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Background: Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS)., Objectives: To investigate the effect of high-dose vitamin D 3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels., Methods: This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D 3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored., Results: The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D 3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures., Conclusion: High-dose vitamin D 3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been the first class of antiretroviral drugs used against HIV infection. Despite NRTI-free regimens have been eagerly sought over the years in an effort for treatment simplification, NRTIs remain in most antiretroviral combination treatment. There has been generally a limited interest for their therapeutic drug monitoring, arguably because NRTIs levels measured in plasma poorly predict the concentration of pharmacologically active metabolites in cells. Plasma concentrations do impact cellular levels, while large differences between NRTIs have been found with regard to their ability to distribute into the cerebrospinal fluid (CSF) compartment. The renewed interest for the measurements of NRTIs concentrations in plasma and CSF was raised by ongoing efforts to understand some instances of toxicity or for determining their actual implication in the development of HIV-associated neurological disorders. In this context, a 5-min multiplex ultra-high-pressure chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis in human plasma and CSF was developed for NRTIs used in clinical practice: abacavir, emtricitabine, lamivudine, tenofovir and zidovudine along with zidovudine glucuronide (Gln-ZDV). The 200-fold dilution of blank human plasma was shown to be a reliable surrogate matrix for quantification of NRTIs and Gln-ZDV in CSF. Both methodologies were fully validated over the clinically relevant concentrations, and satisfactorily fulfilled all parameters for bioanalytical methods validation. This sensitive, rapid, and robust UHPLC-MS/MS assay offers a methodology for increasing our understanding of the ability of NRTIs to cross the blood-brain barrier and their potential implication in neuropsychological disorders observed in HIV-infected patients., (© 2018 Published by Elsevier B.V. on behalf of The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL).)

Competing Interests: The authors declare no conflict of interest.

Ocrelizumab (Ocrevus), an anti-CD20 monoclonal antibody, has been approved for the treatment of multiple sclerosis. Eculizumab (Soliris) has been approved in several countries for refractory forms of generalized seropositive severe myasthenia gravis. A form of gene therapy, patisiran, has shown positive results in transthyretin familial amyloidosis. In the treatment of headaches, particularly migraines, non-pharmacological approaches have shown some interesting results. The criteria for Lewy body dementia have been revised. Generic use of lamotrigine does not result in recrudescence of epileptic seizures or adverse effects., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: To evaluate the long-term effects of treatments used in MS on the T-cell trafficking profile., Methods: We enrolled 83 patients with MS under fingolimod (FTY), natalizumab (NTZ), dimethyl fumarate (DMF), or other disease-modifying treatments (DMTs). Blood was drawn before treatment onset and up to 36-48 months. The ex vivo expression of CNS-related integrins (α4β1 and α L subunit of LFA-1) and the gut-related integrin (α4β7) was assessed using flow cytometry on CD4 + and CD8 + T cells. The adhesion profiles of CD3 + T cells to specific integrin ligands (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and mucosal vascular addressin cell adhesion molecule-1 [MAdCAM-1]) were measured in vitro before and after 12 and 36-48 months., Results: NTZ decreased the frequency of α4β1 + and α4β7 + integrin expressing T cells and the binding of these cells to VCAM-1 and MAdCAM-1, respectively. After 12 months, DMF induced a decreased frequency of α L high CD4 + T cells combined with reduced binding to ICAM-1. By contrast, with FTY, there was a doubling of the frequency of α4β1 + and α L high , but a decreased frequency of α4β7 + T cells. Strikingly, the binding of α4β1 + , α4β7 + , and to a lesser extent of α L high T cells to VCAM-1, MAdCAM-1, and ICAM-1, respectively, was decreased at month 12 under FTY treatment. The presence of manganese partially restored the binding of these T cells to VCAM-1 in vitro, suggesting that FTY interferes with integrin activation., Conclusions: In addition to NTZ, DMF and FTY but not other tested DMTs may also decrease T-cell-mediated immune surveillance of the CNS. Whether this mechanism may contribute to the onset of CNS opportunistic infections remains to be shown.

