Cerebellar volume loss in radiologically isolated syndrome.

Radiologically isolated syndrome (RIS), in which asymptomatic demyelinating-appearing lesions are detected incidentally on MRI, can be a pre-clinical form of multiple sclerosis (MS). In this study, we measured cerebellar volumes on 3D T1-weighted 3T MR images in 21 individuals with RIS and 38 age- and sex-matched healthy controls (HC). Normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in RIS compared to HC (p = 0.003 and p = 0.005, respectively). Our findings support reports of regional brain atrophy in RIS prior to the development of a seminal attack related to inflammatory demyelination.

De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine.

BACKGROUND: Dalfampridine extended release (DAL) is a broad-spectrum voltage-gated potassium channel blocker that is indicated in multiple sclerosis to improve the nerve conduction of demyelinated axons. Seizures are a known side effect of DAL, which is contraindicated in patients with a history of epilepsy. OBJECTIVE: Three cases of multiple sclerosis (MS) with de novo convulsive status epilepticus (CSE) probably related to dalfampridine administration are described. METHODS: No patients had a history of seizures or renal impairment. Biological tests were normal. A brain magnetic resonance imaging (MRI) showed diffuse cortical and subcortical atrophy without active inflammatory lesions. RESULTS: All three patients presented with CSE that was attributed to DAL and so was discontinued. CONCLUSION: These case reports illustrate that, aside from seizures, de novo CSE is a potential complication of MS patients treated with DAL.

Cerebrospinal fluid chitinase-3-like protein 1 level is not an independent predictive factor for the risk of clinical conversion in radiologically isolated syndrome.

BACKGROUND: Younger age, male sex and presence of spinal cord lesion(s) increase the risk of conversion from radiologically isolated syndrome (RIS) to relapsing-remitting multiple sclerosis (RRMS). Elevated cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) levels predict conversion from clinically isolated syndrome (CIS) to RRMS. OBJECTIVE: To evaluate the prognostic value of CSF CHI3L1 in RIS patients for conversion to RRMS. METHODS: We compared CSF CHI3L1 concentrations in RIS, CIS, RRMS and symptomatic controls (SCs). We analysed the influence of epidemiological, radiological and CSF parameters on the risk of clinical event. RESULTS: A total of 211 patients (71 RIS, 48 CIS, 50 RRMS and 42 SC) were included. CSF CHI3L1 levels were lower in RIS than in RRMS and higher in RIS with positive CSF versus negative CSF and SC. The presence of at least one spinal cord lesion was the only independent predictor of faster conversion to RRMS. Association of high CSF CHI3L1 levels, positive CSF (presence of oligoclonal bands and/or an elevated IgG index) or four Barkhof criteria with any spinal cord lesion showed a tendency for reduced mean conversion time. CONCLUSION: CSF CHI3L1 correlates with positive CSF but is not an independent predictor of the risk of conversion from RIS to RRMS.

Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome.

OBJECTIVE: The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS). METHODS: A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts. RESULTS: Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6-5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS. INTERPRETATION: Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age-dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum.

Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.

BACKGROUND: High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration. METHODS: We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18-55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984. FINDINGS: Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0·5%, 90% CI -9·5 to 10·4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]). INTERPRETATION: Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians. FUNDING: French Health Ministry, Ligue Française contre la SEP, Teva.

False positivity of anti aquaporin-4 antibodies in natalizumab-treated patients.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) represent a differential diagnosis of multiple sclerosis (MS). Detection of anti-aquaporin-4 antibodies (AQP4-Ab) is the strongest argument to confirm NMOSD. Diagnosing NMOSD is a major concern because specific MS disease modifying drugs can lead to neurological worsening. OBJECTIVE: To report the case of two natalizumab (NTZ) treated patients who presented a false positive result for AQP4-Ab. METHODS: A retrospective analysis of NTZ-treated patients who were tested positive for AQP4-Ab in our MS center. RESULTS: Two patients treated by NTZ presented a false positive result. CONCLUSIONS: Clinicians should be aware of potential technical issues in detecting AQP4-Ab in NTZ-treated patients leading to false positive results.

Increased risk of multiple sclerosis relapse after in vitro fertilisation.

