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Caloric irrigation (CI) is the gold standard to investigate peripheral vestibular dysfunction. The video head impulse test (vHIT) is faster and more accessible and may be useful during acute vertigo stroke risk differentiation. Comparative studies between the two methods are needed. The objective of this study was to compare vestibular function data derived from caloric irrigation with that from vHIT. This study included 80 patients with acute onset vertigo who underwent caloric irrigation and vHIT. CI derived sum of slow phase velocities (SPVs) and unilateral weakness (UW) were compared with vHIT vestibulo-ocular reflex (VOR) gain and gain asymmetry (GA) using correlation analyses. Optimal cut offs for vHIT VOR gain and GA were calculated using Youden indexes. There was a strong positive correlation between the asymmetry measures UW and GA whereas the correlation between the sum of SPVs and VOR gain was weaker. The optimal cut offs to diagnose unilateral vestibular weakness were 0.80 for VOR gain and 28% for GA; with specificities for predicting normal caloric irrigation results of 55% and 93%, respectively. In one third of cases the results from caloric irrigation and vHIT dissociated. The results from vHIT correlated with those from CI, still neither test seem to have the accuracy to replace the other. GA appears as an attractive measure in acute vertigo as the high specificity can be used to identify those with a substantial probability of normal vestibular function in need of more comprehensive work-up for central causes. To diagnose vestibular dysfunction, CI remains gold standard.

BACKGROUND AND PURPOSE: High levels of 25-hydroxyvitamin D3 (25[OH]D3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D3 and DBP as risk factors for MS. METHODS: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D3 was approximated as free vitamin D3 index: (25[OH]D3 /DBP) × 103 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Serum samples from 660 pairs of matched cases and controls were included. At

BACKGROUND AND PURPOSE: Systematic analysis of angulation-related variability of idiopathic normal pressure hydrocephalus imaging biomarkers has not been published yet. Our aim was to evaluate the variability of these radiologic biomarkers with respect to imaging plane angulation. MATERIALS AND METHODS: Eighty subjects (35 with clinically confirmed idiopathic normal pressure hydrocephalus and 45 age- and sex-matched healthy controls) were prospectively enrolled in a 3T brain MR imaging study. Two independent readers assessed 12 radiologic idiopathic normal pressure hydrocephalus biomarkers on sections aligned parallel or perpendicular to the bicallosal, bicommissural, hypophysis-fastigium, and brain stem vertical lines, respectively. RESULTS: Disproportionately enlarged subarachnoid space hydrocephalus, simplified callosal angle, frontal horn diameter, z-Evans Index, and cella media vertical width did not show significant systematic differences in any of 6 section plane combinations studied. The remaining 7 biomarkers (including the Evans Index and callosal angle) showed significant differences in up to 4 of 6 mutually compared section plane combinations. The values obtained from sections aligned with the brain stem vertical line (parallel to the posterior brain stem margin) showed the most deviating results from other section angulations. CONCLUSIONS: Seven of 12 idiopathic normal pressure hydrocephalus biomarkers including the frequently used Evans Index and callosal angle showed statistically significant deviations when measured on sections whose angulations differed or did not comply with the proper section definition published in the original literature. Strict adherence to the methodology of idiopathic normal pressure hydrocephalus biomarker assessment is, therefore, essential to avoid an incorrect diagnosis. Increased radiologic and clinical attention should be paid to the biomarkers showing low angulation–related variability yet high specificity for idiopathic normal pressure hydrocephalus–related morphologic changes such as the z-Evans Index, frontal horn diameter, or disproportionately enlarged subarachnoid space hydrocephalus.