Objective: Quantitative and semi-quantitative MRI (qMRI) metrics provide complementary specificity and differential sensitivity to pathological brain changes compatible with brain inflammation, degeneration, and repair. Moreover, advanced magnetic resonance imaging (MRI) metrics with overlapping elements amplify the true tissue-related information and limit measurement noise. In this work, we combined multiple advanced MRI parameters to assess focal and diffuse brain changes over 2 years in a group of early-stage relapsing-remitting MS patients., Methods: Thirty relapsing-remitting MS patients with less than 5 years disease duration and nine healthy subjects underwent 3T MRI at baseline and after 2 years including T1, T2, T2* relaxometry, and magnetization transfer imaging. To assess longitudinal changes in normal-appearing (NA) tissue and lesions, we used analyses of variance and Bonferroni correction for multiple comparisons. Multivariate linear regression was used to assess the correlation between clinical outcome and multiparametric MRI changes in lesions and NA tissue., Results: In patients, we measured a significant longitudinal decrease of mean T2 relaxation times in NA white matter ( p  = 0.005) and a decrease of T1 relaxation times in the pallidum ( p  < 0.05), which are compatible with edema reabsorption and/or iron deposition. No longitudinal changes in qMRI metrics were observed in controls. In MS lesions, we measured a decrease in T1 relaxation time ( p -value < 2.2e-16) and a significant increase in MTR ( p -value < 1e-6), suggesting repair mechanisms, such as remyelination, increased axonal density, and/or a gliosis. Last, the evolution of advanced MRI metrics-and not changes in lesions or brain volume-were correlated to motor and cognitive tests scores evolution (Adj- R 2  > 0.4, p  < 0.05). In summary, the combination of multiple advanced MRI provided evidence of changes compatible with focal and diffuse brain repair at early MS stages as suggested by histopathological studies.

Neurodegenerative disorders are a major public health problem because of the high frequency of these diseases. Genome editing with the CRISPR/Cas9 system is making it possible to modify the sequence of genes linked to these disorders. We designed the KamiCas9 self-inactivating editing system to achieve transient expression of the Cas9 protein and high editing efficiency. In the first application, the gene responsible for Huntington's disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease. Sequencing of potential off-targets with the constitutive Cas9 system in differentiated human iPSC revealed a very low incidence with only one site above background level. This off-target frequency was significantly reduced with the KamiCas9 system. These results demonstrate the potential of the self-inactivating CRISPR/Cas9 editing for applications in the context of neurodegenerative diseases., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

The neurocognitive complaints among HIV infected patients remain frequent, and to establish their etiology can be challenging. We created in 2011 an outpatient Neuro-HIV clinical platform that takes advantage of a multidisciplinary approach with 5 specialists (neuropsychologist, neurologist, psychiatrist, infectiologist and neuroradiologist). In order to estimate its utility, we conducted two questionnaire-based interviews by phone calls with the patients and their referring physicians. Three quarters of both the patients and the physicians interviewed consider the platform useful or essential. Even though there is often no immediate treatment for cognitive disorders, the patients receive from this multidisciplinary approach a better understanding of their disease, which may help them to better cope with their anxieties in daily life., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cette étude.

Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are defined according to their diagnostic degrees as follows: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Because high adherence to combined antiretroviral therapy (cART) is required to maintain viral suppression among HIV-infected patients, it is important to investigate the impact of HAND on medication adherence. Our study hypothesis was that patients with HAND had a lower medication adherence than patients who did not have HAND., Methods: This was an observational, exploratory, 2-center pilot study of patients who had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015 while also being followed at their respective adherence clinics. Adherence was measured with electronic monitors. Patients' sociodemographic characteristics, HIV viral load, and CD4 counts were retrieved from the Swiss HIV Cohort Study database. At each time t , adherence was computed as the proportion of patients taking medication as prescribed at that time., Results: We included 59 patients, with a median (Q1, Q3) age of 53 years (47-58) and 39 (66%) were male participants. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit (implementation stayed 90% during follow-up)., Conclusions: Our findings support the hypothesis that HAND is associated with reduced cART adherence.

