Restless leg syndrome in multiple sclerosis: a case–control study

ObjectivesThis study assessed the prevalence of restless leg syndrome (RLS) among patients with multiple sclerosis (pwMS) and the association between RLS and MS disease duration, sleep disturbance, and daytime fatigue.MethodsIn this cross-sectional study, we interviewed 123 patients via phone calls using preset questionnaires containing the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS) diagnostic criteria validated in both Arabic and English. The prevalence of RLS in MS was compared to a group of healthy controls.ResultsThe prevalence of RLS in pwMS, defined by meeting all four requirements included in the IRLSSG diagnostic criteria, was 30.3% compared to 8.3% in the control group. About 27.3% had mild RLS, 36.4% presented with moderate, and the remaining had severe or very severe symptoms. Patients with MS who experience RLS had a 2.8 times higher risk of fatigue compared to pwMS without RLS. pwMS with RLS had worse sleep quality, with a mean difference of 0.64 in the global PSQI score. Sleep disturbance and latency had the most significant impact on sleep quality.ConclusionThe prevalence of RLS among MS patients was significantly higher compared to the control group. We recommend educating neurologists and general physicians to increase their awareness of the increasing prevalence of RLS and its association with fatigue and sleep disturbance in patients with MS

Early-onset convulsive seizures induced by brain hypoxia-ischemia in aging mice: effects of anticonvulsive treatments

Sherpa Romeo green journal. Open access article. Creative Commons Attribution License applies.Aging is associated with an increased risk of seizures/epilepsy. Stroke(ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures area poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxiaalone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes.Ye

Clinical and economic evaluations of natalizumab, rituximab, and ocrelizumab for the management of relapsing-remitting multiple sclerosis in Saudi Arabia

Abstract Introduction The advent of new disease-modifying therapies (DMTs), such as monoclonal antibodies (mAbs), resulted in significant changes in the treatment guidelines for Multiple sclerosis (MS) and improvement in the clinical outcomes. However, mAbs, such as rituximab, natalizumab, and ocrelizumab, are expensive with variable effectiveness rates. Thus, the present study aimed to compare the direct medical cost and consequences (e.g., clinical relapse, disability progression, and new MRI lesions) between rituximab and natalizumab in managing relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia. Also, the study aimed to explore the cost and consequence of ocrelizumab in managing RRMS as a second-choice treatment. Methods The electronic medical records (EMRs) of patients with RRMS were retrospectively reviewed to retrieve the patients’ baseline characteristics and disease progression from two tertiary care centers in Riyadh, Saudi Arabia. Biologic–naïve patients treated with rituximab or natalizumab or those switched to ocrelizumab and treated for at least six months were included in the study. The effectiveness rate was defined as no evidence of disease activity (NEDA-3) (i.e., absence of new T2 or T1 gadolinium (Gd) lesions as demonstrated by the Magnetic Resonance Imaging (MRI), disability progression, and clinical relapses), while the direct medical costs were estimated based on the utilization of healthcare resources. In addition, bootstrapping with 10,000 replications and inverse probability weighting based on propensity score were conducted. Results Ninety–three patients met the inclusion criteria and were included in the analysis (natalizumab (n = 50), rituximab (n = 26), ocrelizumab (n = 17)). Most of the patients were otherwise healthy (81.72%), under 35 years of age (76.34%), females (61.29%), and on the same mAb for more than one year (83.87%). The mean effectiveness rates for natalizumab, rituximab, and ocrelizumab were 72.00%, 76.92%, and 58.83%, respectively. Natalizumab mean incremental cost compared to rituximab was $35,383 (95$25,401.09– $49,717.92), and its mean effectiveness rate was 4.92% lower than rituximab (95% CI: -30–27.5) with 59.41% confidence level that rituximab will be dominant. Conclusions Rituximab seems to be more effective and is less costly than natalizumab in the management of RRMS. Ocrelizumab does not seem to slow the rates of disease progression among patients previously treated with natalizumab

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial

BackgroundMethylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.MethodsIn this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.FindingsBetween Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).InterpretationAmantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.FundingPatient-Centered Outcomes Research Institute

Ipsilateral brain injury or infarctions in aging mice with post-HI CS.