Background Rituximab is safe and effective for treating relapsing–remitting multiple sclerosis (RRMS) according to phase II and observational studies. There are limited data on disease activity after discontinuation and dose reduction. The objective of this study was to evaluate the effects on inflammatory disease activity after discontinuation or dose reduction of rituximab in patients with RRMS or clinically isolated syndrome (CIS). Methods In this retrospective observational study, we included all RRMS and CIS patients ever treated with rituximab at the University Hospital of Umeå who had either; (1) discontinued treatment at any time or (2) reduced the dose to a mean of Results A total of 225 patients treated with mean (SD) 6256 (2456) mg rituximab during mean (SD) 6.5 (2.0) years were included. There were no differences regarding the annualized relapse rates during full dose versus reduced dose or off treatment (0.02 versus p = 0.09), neither regarding proportion MRI scans with new or enlarged T2 lesions (0.03 versus 0.01 and 0.03, p = 0.37) or contrast-enhancing lesions (p = 0.22). Conclusions This study indicates that rituximab has long-term effects on inflammatory disease activity and that disease reactivation is rare in MS patients who discontinued treatment for any reason. It also suggests that treatment with low-dose rituximab (

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments. Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

High levels of 25-hydroxyvitamin DA nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)DSerum samples from 660 pairs of matched cases and controls were included. At20 years of age, high levels of free vitamin DThese findings support the hypothesis that high levels of free 25(OH)D

B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.Swedish Research Council.

Background C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS). Objectives To assess CRP as a risk factor for MS. Methods Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z-scored CRP values. Results Levels of CRP were not associated with MS risk. Conclusions We found no association between CRP levels and risk of MS development.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS.Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models.A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ.In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

Purpose There is a paucity of age- and vascular risk factor-stratified video head impulse test (vHIT) vestibulo-ocular reflex (VOR) data in the literature. The aim of this study was to investigate the vHIT VOR properties in healthy subjects of different ages and subjects with vascular risk factors. Methods This was a prospective observational single-center study at a tertiary referral university hospital in northern Sweden. Healthy participants and subjects with vascular risk factors were investigated with a floor standing external camera vHIT device. Age-stratified mean VOR gain among healthy adults and between group gain and gain asymmetry differences were calculated. Results We included eighty-eight healthy adults with a mean (range) age of 50 (22–85) years and n = 48 stroke ward patients with vascular risk factors (but without vestibular disease) with a mean (range) age of 74 (42–92) years. The mean VOR gain of horizontal canals decreased at higher ages in healthy subjects (r = − 0.32, p n = 167 canals). The age-stratified mean (SD) VOR gains were Conclusions Age, but not vascular risk factors influence VOR gain. Age-adjusted vHIT-measurements may be useful in acute vertigo stroke risk differentiation.

Background and purpose: We investigated 952 subjects undergoing diagnostic lumbar puncture (LP) to study the effects of needle size, needle design and stylet reinsertion on the risk of post‐dural puncture headache (PDPH). Methods: This randomized double‐blind study was performed at Umeå University Hospital in Sweden during 2013–2018. Subjects were randomly assigned one of three needles [22 gauge (G) atraumatic, 25G atraumatic and 25G cutting] and stylet reinsertion before needle withdrawal or not. The main outcome measure was PDPH assessed by standardized telephone interview(s) 5 days after the LP, repeated until headache cessation. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PDPH. Results: The mean (SD) age was 51.1 (16.7) years and 53.6% were females. The smaller bore (25G) atraumatic needle incurred a lower risk of headache compared with the larger bore (22G) atraumatic needle [22.0% (69/314) vs. 30.2% (98/324); OR, 0.65; 95% CI, 0.45–0.93] and compared with the cutting needle [32.8% (103/314); OR, 0.58; 95% CI, 0.40–0.82]. Reinserting the stylet before needle withdrawal did not reduce the risk of headache. Conclusions: These data suggest that a 25G atraumatic needle is superior to a larger atraumatic needle, and to a same‐sized cutting needle, in preventing PDPH after diagnostic LP. In contrast to one earlier report, this study did not find that stylet reinsertion was effective in preventing PDPH. This study provides class I evidence that a small atraumatic needle decreases the risk of PDPH and that stylet reinsertion does not influence PDPH risk.

Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoenceph ...

