Search

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis., Methods: Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood-brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline., Results: At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTRnorm values (p<0.03) in USPIO(+)/Gd(+) lesions (n=16; MTRnormUSPIO(+)/Gd(+)=0.78 at baseline, MTRnormUSPIO(+)/Gd(+)=0.81 at M12) relative to USPIO(-)/Gd(+) lesions (n=67; MTRnormUSPIO(-)/Gd(+)=0.82 at baseline, MTRnormUSPIO(-)/Gd(+)=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type × time)., Conclusion: Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline., (© The Author(s), 2015.)

Niemann-Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the 'continued' subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat.

Unlabelled: Memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients., Aims: The purpose of the "EMERITE" (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS)., Methods: The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18-60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial., Results: Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p=0.88). Adjusted mean score difference (memantine minus placebo), was -0.40 (95% confidence interval: -5.5; +4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine., Conclusions: No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Competing Interests: A. Tourbah déclare avoir reçu des aides à la recherche et des invitations lors de congrès réunions et symposium de la part de Medday, Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharma, et Roche.

Background: No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis., Objectives: The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS., Study Design: Uncontrolled, non-blinded proof of concept study, Methods: 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures., Results: In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset., Conclusions: These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

The introduction of the McDonald criteria has enabled earlier diagnosis of multiple sclerosis (MS). However, even with the 2010 revised criteria, nearly 50% of patients remain classified as "possible MS" following the first MRI. The present study aimed to demonstrate that time to MS diagnosis could be shorter than 2010 revised criteria, and established after a single early MRI in most patients with the association of the symptomatic lesion and at least one suggestive asymptomatic lesion. We also evaluated the short-term predictive capacity of an individual suggestive lesion on disease activity. We analyzed initial MRI results from 146 patients with MS from a multicenter retrospective study. Visualization of the symptomatic lesion was used as a primary criterion. Secondary criteria included one suggestive lesion (SL) aspect or topography on MRI, or one non-specific lesion associated with positive CSF. The proposed criteria led to a positive diagnosis of MS in 100% of cases, from information available from the time of the first MRI for 145 patients (99.3%). At least one SL was observed for 143 patients (97.9%), and positive CSF for the 3 others. Compared to the McDonald criteria, the proposed criteria had 100% sensitivity, with a significantly shorter mean time to reach a positive diagnosis. Furthermore, the simultaneous presence of corpus callosum, temporal horn, and ovoid lesions was associated with radiological or clinical activity after a year of follow-up. The proposed diagnostic criteria are easy to apply, have a good sensitivity, and allow an earlier diagnosis than the 2010 McDonald criteria. Nevertheless, prospective studies are needed to establish specificity and to confirm these findings.

Background and Objective: Cognitive and behavioural symptoms are common in multiple sclerosis (MS), but they are rarely the inaugural and predominant manifestation of the disease. Our objective is to characterize the clinical and radiological features of cognitive-multiple sclerosis (cog-MS), defined as MS subjects who entered into the disease with cognitive symptoms, which subsequently remain the predominant manifestation., Methods: We describe the disease course, and clinical and radiological features of 18 subjects with a cognitive form of MS., Results: Memory loss and behavioural changes were the primary symptoms at disease onset. They remained prominent and led to severe cognitive impairment during disease course. The main associated manifestations were depression, pathological laughing and/or crying, urinary incontinence and gait disturbance suggestive of high-level gait disorder. Motor, sensory or cerebellar abnormalities were uncommon. During disease course, superimposed neurological relapses occurred in 61% of cases. Brain MRI revealed multiple periventricular lesions that were extensive and confluent in half of cases, and a severe atrophy measured as an increase in the third ventricular width compared to age-matched healthy controls. Gadolinium-enhancing lesions were common (72%). The mean diagnosis delay from disease onset was 2 years. A principal component analysis on the neuropsychological results revealed that verbal memory assessment is complementary to global cognitive functioning evaluation in these patients with severe cognitive deficit. Verbal memory deficit was associated with high EDSS., Conclusions: cog-MS patients might represent a challenging diagnosis, which needs to be individualized for an early management., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large-scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3-5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age-matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage., (Copyright © 2014 Wiley Periodicals, Inc.)