<p><b>A</b>-<b>D</b>, images of cresyl violet-stained brain sections were obtained from 4 aging mice. Left, low power views at three coronal levels. Right, magnified views of the dorsal hippocampal areas (denoted by black dots on low power view). Time of histologic preparation, experimental group, and CS occurrence were indicated for each animal above their respective low power images. <b>E</b>, ratios of ipsilateral relative to contralateral hemispheric areas were obtained at 8 coronal levels and averaged for each animal. Data (%, mean±SE) for individual animals were pooled together according to the indicated experimental groups. *, p<0.05, sham controls vs. other experimental groups, one way ANOVA.</p

Decreases of ipsilateral EEG signals in aging mice with early-onset CS.

<p><b>A</b>-<b>C</b>, representative EEG traces collected from 3 aging mice during baseline monitoring (left), at the end of ambient air exposure or hypoxia (middle), and 24 hours later (right). Tethered recordings were made from the ipsilateral hippocampus and contralateral parietal cortex for each animal. Note the ipsilateral EEG suppression in the animal with post-HI CS (B), recovered ipsilateral EEG in the animal without CS (C) and the lack of EEG suppression in the control animal (A). <b>D</b>, 30-sec EEG segments were collected during baseline monitoring, at the end of either hypoxia or ambient air exposure, then at 1 hour, and 24 hours following either a sham operation or HI. The root mean square (RMS) of the EEG signals was calculated and normalized as a percentage of the baseline RMS. Animals are grouped as sham controls and post-HI with and without CS. Data (mean±SE) for the ipsilateral hippocampus (left) and the contralateral cortex (right) are presented separately. *, p<0.05, sham control vs. others, one way ANOVA.</p

Ipsilateral brain injuries observed histologically from individual aging mice.

<p>Ipsilateral brain injury was recognized through hypochromic staining when examined at 24–48 hours post-HI or cystic infarctions at 4–5 weeks post HI. Column 1: Animal ID of each aging mouse examined. Columns 2–6: injured brain structures indicated by ‘+’. Abbreviations: HIPP—hippocampus; LAT CORT—lateral cortex; STR—striatum; TH—thalamus; MB/BST—midbrain and brainstem areas. Column 7: ipsilateral regions with hypochromic staining where clearly recognized boundaries were present and quantifiable in 6 animals. These regions were measured at 8 coronal levels (bregma 1.9, 1.2, 0.5, -0.2, -1.1, -1.5, -2.4 and -3.2 mm respectively) and normalized as a % of total ipsilateral hemispheric area. The mean±SE from multiple coronal levels were presented for each animal. Column 8: ipsilateral brain injury observed for other animals in which injury margins were difficult to demarcate. For these animals, the coronal levels at which hypochromic staining or infarctions were observed were indicated for each animal instead.</p><p>Ipsilateral brain injuries observed histologically from individual aging mice.</p

Abundant Fluoro-Jade positive cells in aging mice with post-HI CS.

<p><b>A-F,</b> representative images were collected from 2 aging mice 24 hours following HI, one with CS (D-F, right), the other without (A-C, left). Brain regions in which Fluoro-Jade positive cells were analyzed are indicated diagrammatically in middle column (by red squares). <b>G</b>, an enlarged image was taken from a selected cortical area (indicated by a yellow square in F). <b>H</b>, regional counts of Fluoro-Jade positive cells in 8 post-HI aging mice with and without CS (mean±SE; n = 4 in each group). *, p<0.05, ipsilateral cell counts in animals with CS vs. contralateral cell counts and cell counts in animals without CS, one way ANOVA.</p

EEG and histological measures from aging mice in the untreated/post-CS treated or prophylactically treated cohort.

<p>Post-CS and prophylactic anticonvulsive treatments were conducted in two separate cohorts of aging mice (n = 24 and 21 respectively). <b>Panel A</b>: Changes in ipsilateral hippocampal EEG signals were analyzed in 8 and 5 animals with CS from these two cohorts respectively. Ipsilateral hippocampal EEG signals were normalized as a % of the baseline. The numbers of animals examined at different post-HI time points are indicated in the parentheses. <b>Panel B</b>: ipsilateral EEG signals were analyzed in untreated animals and prophylactically treated animals (n = 6 each) that did not exhibit CS and ipsilateral infarctions on later histological assessment. Data are similarly presented in Panel A. <b>Panel C</b>: The ratio of the ipsilateral to contralateral hemispheric areas measured in histological brain sections. These measurements were made in 4 untreated/post-CS treated animals and 7 prophylactically treated animals 4–5 weeks post-HI. There were no significant group differences in any EEG or histological measures (p>0.05, t test or Mann-Whitney Rank Sum Test).</p><p>EEG and histological measures from aging mice in the untreated/post-CS treated or prophylactically treated cohort.</p