Purpose: This study aims to evaluate whether a management algorithm has improved the effectiveness of care for dizzy patients at Umea University Hospital. Methods: This was an interventional study using medical records to collect data for acute dizziness presentations before (period 1, 2012-2014) and after (period 2, 2016-2017) the implementation of a management algorithm. Outcomes were changes in a set of pre-defined effectiveness markers and health economic effects. Results: Total n = 2126 and n = 1487 acute dizziness presentations were identified in period 1 and 2, respectively. Baseline characteristics were similar. The proportion of patients undergoing Dix-Hallpike testing increased, 20.8% [95% confidence interval (CI) 18.8-23.0%] vs. 37.7% (95% CI 35.2-40.2%), as did BPPV diagnoses, 7.6% (95% CI 6.6-8.8%) vs. 15.3% (95% CI 13.6-17.3%). Hospitalization became less common, 61.5% (95% CI 59.4-63.6%) vs. 47.6% (95% CI 45.1-50.2%). The proportion undergoing any neuroradiological investigation decreased, 44.8% (95% CI 42.7-47.0%) vs. 36.3% (95% CI 33.8-38.7%) with a shift from CT to MRI, with unchanged sensitivity for diagnosing cerebrovascular causes. The average cost for the care of one dizzy patient decreased from $2561 during period 1 to $1808 during period 2. Conclusions: This study shows that the implementation of a management algorithm for dizzy patients was associated with improved effectiveness of care.

Background Most multiple sclerosis patients on disease-modifying treatment at Umeå University Hospital are treated with rituximab and the prevalence of vitamin D supplementation has increased over time. Follow-up studies of these off-label treatments are needed. Objective To study inflammatory activity and adverse effects in rituximab-treated multiple sclerosis patients, and associations with 25-hydroxy-vitamin D levels. Methods Retrospectively collected data on repeated estimates of relapses, disability, side effects, magnetic resonance imaging, laboratory measures including 25-hydroxy-vitamin D levels and self-perceived health. Results In 272 multiple sclerosis patients with a mean follow-up of 43 months, we identified seven possible relapses during active rituximab treatment. On magnetic resonance imaging examination, new T2 lesions were seen in 1.3% (10 out of 792 scans), and 0.25% (two out of 785 scans) showed contrast enhancement. Adjusted 25-hydroxy-vitamin D levels in samples drawn close to all magnetic resonance images with new T2 lesions were lower compared to the remainder (62 vs. 81 nmol/l; P = 0.030). Levels of 25-hydroxy-vitamin D were associated with self-perceived health ( r = 0.18, P = 0.041, n = 130) and C-reactive protein ( r = –0.13, P = 0.042) but not with the risk of side effects. Conclusion The inflammatory activity in this rituximab-treated multiple sclerosis population that increasingly used vitamin D supplementation was extremely low. Higher 25-hydroxy-vitamin D levels were associated with beneficial outcomes.

Background - To lower the risk for post lumbar puncture (LP) headache the American Academy of Neurology (AAN) recommended using small bore atraumatic needles together with stylet reinsertion in a report from 2005. It is unclear whether these recommendations are followed or not. Objectives - To investigate the diagnostic LP preferences with respect to the AAN guidelines among neurologists by use of a short online questionnaire, and to review previously published literature on the subject. Results - A total of 284 respondents who performed diagnostic LPs completed the questionnaire. Almost half (41%) answered that they always use atraumatic needles. The most common reason (73%) for not using atraumatic needles was that these were not available. Less than half of the respondents who performed LPs had knowledge about the AAN guidelines for diagnostic LPs, and 48-76% agreed with the different recommendations therein. Five previously (1998-2015) published studies investigating LP practice among neurologists were identified. The reported frequency of atraumatic needle use (always/routinely) varied between 2 and 16%. Discussion - Atraumatic needle use was more common in this study compared with previous publications. There is still skepticism regarding some of the AAN recommendations, and needle availability appears to be the most important factor preventing atraumatic needle use. To increase the use of atraumatic needles we may perform additional studies investigating their potential benefits, and arrange training sessions for neurologists to increase their awareness and level of comfort with the atraumatic LP technique.Háttér - Az Amerikai Neurológus Társaság (American Aca­demy of Neurology, AAN) 2005-ben a posztpunkciós fej­fájás csökkentésére kis átmérőjű, atraumatikus lumbálpunk­ciós (LP) tűk használatát javasolta a mandrin visszahelyezésével. Nincsenek pontos adatok arra vonatkozólag, hogy ezeket az ajánlásokat a neurológusok alkalmazzák-e. Célkitűzés - A neurológusok LP-s szokásainak felmérését tűztük ki célul az AAN-ajánlások tükrében, melyet rövid online kérdőív kitöltésével követtünk, valamint áttekintettük a legújabb szakirodalmat a témában. Eredmények - Összesen 284 diagnosztikus LP-t végző válaszadó töltötte ki a kérdőívet. Majdnem a fele (41%) azt válaszolta, hogy mindig atraumatikus tűt használ. A leggyako­ribb ok, hogy nem atraumatikus tűvel történt a beavatkozás (73%), a tű elérhetetlensége volt a munkahelyen. Az LP-t végző megkérdezettek kevesebb mint fele ismerte az AAN-ajánlásokat, és 48-76%-a egyetértett az ott szereplő különböző javaslatokkal. Öt korábbi (1998-2015) közleményt találtunk, mely a neurológusok LP-s technikáját vizsgálta. Az atraumatikus tűk (állandó/rutinszerű) használatának gyakorisága 2 és 16% között váltakozott. Megbeszélés - Az atraumatikus tűk használatát gyakoribbnak találtuk kérdőívünk alapján, mint azt a korábbi közleményekben leírták. Míg az AAN-ajánlásoknak továbbra is szkeptikus a fogadtatása, az atraumatikus tűk használatá­nak legnagyobb kerékkötője a tűk elérhetetlensége az adott munkahelyeken. Az atraumatikus tűk használatának elő­mozdítására kiegészítő vizsgálatok szükségesek, melyek tanulmányozzák a potenciális előnyeiket, valamint továbbképzések szervezésével felhívhatjuk a neurológusok figyel­mét az atraumatikus tűk használatára és a technikai jártasság megszerzésével az új módszer kényelmesebben illeszthető a napi rutinba.