BACKGROUND: Exogenous sexual steroids together with pregnancy have been shown to influence the risk of relapses in multiple sclerosis (MS). Treatments used during assisted reproductive techniques may consequently influence the short term evolution of MS by modifying the hormonal status of the patient. The objective of this study was to determine if there was an increased risk of developing exacerbations in women with MS after in vitro fertilisation (IVF). METHODS: MS and IVF data were either automatically extracted from 13 French university hospital databases or obtained from referring neurologists. After matching databases, patient clinical files were systematically reviewed to collect information about MS and the treatments used for IVF. The association between IVF and the occurrence of MS relapses was analysed in detail using univariate and multivariate statistical tests. FINDINGS: During the 11 year study period, 32 women with MS had undergone 70 IVF treatments, 48 using gonadotrophin releasing hormone (GnRH) agonists and 19 using GnRH antagonists. A significant increase in the annualised relapse rate (ARR) was observed during the 3 month period following IVF (mean ARR 1.60, median ARR 0) compared with the same period just before IVF (mean ARR 0.80, median ARR 0) and to a control period 1 year before IVF (mean ARR 0.68, median ARR 0). The significant increase in relapses was associated with the use of GnRH agonists (Wilcoxon paired test, p=0.025) as well as IVF failure (Wilcoxon paired test, p=0.019). INTERPRETATION: An increased relapse rate was observed in this study after IVF in patients with MS and may be partly related both to IVF failure and the use of GnRH agonists.

Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study.

INTRODUCTION: Few data are available about the effect of rituximab (RTX) on refractory (RM) and non-refractory (NRM) myasthenia. METHODS: This retrospective multicenter study involved 13 RM and 7 NRM patients treated with sequential RTX infusions over 2 years, on average. RTX was used as a substitute for corticosteroids in NRM patients. Disability was assessed using the annualized relapse rate (ARR) and Myasthenia Gravis Foundation of America (MGFA) scores. RESULTS: RTX induction decreased the ARR from 2.1 to 0.3 (P < 0.001), and lowered MGFA scores from 5-3b to 4b-0 in RM patients, and from 1.9 to 0.1 (P < 0.001) and 4b-2b to 3b-0 in NRM patients. No side effects were reported in either group, except for 1 case of spondylodiscitis 1 year after the last RTX infusion. Within a year after RTX induction, complete corticosteroid withdrawal was obtained in 7 RM and 4 NRM patients. CONCLUSIONS: RTX is efficacious and well-tolerated. Its use allows for dose reduction or withdrawal of corticosteroids.

Digital biomarkers can highlight subtle clinical differences in radiologically isolated syndrome compared to healthy controls.

OBJECTIVE: To explore the use of digital biomarkers to distinguish healthy controls (HC) from subjects with a radiologically isolated syndrome (RIS). METHODS: We developed a smartphone application called MS Screen Test (MSST) to explore several dimensions of the neurological exam such as finger tapping speed, agility, hand synchronization, low contrast vision and cognition during a short evaluation. This app was tested on a cohort of healthy volunteers including a subset of subjects who underwent two evaluations on the same day to assess reproducibility. In a second step, the app was tested on a cohort of RIS subjects. Performances of RIS subjects were compared with age and genre-matched HC. RESULTS: HC underwent two consecutive evaluations on MSST. The analysis showed good reproducibility for all measures. Then 21 RIS subjects were compared to 32 matched HC. Compared to HC, we found that RIS subjects had a lower finger tapping speed on the dominant hand (5.6 versus 6.5 taps per second; p = 0.005), a longer inter hand interval during the hand synchronization task (14.4 versus 11.3 ms; p = 0.03) and significantly poorer scores on the low contrast vision and cognition tests. CONCLUSION: MSST only requires a smartphone to obtain digital biomarkers relative to several dimensions of the neurological examination. Our results highlighted subtle differences between HC and RIS subjects. We plan to evaluate this tool in MS patients, which will allow us to get a much larger sample of subjects, to determine whether digital biomarkers can predict disease course.

Cognitive function in radiologically isolated syndrome.