Background: Natalizumab, a treatment used in multiple sclerosis (MS), is associated with cases of progressive multifocal leukoencephalopathy (PML)., Objective: We describe two cases of PML in related but not genetically apparented natalizumab-treated MS patients who are stepsisters. Reported cases/outcomes: While Patient 1 developed PML, Patient 2 was on natalizumab and had contacts with Patient 1. Patient 2 was diagnosed with PML 5 months after Patient 1., Conclusion: The clinical and temporal data highly suggest that there was JC virus (JCV) transmission from one patient to the other with development of PML as primo-infection in Patient 2.

The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory CD4 + T lymphocytes migrate specifically in response to 7α,25-dihydroxycholesterol (7α,25-OHC) via EBI2 in the MS murine model experimental autoimmune encephalomyelitis. However, the EBI2 expression profile in human lymphocytes in both healthy and MS donors is unknown. Here, we characterize EBI2 biology in human lymphocytes. We observed that EBI2 is functionally expressed on memory CD4 + T cells and is enhanced under natalizumab treatment. These data suggest a significant role for EBI2 in human CD4 + T cell migration, notably in patients with MS. Better knowledge of EBI2 involvement in autoimmunity may therefore lead to an improved understanding of the physiopathology of MS., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/objectives: Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies., Methods: A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay., Results: NfL levels in serum were highly correlated to levels in CSF (r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline (p = 0.004) and follow-up (p = 0.0009) and did not change over time (p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume (r = 0.68, p < 0.0001), mean T1 (r = 0.40, p = 0.034) and T2* relaxation time (r = 0.49, p = 0.007) and with magnetization transfer ratio in normal appearing WM (r = -0.41, p = 0.029)., Conclusion: CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials., (© The Author(s), 2016.)

Purpose: To develop a method to automatically detect multiple sclerosis (MS) lesions, located both in white matter (WM) and in the cortex, in patients with low disability and early disease stage., Materials and Methods: We developed a lesion detection method, based on the k-nearest neighbor (k-NN) technique, to detect lesions as small as 0.0036 mL. This method uses the image intensity information from up to four different 3D magnetic resonance imaging (MRI) sequences (magnetization-prepared rapid gradient-echo, MPRAGE; magnetization-prepared two inversion-contrast rapid gradient-echo, MP2RAGE; 3D fluid-attenuated inversion recovery, FLAIR; and 3D double-inversion recovery, DIR), acquired on a 3T scanner. To these intensity features we added the information obtained by the spatial coordinates and tissue prior probabilities provided by the International Consortium for Brain Mapping (ICBM). Quantitative assessment was done in 39 early-stage MS patients with a "leave-one-out" cross-validation., Results: The best lesion detection rate (DR) performance in WM was obtained using MP2RAGE, FLAIR, and DIR intensities (77% for lesions ≥0.0036 mL; 85% for lesions ≥0.005 mL). Similar results were obtained excluding the DIR intensity as well as when using only MPRAGE and FLAIR (DR = 75%, P = 0.5720). However, the combination of FLAIR with DIR and MP2RAGE appeared to be the best for detecting cortical lesions (DR = 62%), compared to the other combination of sequences (P < 0.001)., Conclusion: For WM lesion detection, similar results were observed when only conventional clinical sequences (FLAIR, MPRAGE) were used compared to a combination of conventional and "advanced" sequences (MP2RAGE, DIR). Cortical lesion detection increased significantly when "advanced" sequences were used. J. Magn. Reson. Imaging 2015. J. Magn. Reson. Imaging 2016;43:1445-1454., (© 2015 Wiley Periodicals, Inc.)

Objective: To establish the sensitivity and specificity of serum and CSF antibodies targeting the gangliosides GQ1b (GQ1bAb) in isolated ophthalmologic syndromes, such as acute ophthalmoplegia (AO) and optic neuritis (ON), caused by disorders other than Miller-Fisher syndrome (MFS)., Methods: We measured serum and CSF GQ1bAb in patients with MFS and with AO or ON caused by other disorders than MFS., Results: Twenty-one patients with AO (21 serum, 9 CSF), 13 with ON (13 serum, 13 CSF), and 12 with MFS (12 serum, 10 CSF) were included in the study. There were no significant differences in age, sex, and CSF findings between the AO and MFS groups. Elevated serum GQ1b titers occurred in 11 of 12 patients with MFS but in only 1 of the 34 patients without MFS. Sensitivity was 92% (95% confidence interval [CI] 62%-100%) and specificity 97% (95% CI 85%-100%). In CSF, GQ1bAb were identified in 2 of 10 patients with MFS but in none with other disorders. Sensitivity was 20% (95% CI 2%-56%) and specificity 100% (95% CI 85%-100%)., Conclusions: Increased serum GQ1bAb are highly specific for MFS. Measurement of GQ1bAb in CSF does not improve diagnosis., Classification of Evidence: This study provides Class III evidence that serum GQ1bAb accurately distinguish MFS from other disorders (sensitivity 92%, 95% CI 62%-100%; specificity 97%, 95% CI 85%-100%)., (© 2016 American Academy of Neurology.)