Paediatric onset multiple sclerosis (POMS) is characterized by high inflammatory activity. No disease modifying treatment has been approved for POMS. The objective of this report was to report the use of rituximab, a B cell depleting monoclonal anti-CD20-antibody, in POMS. This is a retrospective case series at four specialized MS centres in Sweden. Participants were identified through the Swedish MS-registry and our own patient stocks. Data were collected through medical charts review. We identified 14 POMS patients treated with i.v. rituximab 500-1000 mg every 6th to 12th months. Median age at disease onset was 14.7 years, median age at rituximab treatment initiation was 16.5 years, and median treatment duration was 23.6 months. No relapses were reported, and the EDSS scores remained stable or decreased in 13 of 14 cases during rituximab treatment. Beyond 6 months from initiating rituximab treatment, only one new lesion was detected on MRI. No serious AEs were reported. The drug survival was 86%. Our data indicate that rituximab treatment is safe, effective and well tolerated in children with MS. Nine POMS cases treated with rituximab have previously been published. They had higher disease activity pre-rituximab, but similar safety and efficacy outcomes after treatment. An RCT of rituximab in POMS is warranted.

Background: Previous studies in patients with multiple sclerosis (MS) have shown an association between high serum 25-hydroxyvitamin D (25[OH]D) levels and decreased inflammatory activity. Objective: The purpose of this study was to examine the association between 25(OH)D levels and axonal injury in MS. Cerebrospinal fluid neurofilament light (CSF-NFL) was used as a marker for axonal injury. Methods: Patients were identified through clinical practice at the Department of Neurology in Umeå University Hospital, Sweden. Blood draw, magnetic resonance imaging, scoring of disability and lumbar puncture were performed at inclusion in 153 patients, and also at median 12 months follow-up in 87 patients. For analyses of serum 25(OH)D levels and CSF-NFL, enzyme-linked immunosorbent assays were used. Results: There was an inverse association between serum 25(OH)D and CSF-NFL levels in categorical (dichotomized at 75 or 100 nmol/l) analyses. A dose-response effect for 25(OH)D levels on CSF-NFL levels ( p for trend=0.034) was also present. Serum 25(OH)D levels above 100 nmol/l were associated with lower CSF-NFL levels independently of ongoing MS treatment. Conclusion: High 25(OH)D levels are associated with decreased axonal injury in MS.

