterations of oxidative phosphorylation, which could result from lipid anabolism dysfunctions, especially on TCA cycle intermediates. A better knowledge of mitochondrial associated dysfunctions triggered by 7KC will contribute to bring new information on the demyelination processes which are linked with oxidative stress and lipid peroxidation, especially in MS.

Impact of C24:0 on actin-microtubule interaction in human neuronal SK-N-BE cells: evaluation by FRET confocal spectral imaging microscopy after dual staining with rhodamine-phalloidin and tubulin tracker green.

Disorganization of the cytoskeleton of neurons has major consequences on the transport of neurotransmitters via the microtubule network. The interaction of cytoskeleton proteins (actin and tubulin) was studied in neuronal SK-N-BE cells treated with tetracosanoic acid (C24:0), which is cytotoxic and increased in Alzheimer's disease patients. When SK-N-BE cells were treated with C24:0, mitochondrial dysfunctions and a non-apoptotic mode of cell death were observed. Fluorescence microscopy revealed shrunken cells with perinuclear condensation of actin and tubulin. Impact of C24:0 on actin-microtubule interaction in human neuronal SK-N-BE cells: evaluation by FRET confocal spectral imaging microscopy after dual staining with rhodamine-phalloidin and tubulin tracker green After staining with rhodamine-phalloidin and with an antibody raised against α-/ß-tubulin, modifications of F-actin and α-/ß-tubulin levels were detected by flow cytometry. Lower levels of α-tubulin were found by Western blotting. In C24:0-treated cells, spectral analysis and fluorescence recovery after photobleaching (FRAP) measured by confocal microscopy proved the existence of fluorescence resonance energy transfer (FRET) when actin and tubulin were stained with tubulin tracker and rhodamine-phalloidin demonstrating actin and tubulin co-localization/interaction. In control cells, no FRET was observed. Our data demonstrate quantitative changes in actin and tubulin, and modified interactions between actin and tubulin in SK-N-BE cells treated with C24:0. They also show that FRET confocal imaging microscopy is an interesting method for specifying the impact of cytotoxic compounds on cytoskeleton proteins.

Comorbidities at multiple sclerosis diagnosis.

The nature and frequency of comorbidities upon notification of multiple sclerosis (MS) are not well known. In France, MS is one of the 30 long-term illnesses (affections de longue durée, ALD) for which 100 % of patients' health care costs are covered by the main French health insurance system. We conducted a study among 22,087 patients who had contracted MS before their 45th birthday and had obtained ALD status between 1995 and 2004. Comorbidities diagnosed at MS notification were described. The age at which MS was registered in patients with a previous comorbidity was compared with that in those patients with no previous comorbidities. Among the 22,087 patients, 21,119 (95 %) had ALD status for MS only, 653 (3 %) had a comorbidity status diagnosed at the same time as MS. Of these comorbidities, 86.8 % could be grouped into five main categories: psychiatric disease (40.2 %), autoimmune disease (24.5 %), cardiovascular disease (16.2 %), cancer (12.2 %), and metabolic disease (9.0 %). Psychiatric disorders and diabetes were more frequent in MS patients than in the general population of the same age. The mean age at request for ALD status for MS in patients with no comorbidity was 33.6 ± 7.2 years, whereas it was 36.9 ± 6.5 years in those with comorbidities. Comorbidities at MS notification are rare. Psychiatric disorders and diabetes were more frequent in MS patients than in the general population.

[Plasma exchanges in severe and acute inflammatory demyelinating attacks of the central nervous system]. / Échanges plasmatiques dans les maladies inflammatoires démyélinisantes aiguës sévères du système nerveux central.