Paraneoplastic neurological syndromes are a group of neurological syndromes secondary to an underlying malignancy. Associated autoantibodies can be classified according to the cellular localization of the antigen target. Onconeuronal autoantibodies (targeting intracellular antigens) strongly associate with cancer and the response to immunotherapy is often disappointing. Identifying and treating the underlying malignancy is a high priority. However, immunomodulation can provide a favourable outcome for neurological symptoms associated with autoantibodies specific for cell membrane antigens. An early recognition of these disorders following the triad "clinical neurological syndrome--specific autoantibodies--tumour research" is important so that patients can benefit from appropriate targeted treatments.

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.

Objective: To assess longitudinally the antiviral immune response of T cells from patients with multiple sclerosis (MS) treated with fingolimod (FTY) vs other disease-modifying treatments (DMTs)., Methods: We assessed cellular immune responses specific to influenza virus (FLU), JC virus (JCV), and varicella-zoster virus (VZV) using quantification of interferon-γ secretion by enzyme-linked immunospot in patients with MS on FTY (n = 31), including 2 with herpes zoster (HZ), natalizumab (n = 11), and other DMTs (n = 11). We used viral lysates for FLU and VZV and a pool of peptides for FLU, JCV (VP-1), and VZV (IE63)., Results: Besides an expected drop of T cells, we found that, proportionally to the number of CD3(+) T cells, only FTY-treated patients with MS exhibited an increased VZV/IE63-specific T cell response peaking 6 months into treatment, a response that returned to baseline after 12 and 24 months. Two FTY-treated patients developed an HZ 6 months into treatment, coinciding with an absent VZV/IE63-specific T cell response. However, cellular immune responses specific to VZV lysate, JCV, and FLU (lysate and pool of peptide epitopes) were similar between all 3 categories (FTY, natalizumab, and other DMTs) of study patients., Conclusions: FTY-treated patients with MS exhibit an increased VZV/IE63-specific cellular immune response after 6 months of treatment. FTY-treated patients who develop an HZ are not able to mount such a response, suggesting that a T cell response directed against this viral protein may be key in preventing the occurrence of HZ.

Introduction: The existence of partial volume effects in brain MR images makes it challenging to understand physio-pathological alterations underlying signal changes due to pathology across groups of healthy subjects and patients. In this study, we implement a new approach to disentangle gray and white matter alterations in the thalamus and the basal ganglia. The proposed method was applied to a cohort of early multiple sclerosis (MS) patients and healthy subjects to evaluate tissue-specific alterations related to diffuse inflammatory or neurodegenerative processes., Method: Forty-three relapsing-remitting MS patients and nineteen healthy controls underwent 3T MRI including: (i) fluid-attenuated inversion recovery, double inversion recovery, magnetization-prepared gradient echo for lesion count, and (ii) T1 relaxometry. We applied a partial volume estimation algorithm to T1 relaxometry maps to gray and white matter local concentrations as well as T1 values characteristic of gray and white matter in the thalamus and the basal ganglia. Statistical tests were performed to compare groups in terms of both global T1 values, tissue characteristic T1 values, and tissue concentrations., Results: Significant increases in global T1 values were observed in the thalamus (p = 0.038) and the putamen (p = 0.026) in RRMS patients compared to HC. In the Thalamus, the T1 increase was associated with a significant increase in gray matter characteristic T1 (p = 0.0016) with no significant effect in white matter., Conclusion: The presented methodology provides additional information to standard MR signal averaging approaches that holds promise to identify the presence and nature of diffuse pathology in neuro-inflammatory and neurodegenerative diseases.