It is with great interest that we read the recent article by Jadhav et al[1][1] concerning subgroup assessments in the SWIFT PRIME trial, especially for collateral status. They reported, “Outcomes stratified by collateral status had a benefit with thrombectomy across all groups: none-to-fair

IMPORTANCE: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. OBJECTIVE: To examine the risk of serious infections associated with disease-modifying treatments for MS. DESIGN, SETTING, AND PARTICIPANTS: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. EXPOSURES: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. MAIN OUTCOMES AND MEASURES: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. RESULTS: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]). CONCLUSIONS AND RELEVANCE: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

Numerous radiological measures have been proposed as imaging biomarkers of idiopathic normal pressure hydrocephalus (iNPH), however, the number of studies systematically comparing their diagnostic values remains limited. The study objective was to compare the diagnostic performance of fifteen cross-sectional imaging iNPH biomarkers.Eighty subjects were prospectively enrolled in the study: 35 subjects with clinically confirmed iNPH and 45 matched healthy controls (HC). Values of linear, angular and index measurements including three newly proposed biomarkers were obtained from 3T brain MRI studies by two independent readers. Diagnostic performance of biomarkers was studied by using receiver operating characteristic (ROC) analysis and t-statistic.All biomarkers studied were able to reliably differentiate iNPH subjects from HC (p .001) except for cella media-to-temporal horn ratio. Z-Evans index, vertical cella media and vertical frontal horn diameters showed the highest discriminatory power between iNPH and HC groups (area under curve0.99). Simple linear measurements of vertical (0.99) or horizontal (0.95) frontal horn diameters showed results comparable to calculated ratios, i.e. z-Evans (0.99) and Evans (0.96) indexes, respectively.The best diagnostic performance among fifteen radiological iNPH biomarkers was found in linear measurements referring to caudocranial alterations of the ventricular geometry, outweighing those referring to laterolateral ventricular enlargement (as e.g. commonly used Evans index). Simple linear measurements of vertical or horizontal frontal horn diameters showed comparable results to calculated, more time-consuming z-Evans or Evans indexes, respectively.

We are presently faced with the competing notions of modern life being a 'state of vitamin D depletion', implying a widespread need to supplement with vitamin D, or, the opposite view, which is that the present evidence can only support at best selective targeted vitamin D intervention. This is important as there is evidence that over the last 40-50 years there were downwards global trends in serum 25(OH)D concentrations, while individual consumption of vitamin D as supplements rose. For this reason and many others, a large population-based interventional study, the VITAL trial, was designed to try to establish the health value of vitamin D supplementation. VITAL is a huge primary prevention trial looking at the effects of vitamin D repletion in preventing cancer and cardiovascular disease in a fundamentally healthy population. This may seem an unusual approach given that what we mostly know about vitamin D is that is has some effects on the skeleton. This review looks to explore current knowledge about vitamin D in health and disease, and at how this is now undergoing significant reappraisal and revision. We will carefully critique the VITAL study design to see if it will allow for the construction of the detailed portfolio of clinical evidence so urgently needed to allow us better to understand role of vitamin D supplementation in health and disease.

The multiple sclerosis (MS) risk factors smoking and remote Epstein-Barr virus (EBV) infection have been suggested to interact statistically, but the results are conflicting. In a prospective study on 192 MS cases and 384 matched controls, we analysed levels of cotinine as a marker of smoke exposure, and Epstein-Barr Nuclear Antigen-1 antibody reactivity. We assessed interaction on the additive and multiplicative scales, and estimated the effects of the risk factors across strata of each other. The results suggest that a negative interaction may be present in samples drawn at a young age, and a positive interaction among older subjects.

Background: The antibody reactivity against Epstein-Barr nuclear antigen-1 (EBNA-1), and 25-hydroxyvitamin D (25(OH)D) status have been associated with multiple sclerosis (MS) risk. Interaction between these two factors has been proposed. Objectives: The objective of this paper is to examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk of MS, and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples. Methods: Antibody reactivity and 25(OH)D levels were measured using ELISAs in n = 192 MS cases and n = 384 matched controls. The risk of MS was analysed using matched logistic regression. Interaction on the additive scale was assessed. Results: The risk of MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1402–502, and domain EBNA-1385–420; p trends < 0.001. In young individuals (below median age at sampling, < 26.4 years), these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains. No statistical interaction was found. Conclusions: We confirm that increased antibody reactivity against EBNA-1 is a risk factor of MS. 25(OH)D status might influence the immune response towards Epstein-Barr virus in young subjects, and thereby modulate MS risk.