BACKGROUND: Radiologically isolated syndrome (RIS) is characterized by patients with asymptomatic T2 hypersignals detected by brain MRI fulfilling dissemination in space criteria and is suggestive of subclinical multiple sclerosis (MS). In previous studies, it was demonstrated that visual evoked potential and cerebrospinal fluid help to identify pejorative markers in converting to MS. OBJECTIVE: To date the cognitive function has never been investigated in a cohort of RIS. The objective of this study was to investigate cognitive function in a cohort of 26 RIS patients. METHODS: We prospectively assessed the BCcogSEP (a French adaptation of the Brief Repeatable Battery (BRB) including eight cognitive tests) of 26 patients with RIS, compared with 26 MS patients and 26 healthy subjects matched for age, sex and level of education. RESULTS: When comparing the three groups, the cognitive performance was significantly lower in the RIS and MS groups compared with healthy subjects for the Paced Auditory Serial Addition Test (PASAT) 3 seconds (p = 0.002), phonemic fluencies (p = 0.02), the code of the WAIS (p = 0.05), the direct (p = 0.002) or indirect (p = 0.007) digit span test, the cross-taping test (p = 0.019) and Go-No-Go (p = 0.001). When we compared RIS and MS, the cognitive performance was significantly lower in MS patients for the direct span number (p = 0.003) and cross-tapping test (p = 0.05). We did not find significant differences between the three groups for the other tests. We did not find a correlation between clinical, biological and MRI results and cognitive dysfunctions. CONCLUSIONS: This study confirms the recently developed concept of RIS patients who present similar features to MS patients. Further studies are necessary to confirm these initial results and to correlate cognitive disorders with MRI surrogate markers.

Tear analysis in clinically isolated syndrome as new multiple sclerosis criterion.

In clinically isolated syndrome (CIS), the detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is critical for space dissemination validation when magnetic resonance imaging (MRI) diagnostic criteria are not fulfilled. However, lumbar puncture for CSF collection is considered relatively invasive. Previous studies have demonstrated applicability of OCB detection in tears to the diagnosis of multiple sclerosis (MS). The objective of the present study was to assess concordance between OCB detection in tears and in CSF. We have prospectively included patients with CIS and compared results of CSF and tear OCB detection by isoelectric focusing (IEF). Tears were collected using a Schirmer strip. We included 82 patients. For 69 of them, samples were analysable. OCBs were detected in CSF for 63.8% and in tears for 42% of patients. All patients with tear OCBs had CSF OCBs. We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with CIS. This would circumvent the practice of invasive lumbar punctures currently used in MS diagnosis.

Immunization and multiple sclerosis: Recommendations from the French multiple sclerosis society.

OBJECTIVES: To establish recommendations on immunization for patients with multiple sclerosis (MS) BACKGROUND: Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients. METHODS: The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975-June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain. RESULTS: Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs. CONCLUSION: Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS.

Multiple sclerosis with atypical MRI presentation: Results of a nationwide multicenter study in 57 consecutive cases.

BACKGROUND: The recent 2017 modification have increased the sensitivity of McDonald criteria for MS. Nevertheless, some MS patients with atypical MRI findings have been identified, leading to prolonged delay to diagnosis and high costs to look for alternative diagnoses. OBJECTIVE: To describe a series of MS patients with atypical MRI presentation. MATERIAL AND METHODS: Patients with atypical MS were identified through a nationwide retrospective study. We established a five groups classification: tumefactive demyelinating lesion (TDL)-onset MS, acute disseminated encephalomyelitis (ADEM)-like MS, cavitary MS and leukodystrophy-like MS. All the patients meeting our radiological criteria for atypical MS were included. RESULTS: A total of 57 patients met the inclusion criteria. 7 cases were classified in the TDL-onset group, 10 in the ADEM-like group, 26 in the cavitary group and 14 in the leukodystrophy-like group. Overall risk of conversion to MS after an isolated TDL was around 30% at five years. Patients in the TDL-onset and ADEM-like groups globally presented an acute onset and a relapsing-remitting evolution. Conversely, patients in the cavitary and leukodystrophy- groups largely evolved with a progressive and severe course. CONCLUSION: A significant number of MS patients can have a striking atypical presentation and may be misdiagnosed. This preliminary analysis helps to refine the spectrum of atypical MS patients.

Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome.

BACKGROUND: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination. OBJECTIVES: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome. METHODS: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria. RESULTS: Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%). CONCLUSIONS: Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.