Demonstration of survival and outcome of progressive multifocal leukoencephalopathy (PML) in a 56-year-old patient with common variable immunodeficiency, consisting of severe hypogammaglobulinemia and CD4+ T lymphocytopenia, during continuous treatment with mirtazapine (30 mg/day) and mefloquine (250 mg/week) over 23 months. Regular clinical examinations including Rankin scale and Barthel index, nine-hole peg and box and block tests, Berg balance, 10-m walking tests, and Montreal Cognitive Assessment (MoCA) were done. Laboratory diagnostics included complete blood count and JC virus (JCV) concentration in cerebrospinal fluid (CSF). The noncoding control region (NCCR) of JCV, important for neurotropism and neurovirulence, was sequenced. Repetitive MRI investigated the course of brain lesions. JCV was detected in increasing concentrations (peak 2568 copies/ml CSF), and its NCCR was genetically rearranged. Under treatment, the rearrangement changed toward the archetype sequence, and later JCV DNA became undetectable. Total brain lesion volume decreased (8.54 to 3.97 cm(3)) and atrophy increased. Barthel (60 to 100 to 80 points) and Rankin (4 to 2 to 3) scores, gait stability, and box and block (7, 35, 25 pieces) and nine-hole peg (300, 50, 300 s) test performances first improved but subsequently worsened. Cognition and walking speed remained stable. Despite initial rapid deterioration, the patient survived under continuous treatment with mirtazapine and mefloquine even though he belongs to a PML subgroup that is usually fatal within a few months. This course was paralleled by JCV clones with presumably lower replication capability before JCV became undetectable. Neurological deficits were due to PML lesions and progressive brain atrophy.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Inflammation-related epilepsy is increasingly recognized; however, studies on status epilepticus (SE) are very infrequent. We therefore aimed to determine the frequency of inflammatory etiologies in adult SE, and to assess related demographic features and outcomes., Methods: This was a retrospective analysis of a prospective registry of adult patients with SE treated in our center, from January 2008 to June 2014, excluding postanoxic causes. We classified SE episodes into 3 etiologic categories: infectious, autoimmune, and noninflammatory. Demographic and clinical variables were analyzed regarding their relationship to etiologies and functional outcome., Results: Among the 570 SE consecutive episodes, 33 (6%) were inflammatory (2.5% autoimmune; 3.3% infectious), without any change in frequency over the study period. Inflammatory SE episodes involved younger patients (mean age 53 vs 61 years, p = 0.015) and were more often refractory to initial antiepileptic treatment (58% vs 38%, odds ratio = 2.19, 95% confidence interval = 1.07-4.47, p = 0.041), despite similar clinical outcome. Subgroup analysis showed that, compared with infectious SE episodes, autoimmune SE involved younger adults (mean age 44 vs 60 years, p = 0.017) and was associated with lower morbidity (return to baseline conditions in 71% vs 32%, odds ratio = 5.41, 95% confidence interval = 1.19-24.52, p = 0.043) without any difference in mortality., Conclusions: Despite increasing awareness, inflammatory SE etiologies were relatively rare; their occurrence in younger individuals and higher refractoriness to treatment did not have any effect on outcome. Autoimmune SE episodes also occurred in younger patients, but tended to have better outcomes in survivors than infectious SE., (© 2015 American Academy of Neurology.)

Nervous system involvement in Lyme disease often mimics other conditions and thus represents a diagnostic challenge, especially in an emergency department setting. We report a case of a female teenager presenting with sudden-onset aphasia and transient right-sided faciobrachial hemiplegia, along with headache and agitation. Ischemia, vasculitis, or another structural lesion was excluded by brain imaging. Toxicologic evaluation results were negative. Cerebral perfusion computed tomography and electroencephalography showed left parietotemporal brain dysfunction. Lumbar puncture result, although atypical, suggested bacterial infection and intravenous ceftriaxone was initiated. Finally, microbiological cerebrospinal fluid analysis revealed Lyme neuroborreliosis, showing specific intrathecal antibody production and high level of C-X-C motif chemokine 13. The patient rapidly recovered. To our knowledge, this report for the first time illustrates that acute-onset language and motor symptoms may be directly related to Lyme neuroborreliosis. Neuroborreliosis may mimic other acute neurologic events such as stroke and should be taken into diagnostic consideration even in the absence of classic symptoms and evolution., (Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation., Objective: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments., Methods: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied., Results: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI., Conclusion: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period., (© The Author(s) 2014.)