Relapsing-remitting multiple sclerosis has a variable prognosis and lacks a reliable laboratory prognostic marker. Our aim in this study was to investigate the association between neurofilament light levels in cerebrospinal fluid in early multiple sclerosis and disease severity at long-term follow-up. Neurofilament light levels in cerebrospinal fluid collected at diagnostic lumbar puncture were measured in 99 multiple sclerosis cases. Clinical data were obtained from 95 out of those at follow-up visits made 14 years (range 8—20 years) after disease onset. Significant correlations between neurofilament light levels and the multiple sclerosis severity score were found for all cases ( r = 0.30, p = 0.005), for relapsing-remitting multiple sclerosis cases ( r = 0.47, p < 0.001) and for cases with a recent relapse ( r = 0.60, p < 0.001). In the multivariate logistic regression analysis, neurofilament light levels >386 ng/L (median value of cases with detectable levels) increased the risk for severe multiple sclerosis fivefold (odds ratio 5.2, 95% confidence interval 1.8—15). Kaplan—Meier analysis showed that conversion to secondary-progressive multiple sclerosis was more likely in cases with neurofilament light levels >386 ng/L than in those with neurofilament light levels

This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnan ...

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades >= 2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.

Background - To lower the risk for post lumbar puncture (LP) headache the American Academy of Neurology (AAN) recommended using small bore atraumatic needles together with stylet reinsertion in a r ...

Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy.We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umeå, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%).Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center).Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns. Ann Neurol 2016;79:950-958.

The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level - YES

There are several associations that intriguingly indicate a protective role for the sunshine vitamin, vitamin D, in multiple sclerosis (MS) etiology [1,2]. Long ago the epidemiological observation was made that the incidence of MS increases with greater distance from the equator. The simplest explanation for this would be that differences regarding climate, and most obviously sun exposure, account for this observation. The epidemiological data that suggest an environmental factor are further strengthened by migration studies, which show that an individual’s risk for MS decreases if he or she moves from a highto a low-risk area [3].

Axonal loss from relapses and neurodegeneration is a main element of multiple sclerosis (MS) pathology, so an objective biomarker to detect and quantify it should be of great value. Neurofilaments belong to the intermediate filament family of proteins and are the major components of the cytoskeleton of neurons. They consist of 3 isotypes: a neurofilament light (NfL) chain of 68 kDa, a neurofilament intermediate (NfM) chain of 150 kDa, and a neurofilament heavy (NfH) chain of 190 to 210 kDa.1 During the process of axonal injury, intracellular components, including neurofilaments, are released into the extracellular fluid and subsequently into the CSF. Thus, analysis of neurofilament levels in the CSF may reliably capture the extent of axonal damage and neurodegeneration in the CNS, regardless of the underlying cause.1 Evidence for increased CSF neurofilament levels in MS mainly exists for NfH and NfL, whereas NfM has not been extensively studied so far.1 Several test systems exist to determine NfH and NfL, and a commercially available ELISA to detect NfL is advantageous in discriminating patients with MS from controls.2

Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Västerbotten Counties were identified from a Swedish multiple sclerosis registry.All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores.Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively).Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

To update the incidence and prevalence of multiple sclerosis (MS) in Västerbotten County, Sweden, and to compare this to previous investigations in the same area.Northern Sweden is a high-risk area for developing MS. Västerbotten County has previously been surveyed in detail regarding the occurrence of MS. In several countries, increases in MS prevalence and incidence as well as a change in the sex ratio have been reported.Multiple sources were used to identify MS cases in Västerbotten that either had their onset of the disease from 1998 to 2010 and/or lived in Västerbotten, the two dates chosen for prevalence calculation: the 31st of December 2005 and 2010.The mean yearly incidence of MS in Västerbotten during the entire period 1998-2010 was 6.0/100,000. The female to male ratio was 2.1. The prevalence of MS in Västerbotten was 188/100,000 on 31st of December 2005 and 215/100,000 on 31st of December 2010. The MS prevalence increased over time from 1990 to 2010.The prevalence of MS in Västerbotten County has increased between 1990 and 2010, while no statistically significant increase in incidence was seen.

