Anti-Argonaute antibodies as a potential biomarker in NMOSD.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorders (NMOSDs) are a group of diseases mainly characterised by recurrent optic neuritis and/or myelitis. Most cases are associated with a pathogenic antibody against aquaporin-4 (AQP4-Ab), while some patients display autoantibodies targeting the myelin oligodendrocyte glycoprotein (myelin oligodendrocyte glycoprotein antibodies (MOG-Abs)). Anti-Argonaute antibodies (Ago-Abs) were first described in patients with rheumatological conditions and were recently reported as a potential biomarker in patients with neurological disorders. The aims of the study were to investigate if Ago-Abs can be detected in NMOSD and to evaluate its clinical usefulness. METHODS: Sera from patients prospectively referred to our centre with suspected NMOSD were tested for AQP4-Abs, MOG-Abs and Ago-Abs with cell-based assays. RESULTS: The cohort included 104 prospective patients: 43 AQP4-Abs-positive cases, 34 MOG-Abs positive cases and 27 double-negative patients. Ago-Abs were detected in 7 of 104 patients (6.7%). Clinical data were available for six of seven patients. The median age at onset of patients with Ago-Abs was 37.5 [IQR 28.8-50.8]; five of six patients tested positive also for AQP4-Abs. Clinical presentation at onset was transverse myelitis in five patients, while one presented with diencephalic syndrome and experienced a transverse myelitis during follow-up. One case presented a concomitant polyradiculopathy. Median EDSS score at onset was 7.5 [IQR 4.8-8.4]; median follow-up was 40.3 months [IQR 8.3-64.7], and median EDSS score at last evaluation was 4.25 [IQR 1.9-5.5]. CONCLUSION: Ago-Abs are present in a subset of patients with NMOSD and, in some cases, represent the only biomarker of an autoimmune process. Their presence is associated with a myelitis phenotype and a severe disease course.

Dramatic Efficacy of Interferon and Vemurafenib on Psychiatric Symptoms Revealing BRAFV600E -Mutated Erdheim-Chester Disease: A Case Report.

Erdheim-Chester disease (ECD) is a rare condition with underestimated neurological involvement. Mild psychiatric symptoms such as mood swings have been rarely described in the clinical spectrum of neuro-ECD. We here describe the first patient with psychiatric manifestations of delirium revealing ECD with neurological involvement with favorable evolution under interferon followed by BRAF inhibitor monotherapy. An 81-year-old woman was referred to the hospital because of delirium and severe cognitive impairment associated with a cerebellar syndrome. Brain magnetic resonance imaging showed "FLAIR-changes" lesions in the pons and upper cerebellum peduncles. Blood and cerebrospinal fluid (CSF) analyses showed normal results except for an elevated neopterin level in the CSF. Whole-body CT scan (18FDG-PET) showed peri-nephric fat infiltration and aorta adventitia sheathing with radiotracer uptake in the pons, vessels, peri-nephric fat, and bone lesions, which was characteristic of ECD. The diagnosis was confirmed on perirenal tissue biopsy, which also showed a BRAFV600E mutation. Treatment with interferon resulted in the resolution of delirium, and treatment with BRAF inhibitor subsequently resulted in a partial remission of all active sites. This case highlights that delirium can be the first manifestation of neurodegenerative ECD. ECD should be screened in unexplained psychiatric features as interferon and targeted therapy appear to be effective in this situation.

High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics.

OBJECTIVE: To assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments. METHODS: Sixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled 'other') were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection. RESULTS: In 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin. CONCLUSION: This study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

Natalizumab-PML survivors with subsequent MS treatment: Clinico-radiologic outcome.

OBJECTIVE: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT). METHODS: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression. RESULTS: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up. CONCLUSION: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.

Attenuation of 7-ketocholesterol-induced overproduction of reactive oxygen species, apoptosis, and autophagy by dimethyl fumarate on 158N murine oligodendrocytes.

Mitochondrial dysfunctions and oxidative stress are involved in several non demyelinating or demyelinating neurodegenerative diseases. Some of them, including multiple sclerosis (MS), are associated with lipid peroxidation processes leading to increased levels of 7-ketocholesterol (7KC). So, the eventual protective effect of dimethylfumarate (DMF), which is used for the treatment of MS, was evaluated on 7KC-treated oligodendrocytes, which are myelin synthesizing cells. To this end, murine oligodendrocytes 158N were exposed to 7KC (25, 50µM) for 24h without or with DMF (1, 25, 50µM). The biological activities of DMF associated or not with 7KC were evaluated by phase contrast microscopy, crystal violet and MTT tests. The impact on transmembrane mitochondrial potential (ΔYm), O2- and H2O2 production, apoptosis and autophagy was measured by microscopical and flow cytometric methods by staining with DiOC6(3), dihydroethidine and dihydrorhodamine 123, Hoechst 33342, and by Western blotting with the use of specific antibodies raised against uncleaved and cleaved caspase-3 and PARP, and LC3-I/II. DMF attenuates the different effects of 7KC, namely: cell growth inhibition and/or loss of cell adhesion, decrease of ΔΨm, O2- and H2O2 overproduction, PARP and caspase-3 cleavage, nuclear condensation and fragmentation, and activation of LC3-I into LC3-II. The ability of DMF to attenuate 7KC-induced reactive oxygen species overproduction, apoptosis, and autophagy on oligodendrocytes reinforces the interest for this molecule for the treatment of MS or other demyelinating diseases.

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.

Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study.

IMPORTANCE: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge. OBJECTIVE: To collect data from patients with MS switching from natalizumab to fingolimod. DESIGN, SETTING, AND PARTICIPANTS: The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod. MAIN OUTCOMES AND MEASURES: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod. RESULTS: Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). CONCLUSIONS AND RELEVANCE: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

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.

Cancer and multiple sclerosis in the era of disease-modifying treatments.

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

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.

[Pregnancy and multiple sclerosis]. / Grossesse et sclérose en plaques.

Because multiple sclerosis is a disease that affects young women, the question of pregnancy frequently arises early in the management of the disease. Although the relapse rate decreases during the nine months of pregnancy, it rises significantly during the first trimester post-partum, affecting one third of patients. Pregnancy has no influence on disability progression. Patients have no particular difficulties during pregnancy, labor or delivery. No significant fetal risk has been reported. Neither breast-feeding nor epidural analgesia is deleterious. Disease-modifying treatment must be stopped before conception.