Introduction: Malignant variant is a rare subtype of multiple sclerosis (MS) that is rapidly progressive and may lead to significant disability or even death. No consensus exists on best management of this disorder, although corticosteroids and plasmapheresis are commonly used in the acute phase, followed either by MS-specific disease-modifying therapy or an immunosuppressant., Case Report: The patient is a 30-year-old man with relapsing-remitting MS previously well controlled with natalizumab, who has developed fulminant disease activity upon natalizumab cessation. In the acute phase, patient had a suboptimal response to multiple corticosteroid treatments but responded very well to plasmapheresis. Patient continued to have worsening disease activity despite fingolimod treatment. Disease control has been eventually achieved by switching to rituximab., Conclusion: Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual genetic susceptibility seems to influence MS onset and clinical expression, as well as therapeutic responsiveness. Multiple human epidemiological and animal model studies have evaluated the effect of different environmental factors, such as viral infections, vitamin intake, sun exposure, or still dietary and life habits on MS prevalence. Previous Epstein-Barr virus infection, especially if this infection occurs in late childhood, and lack of vitamin D (VitD) currently appear to be the most robust environmental factors for the risk of MS, at least from an epidemiological standpoint. Ultraviolet radiation (UVR) activates VitD production but there are also some elements supporting the fact that insufficient UVR exposure during childhood may represent a VitD-independent risk factor of MS development, as well as negative effect on the clinical and radiological course of MS. Recently, there has been a growing interest in the gut-brain axis, a bidirectional neuro-hormonal communication system between the intestinal microbiota and the central nervous system (CNS). Indeed, components of the intestinal microbiota may be pro-inflammatory, promote the migration of immune cells into the CNS, and thus be a key parameter for the development of autoimmune disorders such as MS. Interestingly most environmental factors seem to play a role during childhood. Thus, if childhood is the most fragile period to develop MS later in life, preventive measures should be applied early in life. For example, adopting a diet enriched in VitD, playing outdoor and avoiding passive smoking would be extremely simple measures of primary prevention for public health strategies. However, these hypotheses need to be confirmed by prospective evaluations, which are obviously difficult to conduct. In addition, it remains to be determined whether and how VitD supplementation in adult life would be useful in alleviating the course of MS, once this disease has already started. A better knowledge of the influence of various environmental stimuli on MS risk and course would certainly allow the development of add-on therapies or measures in parallel to the immunotherapies currently used in MS., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Giant cell arteritis (GCA) is a subacute/chronic vasculitis and represents the most common form of systemic vasculitis in people over the age of 50 years. The absence of clear and specific diagnostic criteria with the highly variable clinical presentation is a diagnostic challenge requesting a multidisciplinary approach. Yet, GCA is an emergency and the treatment must be initiated very rapidly due to the risk of blindness. This article presents a review of GCA as well as the diagnostic and therapeutic institutional guidelines of the University Hospital of Lausanne.