We question the ethical soundness of the RESTORE study.1 RESTORE investigated the consequences of discontinuing natalizumab treatment in multiple sclerosis (MS). Natalizumab temporarily (1–3 months) blocks the migration of lymphocytes into the brain.2,3 Earlier observational studies (n = 11 cited in RESTORE) showed recurrence of disease activity a few months after discontinuing treatment. The RESTORE study, sponsored by Biogen Idec, stated that the study provided Class II evidence of MS inflammatory activity returning after natalizumab interruption. …

Lumbar puncture (LP) with cerebrospinal fluid analysis is a common diagnostic tool in neurology, and may be complicated by post-LP headache (PLPHA). The American Academy of Neurology (AAN) has published guidelines for performing diagnostic LPs with the aim to reduce PLPHA risk, but our clinical hands-on experience suggests that these are not followed. We performed a questionnaire study among Swedish neurologists to investigate the acceptance and implementation of the AAN guidelines. Only one-eighth (22/174) of the respondents performed their LPs according to the AAN guidelines. The poor adherence to the AAN guidelines among Swedish neurologists may be due to perceived low credibility, as the current guidelines cite only one study to support the recommendation to use atraumatic needles, and only one study to support the recommendation to replace the stylet before needle withdrawal. An international survey has been posted ( https://www.surveymonkey.com/s/lumbarpuncturesurvey ) to investigate whether the results of this Swedish questionnaire are representative of neurologists worldwide.

This article briefly introduces the basics of multiple sclerosis' (MS) clinical hallmarks and pathophysiology. Vitamin D is presented, including its metabolism and effects on the immune system. The epidemiological observations linking vitamin D to MS range from a half century old findings of latitude gradients and migrational risk patterns to modern, nested, case-control biobank studies. These observations show an association without doubt although causation has yet to be proven. Vitamin D as a treatment for MS is an emerging concept and both current and anticipated data will be covered. Lastly, we discuss future challenges, ideas on how to move from association to causation, and the prospect of primary prevention of this disabling disease.

Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis : No

Background: Vitamin A is important for the immune system, and might suppress inflammatory activity in multiple sclerosis (MS). Objectives: We aimed to examine if vitamin A levels were associated with MS risk in samples collected prospectively and during gestation. Methods: We measured Retinol Binding Protein (RBP – a surrogate marker for vitamin A) and high-sensitivity C-reactive protein (hs-CRP) levels, in (1) prospectively collected biobank blood samples from MS cases and controls, and (2) gestational samples where the offspring had later developed MS, and gestational control samples. The risk of MS was calculated using matched multivariable logistic regression adjusted for confounders. Results: In prospective samples, RBP levels within the second quintile (vs. the first) were associated with a lower MS risk (OR = 0.38, 95% CI 0.19–0.74). No effect on MS risk in the offspring by gestational RBP levels was found. In young subjects hs-CRP levels ≥10 mg/l in prospective samples were associated with a lower MS risk (OR = 0.36, 95% CI 0.14–0.95). Conclusions: Our results suggest that sub-optimal vitamin A levels may be associated with MS risk. The association between hs-CRP levels and MS risk in young subjects may support the role of the hygiene hypothesis in MS aetiology.

Background: Smoking has been associated with an increased risk for multiple sclerosis, but no studies have measured levels of the nicotine metabolite cotinine in prospectively collected samples to assess exposure. Objective: To investigate the effects of laboratory defined tobacco use on the risk for multiple sclerosis using prospectively collected biobank blood samples. Methods: Levels of cotinine were measured in n=192 cases, and n=384 matched controls, using an immunoassay. The risk for multiple sclerosis was estimated using matched logistic regression. Results: Elevated cotinine levels (≥10 ng/ml) were associated with a significantly increased risk for multiple sclerosis, (odds ratio, OR 1.5, 95% confidence interval, CI 1.0–2.1). This association was only present in young individuals (below median age at blood sampling, Conclusions: This study confirms that smoking is a risk factor for multiple sclerosis. It has the advantage of using analyses of cotinine levels in samples that were collected several years before disease onset, thus excluding any risk for recall bias and minimising the risk for reversed causation. Our results also suggest that the smoking related immunological events that contribute to the development of multiple sclerosis occur early in life.