BACKGROUND: They are severe inflammatory demyelinating diseases of the central nervous system, often called idiopathic inflammatory demyelinating disease (IIDD). These diseases are explosive or pseudotumoral multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), transverse myelitis and neuromyelitis optica (NMO). The usual therapeutic are intraveinous corticosteroids. Sometimes, these diseases are unresponsive to corticosteroids and it is necessary to use more incisive immunoactive treatment such as the plasma exchanges (PE). METHODS: We retrospectively reviewed the medical records of 35 patients (10 of Dijon and 25 of Lyon) corresponding to the definition of IIDD and having treated by PE after failure of corticosteroids. RESULTS: Seventy-four percent of the patients were women, the median age was 38years. Forty-three percent of the patients had MS, 31.5% NMO, 14% ADEM and 11.5% a transverse myelitis. The response of the PE was favorable in 77% of the cases (moderate or marked improvement, at 1month, 3months and more than 6months). They are well tolerated. CONCLUSIONS: Early initiation of PE seems to be a predictor of a good response.

Geographic variations of multiple sclerosis in France.

France is located in an area with a medium to high prevalence of multiple sclerosis, where its epidemiology is not well known. We estimated the national and regional prevalence of multiple sclerosis in France on 31 October 2004 and the incidence between 31 October 2003 and 31 October 2004 based on data from the main French health insurance system: the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. The Caisse Nationale d'Assurance Maladie des Travailleurs Salariés insures 87% of the French population. We analysed geographic variations in the prevalence and incidence of multiple sclerosis in France using the Bayesian approach. On the 31 October 2004, 49 417 people were registered with multiple sclerosis out of the 52 359 912 insured with the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. Among these, 4497 were new multiple sclerosis cases declared between 31 October 2003 and 31 October 2004. After standardization for age, total multiple sclerosis prevalence in France was 94.7 per 100,000 (94.3-95.1); 130.5 (129.8-131.2) in females and 54.8 (54.4-55.3) in males. The national incidence of multiple sclerosis between 31 October 2003 and 31 October 2004 was 7.5 per 100,000 (7.3-7.6); 10.4 (10.2-10.6) in females and 4.2 (4.0-4.3) in males. The prevalence and incidence of multiple sclerosis were higher in North-Eastern France, but there was no obvious North-South gradient. This study is the first performed among a representative population of France (87%) using the same method throughout. The Bayesian approach, which takes into account spatial heterogeneity among geographical units and spatial autocorrelation, did not confirm the existence of a prevalence gradient but only a higher prevalence of multiple sclerosis in North-Eastern France and a lower prevalence of multiple sclerosis in the Paris area and on the Mediterranean coast.

Stroke in the very old: incidence, risk factors, clinical features, outcomes and access to resources--a 22-year population-based study.

BACKGROUND: For several years, the burden of stroke in very old patients has been increasing in western countries. Nevertheless, we have little information about this new challenge in individuals >or=80. METHODS: We ascertained all first-ever strokes in the population of Dijon, France (150,000 inhabitants), from 1985 to 2006. The incidence of stroke, risk factors, clinical presentation, resource mobilization and 1-month outcome were evaluated in individuals >or=80 and compared to the data obtained in younger patients. RESULTS: We collected 1,410 first-ever strokes in people >or=80 years (39%) versus 2,130 in those <80 years. The incidence was 997/100,000, and 68/100,000, respectively. Over the 22 years, the incidence of stroke in individuals >or=80 years rose significantly. A lower prevalence of diabetes, hypercholesterolemia and alcohol intake, as well as a higher prevalence of hypertension, atrial fibrillation, previous myocardial infarction and use of prestroke antiplatelet agents were noted in patients >or=80 years. The clinical presentation was severer and the 1-month outcome in terms of case fatality and handicap was worse, despite improvements observed over time. Finally, in patients >or=80 years, the use of CT scan, MRI, cervical Doppler, angiography and carotid surgery were significantly lower than for younger patients. Length of stay >30 days was more frequent, and discharge to prestroke residence was less common. However, all these improved between the first and the last study periods. CONCLUSIONS: Our findings have important implications not only for clinical management but also for initiating preventive strategies and health policy.