Introduction: Local microstructural pathology in multiple sclerosis patients might influence their clinical performance. This study applied multicontrast MRI to quantify inflammation and neurodegeneration in MS lesions. We explored the impact of MRI-based lesion pathology in cognition and disability., Methods: 36 relapsing-remitting MS subjects and 18 healthy controls underwent neurological, cognitive, behavioural examinations and 3 T MRI including (i) fluid attenuated inversion recovery, double inversion recovery, and magnetization-prepared gradient echo for lesion count; (ii) T1, T2, and T2(*) relaxometry and magnetisation transfer imaging for lesion tissue characterization. Lesions were classified according to the extent of inflammation/neurodegeneration. A generalized linear model assessed the contribution of lesion groups to clinical performances., Results: Four lesion groups were identified and characterized by (1) absence of significant alterations, (2) prevalent inflammation, (3) concomitant inflammation and microdegeneration, and (4) prevalent tissue loss. Groups 1, 3, 4 correlated with general disability (Adj-R (2) = 0.6; P = 0.0005), executive function (Adj-R (2) = 0.5; P = 0.004), verbal memory (Adj-R (2) = 0.4; P = 0.02), and attention (Adj-R (2) = 0.5; P = 0.002)., Conclusion: Multicontrast MRI provides a new approach to infer in vivo histopathology of plaques. Our results support evidence that neurodegeneration is the major determinant of patients' disability and cognitive dysfunction.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Despite that cognitive impairment is a known early feature present in multiple sclerosis (MS) patients, the biological substrate of cognitive deficits in MS remains elusive. In this study, we assessed whether T1 relaxometry, as obtained in clinically acceptable scan times by the recent Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence, may help identifying the structural correlate of cognitive deficits in relapsing-remitting MS patients (RRMS). Twenty-nine healthy controls (HC) and forty-nine RRMS patients underwent high-resolution 3T magnetic resonance imaging to obtain optimal cortical lesion (CL) and white matter lesion (WML) count/volume and T1 relaxation times. T1 z scores were then obtained between T1 relaxation times in lesion and the corresponding HC tissue. Patient cognitive performance was tested using the Brief Repeatable Battery of Neuro-psychological Tests. Multivariate analysis was applied to assess the contribution of MRI variables (T1 z scores, lesion count/volume) to cognition in patients and Bonferroni correction was applied for multiple comparison. T1 z scores were higher in WML (p < 0.001) and CL-I (p < 0.01) than in the corresponding normal-appearing tissue in patients, indicating relative microstructural loss. (1) T1 z scores in CL-I (p = 0.01) and the number of CL-II (p = 0.04) were predictors of long-term memory; (2) T1 z scores in CL-I (β = 0.3; p = 0.03) were independent determinants of long-term memory storage, and (3) lesion volume did not significantly influenced cognitive performances in patients. Our study supports evidence that T1 relaxometry from MP2RAGE provides information about microstructural properties in CL and WML and improves correlation with cognition in RRMS patients, compared to conventional measures of disease burden.

Introduction: In patients with multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) provides only limited insights into the nature of brain damage with modest clinic-radiological correlation. In this study, we applied recent advances in MRI techniques to study brain microstructural alterations in early relapsing-remitting MS (RRMS) patients with minor deficits. Further, we investigated the potential use of advanced MRI to predict functional performances in these patients., Methods: Brain relaxometry (T1, T2, T2*) and magnetization transfer MRI were performed at 3T in 36 RRMS patients and 18 healthy controls (HC). Multicontrast analysis was used to assess for microstructural alterations in normal-appearing (NA) tissue and lesions. A generalized linear model was computed to predict clinical performance in patients using multicontrast MRI data, conventional MRI measures as well as demographic and behavioral data as covariates., Results: Quantitative T2 and T2* relaxometry were significantly increased in temporal normal-appearing white matter (NAWM) of patients compared to HC, indicating subtle microedema (P = 0.03 and 0.004). Furthermore, significant T1 and magnetization transfer ratio (MTR) variations in lesions (mean T1 z-score: 4.42 and mean MTR z-score: -4.09) suggested substantial tissue loss. Combinations of multicontrast and conventional MRI data significantly predicted cognitive fatigue (P = 0.01, Adj-R (2) = 0.4), attention (P = 0.0005, Adj-R (2) = 0.6), and disability (P = 0.03, Adj-R (2) = 0.4)., Conclusion: Advanced MRI techniques at 3T, unraveled the nature of brain tissue damage in early MS and substantially improved clinical-radiological correlations in patients with minor deficits, as compared to conventional measures of disease.

Various neurological and neuropsychological manifestations are still relatively frequently reported in HIV infected patients in the highly active antiretroviral therapy era. A fraction of them could be related to HIV replication in the central nervous system (CNS) despite adequate peripheral viral suppression. This hypothesis is supported by numerous reports of detectable HIV RNA in the cerebrospinal fluid in the context of a low or undetectable viremia in association with neurological or neuropsychological complaints. In addition, some antiviral molecules may not achieve adequate levels in the CNS, thus potentially favoring intracerebral HIV replication and even antiretroviral resistance. Neurologic manifestations in the presence of CNS HIV replication often decrease after antiretroviral treatment CNS penetration optimization.