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.

Theory of Mind (ToM) is the ability to attribute independent mental states to self and others to explain and predict behavior. Impairment of ToM is well established in developmental pathologies. In neurological populations, investigation of ToM is still rare but data suggest that ToM impairment could contribute to behavioral and social disturbances. In addition to neurological signs, multiple sclerosis (MS) presents with disorders of cognition and behavior directly related to brain damage. The aim of this study was to assess ToM abilities and recognition of facial emotional expression in adults with MS. We compared 64 patients with relapsing MS and 30 matched healthy controls on three levels of ToM tasks, a facial emotion recognition task, and a neuropsychological assessment. MS patients performed significantly worse than controls in emotion recognition and all ToM tasks (p < .02). These deficits were not correlated with demographic variables or neuropsychological test performance. These findings underscore the importance of assessing ToM and facial recognition in MS, as dysfunction in these areas may impact upon social interaction and, thus, impair quality of life for both patients with MS and their families.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

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.

We report the case of a 26 years old pregnant woman at 17 weeks amenorrhea, suffering from multiple sclerosis (MS) for 6 years, hospitalized for a relapse. Treatment of MS relapses is based on high dose corticosteroid infusions, A current infection would represent a contra-indication to this treatment. In our patient, C-reactive protein (CRP) levels were moderately increased (38 mg/L). This raised the question of the physiological CRP levels in pregnant woman. After reviewing the literature, we noticed that increased CRP levels may be found in normal pregnancy, however no consensual cut-off value is admitted up to date. Procalcitonin measurement may contribute to therapeutical decision, even if increased levels have also been reported during normal pregnancy.

Background: Subclinical demyelinating lesions may occur in the brains of asymptomatic individuals., Objective: To describe the clinical and magnetic resonance imaging (MRI) follow-up of patients with subclinical demyelinating lesions that fulfill the Barkhof/Tintoré criteria., Design: Prospective study., Setting: University-affiliated teaching hospitals., Patients: Fifty-three women and 17 men with subclinical demyelinating lesions (mean age, 35.63 years)., Main Outcome Measures: Cerebrospinal fluid, MRI, and visual evoked potential measurements., Methods: All patients underwent their first brain MRI for various medical problems that were not suggestive of multiple sclerosis (MS). The patients' physicians proposed that they undergo paraclinical studies (blood, cerebrospinal fluid, and visual evoked potential analysis) and follow-up with MRI., Results: Twenty-three patients (33%) had clinical conversion: 6 to optic neuritis, 6 to myelitis, 5 to brainstem symptoms, 4 to sensitive symptoms, 1 to cerebellar symptoms, and 1 to cognitive deterioration. The mean time between the first brain MRI and the first clinically isolated syndrome was 2.3 years (range, 0.8-5.0 years). Twelve patients had been treated with immunomodulators after a clinically isolated syndrome. Examination of pejorative markers for clinical conversion showed that sex, number of T2 lesions, presence of oligoclonal bands, and IgG index were not statistically different in patients with MS determined by MRI compared with clinically definite MS. Visual evoked potential abnormalities, young age, and gadolinium enhancement on follow-up MRI were more frequent in clinically definite MS than in MS determined by MRI., Conclusions: In this cohort, we determined the rate of clinical conversion (33%) during a mean follow-up of 5.2 years. To our knowledge, this is the first clinically isolated syndrome cohort with preclinical follow-up. Early treatment of these patients with MS determined by MRI should be discussed.

Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.

Natalizumab (Tysabri) is the first monoclonal antibody indicated for the treatment of active relapsing-remitting multiple sclerosis. Natalizumab is reserved for hospital use. Strict monitoring is necessary to detect side effects associated with the perfusion of the product, possible inefficacy of the treatment, and, more rarely, infectious complications, some of which (for example, progressive multifocal leukoencephalitis) are severe. Rigorous collection of efficacy and tolerance data will make it possible to assess the impact of this treatment on the natural history of multiple sclerosis.

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFN beta in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFN beta are now approved in Europe and North America: chronologically IFN beta-1b (Berlex/Schering), IFN beta-1a given intramuscularly (Biogen), and IFN beta-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.