Cognitive functions in neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is characterized by optic neuritis and longitudinally extensive acute transverse myelitis. The brain is generally considered healthy in NMO, though very recent studies have demonstrated that magnetic resonance imaging abnormalities may be observed in various brain regions of NMO patients. To date, cognitive functions have never been investigated in NMO. OBJECTIVE: To investigate cognitive functions in a cohort of 30 patients with NMO. DESIGN: Observational, prospective study. PATIENTS: We studied 30 patients with NMO and compared them with 30 patients with multiple sclerosis and 30 healthy controls matched for age, sex, and educational level. Main Outcome Measure We applied a French translation of the Brief Repeatable Battery of Neuropsychological Tests for Multiple Sclerosis and 3 additional tests. RESULTS: Cognitive performance was significantly lower in the NMO and multiple sclerosis groups than in healthy controls for the 2-second (P< .001) and 3-second (P= .001) Paced Auditory Serial Addition Test, the digit symbol modality test (P= .005), word generation (P= .02), and forward (P= .002) and backward (P= .007) digit span test. We did not observe any difference in test performance between NMO and multiple sclerosis patients. We found no differences between the 3 groups for the other tests. We did not find any correlation between clinical, biological, or magnetic resonance imaging results and cognitive dysfunction. CONCLUSIONS: This study confirms the recent concept of a possible brain involvement in NMO. Additional studies are needed to confirm these initial results and to better understand the mechanisms of such abnormalities.

Cancer Risk in Patients with Multiple Sclerosis: Potential Impact of Disease-Modifying Drugs.

In the 1990s, the first disease-modifying therapies (DMTs) for multiple sclerosis (MS) were injectable immunomodulatory (IM) drugs, including four different interferon-ß preparations and glatiramer acetate. Since 2000, more than 15 immunosuppressant (IS) drugs have been used, with a more or less specific action on inflammation. These include monoclonal antibodies targeting CTL4, the integrin receptor, the interleukin (IL)-2 receptor, CD19, CD20, CD52, and the sphingosine 1 phosphate family. The association between MS and cancer has long been investigated but has led to conflicting results. No studies have reported an increased risk of cancer after long-term exposure to IM. Several reports suggest an increase in cancer risk among MS patients treated with IS such as mitoxantrone, azathioprine and cyclophosphamide. Because of their action on the immune system, and due to a lack of available long-term data, a special warning of the potential risk of cancer accompanies the use of recent IS such as cladribine, fingolimod, natalizumab or alemtuzumab. In most studies, factors such as diet, smoking, solar radiation, and hormone therapy, all of which influence cancer risk, have not been considered. For fingolimod, natalizumab, alemtuzumab, dimethyl fumarate, teriflunomide, daclizumab and ocrelizumab, risk management plans outlined by regulatory agencies are mandatory. They allow prospective detection of some red flags, in particular those for the increased risk of cancer. We review the current evidence behind the increased risk of malignancy in MS patients receiving DMTs, and provide an overview of the DMTs that are currently in use and those in clinical trials. The known risks and benefits of these therapies will be considered.

Anomalies Characteristic of Central Nervous System Demyelination: Radiologically Isolated Syndrome.

Radiologically isolated syndrome (RIS) was defined in 2009 for asymptomatic patients who presented incidentally identified white matter anomalies within the central nervous system suggestive of multiple sclerosis (MS). Approximately one-third of RIS subjects will have a seminal clinical demyelinating event within 5 years of the identification of their abnormal MRI. Clinical evolution mirrors relapsing remitting or progressive forms of MS. Pejorative factors for clinical conversion are male gender, age younger than 35 years, and spinal cord lesions.

Only Follow-Up of Memory B Cells Helps Monitor Rituximab Administration to Patients with Neuromyelitis Optica Spectrum Disorders.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) are identified as a spectrum of inflammatory demyelinating disorders involving the brain, spinal cord and optic nerves. These disorders require early diagnosis and highly active immunosuppressive treatment. Rituximab (RTX) has demonstrated efficacy in limiting relapse in NMOSD when using several administration schedules. We questioned if the CD19+ CD27+ memory B cell count was a more reliable marker to monitor RTX administration than the RTX plasma level and CD19+ B cell count. METHODS: We analyzed 125 blood samples from 17 NMOSD patients treated with RTX and also measured the level of anti-aquaporine-4 antibodies (anti-AQP-4 Abs), human anti-chimeric antibodies to the murine fragment of RTX (HACA-RTX Abs), and the RTX concentration. RESULTS: The mean follow-up time of the cohort was 7.4 (2-16) years. All patients improved with a mean EDSS going from 4 (1-8.5) to 2.7 (1-5.5). The mean interval between RTX infusions was 9.6 months with identification of prolonged responders. Total CD19+ B cell detection with the routine technique did not correlate to re-emergence of CD19+ CD27+ memory B cells. The RTX residual concentration did not correlate with the CD19+ CD27+ memory B cell count or with anti-RTX antibody production. CONCLUSION: In contrast to total CD19+ cell, detected with the routine technique, CD19+ CD27+ memory B cells are a reliable marker for biological relapse and allow a decrease in the frequency of infusions.