Over the last two decades, thanks to the discovery of several pharmaceutical agents, multiple sclerosis (MS) has been transformed into a treatable disorder although the degree of therapeutic response may vary considerably. As more medications find their entry into the MS market, a clinician faces a mounting challenge of comparing risk and benefit profiles of various agents in an attempt to find the best treatment approach for each individual patient. In this review, we aim to summarize the available data on safety profiles of available MS therapies while focusing mostly on serious medication specific potential adverse events without discussing the teratogenic potential of each agent (unless there is a black box warning) or hypersensitivity reactions. Our goal is to provide a clinician with guidance on assuring the appropriate safety monitoring for patients treated with one of the agents discussed. We also comment on the future of risk management in MS and discuss possible enhancements to the current model of drug approval process and general strategies to improve the patient safety., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A new therapeutic era opened for multiple sclerosis (MS) with the appearance of molecules given p.o. and/or molecules with greater efficiency. Early diagnosis is critical, as the time and the choice of therapeutic intervention. The initiation of treatments must be personalized, including the risks associated with MS and those potentially related to the treatment chosen, answering the question >. Monitoring tools that allow to objectively evaluate: I) MS activity and aggressiveness for each patient and 2) the safety of treatments and their risks of complications, must be further investigated.

Anti-neuronal antibodies are implicated in various neurological syndromes that are sometimes associated with tumors. Depending on the antigenic target (nuclear, cytoplasmic or extracellular cell-surface or synaptic) the clinical presentation is different. In neurological syndromes associated with antibodies specific for intracellular antigens, the T-cell mediated immunological response predominates as pathogenic effector and the response to treatment is typically poor. In contrast, in syndromes related to antibodies against extracellular targets, the role of the antibodies is pathogenic and the neurological syndrome often responds better to immunomodulatory treatment, associated or not with an anti-tumoral treatment. We review the spectrum of anti-neuronal antibodies and their corresponding clinical and therapeutic characteristics.

This review describes some dysimmune neuromuscular disorders and their recent management: syndrome of peripheral nerve hyperexcitability (treatment of cramps, immunosuppressors); Guillain-Barré syndrome (new mechanisms and consensus treatment); chronic inflammatory demyelinating polyradiculoneuropathy (new indication for the use of pulse dexamethasone, new scores of activity); importance of subcutaneous immunoglobulin in multifocal motor neuropathy and of infusions of rituximab in myasthenia gravis; new entities in myositis and their treatment.

In 2012, intramuscular midazolam appears as effective as intravenous lorezepam for the first line treatment of convulsive status epilepticus. Perampanel, a new anti-epileptic drug, will be soon available. Two oral treatments are now available for stroke prevention in atrial fibrillation setting. The methylphenidate and the Tai Chi could increase the walk capacity of patients suffering from Parkinson disease. A comprehensive cardiac work-up is essential for some congenital myopathy. A new drug against migraine seems free from vasoconstrictive effect. Antioxidants are harmful in Alzheimer disease. Some oral medication will be available for multiple sclerosis.

We are currently experiencing a key period in the management of patients with relapsing remitting multiple sclerosis. The application of new criteria allows early diagnosis, thus at a stage when the available immune treatments are the most likely to show a good efficacy. The therapeutic offer is expanding but its complexity too. It is thus important, for a given patient, to assess as precisely as possible the degree of severity of his/her disease, in order to give the drug with the optimal risk/benefit ratio.

Objectives: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders., Methods: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients., Results: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE., Conclusions: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

In 2011, new oral anticoagulants for atrial fibrillation are available and the ABCD3-I score predicting stroke after TIA updates the ABCD2 score. New McDonald criteria allow faster MS diagnosis and the first oral treatment (fingolimod) for MS can be prescribed. A new anti-antiepileptic drug (retigabine) is available and sodium valproate has long term neurological adverse effects after in utero exposure. Among Parkinson disease treatments, deep brain stimulation is extending applications and dopamine agonists with extended release are as efficient and well tolerated as standard forms at long term scale. Monoclonal antibodies and immunosuppressant agents are proposed as good alternatives in the treatment of chronic dysimmune polyneuropathies. Gene therapy for the treatment of genetic myopathies is progressing.