Discontinuation of dimethyl fumarate in multiple sclerosis - a nationwide study.

BACKGROUND: Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health care cost in multiple sclerosis (MS). The aim of this study was to investigate rates and reasons for discontinuation of dimethyl fumarate (DMF) among people with MS on a national level and differences between clinics in Denmark. METHODS: This was a nationwide, registry and population study of patients treated with DMF. We calculated standard residuals (SR) demonstrate differences between clinics. For survival analysis regarding discontinuation rates and discontinuation due to specific AEs we used log-rank test Cox-proportional hazards and plotted Kaplan-Meier graphics. RESULTS: We included 2,448 people with MS, treated with DMF from 2013 to 2020. Average treatment duration was 26 months (5,382 treatment years). 49.2 % of patients who initiated treatment with DMF (n = 1205) were continuously treated. Reasons for discontinuation were adverse events (54.5 %, n = 656), active disease (26.1 %, n = 315), pregnancy (9.4 %, n = 113) or other reasons (13.2 %, n = 159). We compared SR to the mean regarding reasons for discontinuation and found significant differences between sites regarding gastrointestinal adverse events, flushing and lymphopenia. Discontinuation due to all adverse events, flushing and lymphopenia were more frequent in female than male patients. CONCLUSION: In this population-based study, we found major differences between the MS clinics in rates and reason for discontinuation of DMF. Our results suggest that management strategies during DMF treatment can reduce discontinuation rates.

A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest.

PURPOSE: This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO2) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO2, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category). RESULTS: We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16-31) vs. high MAP 23 (16-33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO2 during the first 48 h was 69.5% (62.0-75.0%) in the low MAP group and 69.0% (61.3-75.5%) in the high MAP group, p = 0.16. CONCLUSIONS: Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

Multiple sclerosis impairment scale and brain MRI in secondary progressive multiple sclerosis.

OBJECTIVE: To examine the Multiple Sclerosis Impairment Scale (MSIS) in secondary progressive MS (SPMS) in relation to the Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI) outcomes, and mobility. METHODS: In this observational single-center study, 68 secondary progressive multiple sclerosis (SPMS) patients were examined by MSIS, EDSS, functional mobility tests of upper/lower extremities, and multimodal MRI. Participants had EDSS ≥3.5, a decline in daily activities over the last year unrelated to relapses, and/or 6-month confirmed disability progression. RESULTS: Mean disease duration was 23.1 ± 8.3 years and mean age 54.4 ± 8.1 years. MSIS, EDSS, and their corresponding motor, cerebellar, and sensory subscores correlated (p < .0001). Motor subscores of MSIS correlated stronger with Timed-25-Foot-Walk (T25FW) than pyramidal functional system score (FSS) (p = .03), but EDSS had a stronger correlation to T25FW than the total MSIS score (p = .01). MSIS cerebellar subscore correlated stronger with 9-Hole Peg Test (9-HPT) than cerebellar FSS (p = .04). The sensory MSIS subscore also showed correlation with 9-HPT in contrast to sensory FSS (p = .006). MSIS subscores had stronger correlations with MRI volumetry measures than FSS scores (lesion volume and putamen, thalamus, corpus callosum volumetry, p = .0001-0.0017). CONCLUSION: In patients with SPMS, MSIS correlated with functional motor tests. MSIS showed stronger correlations with atrophy of central nervous system areas, and may be more sensitive to scale cerebellar and sensory function than EDSS.

Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study.

BACKGROUND: The complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients. METHODS: This observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, -2, and -3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time. RESULTS: Compared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios. CONCLUSION: ALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS.

Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. OBJECTIVE: This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. METHODS: The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS') was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS' was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. RESULTS AND CONCLUSIONS: Both ΔFS' and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS', is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

OBJECTIVE: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. METHODS: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. RESULTS: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001). CONCLUSION: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.

Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study.

OBJECTIVE: To determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry. METHODS: We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT. RESULTS: We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%-23.0%) and 30.1% (95% CI 23.1%-37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33-0.83, p = 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load. CONCLUSION: We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

Patient Attitudes to Routine Cognitive Testing in Multiple Sclerosis.

BACKGROUND AND AIM: In recent years, cognitive dysfunction (CD) in multiple sclerosis (MS) has received increased attention. Neuropsychological tests have been developed allowing to monitor changes in patients' cognitive functions. Knowledge is lacking, however, about patients' attitudes towards introducing routine cognitive testing. It was the aim of this qualitative study to explore this. MATERIALS AND METHODS: Based on a literature study, semi-structured interview guides were designed and used in qualitative interviews with 12 Danish patients. Participants were selected to represent different perspectives on CD and included patients with relapsing-remitting MS (RRMS) and secondary-progressive MS (SPMS), women and men with varying time since diagnosis and cognitive test scores using the Symbol Digit Modalities Test (SDMT). The data were analysed using a constructivist approach in order to identify significant relations between the quality of life (QoL) impact of CD, and attitudes towards routine cognitive testing. RESULTS: Most participants reported several subtypes of CD, yet objective CD did not coincide with subjective CD nor did it translate directly into poorer QoL. Overall, CD appeared to have larger impact on the QoL of patients with RRMS and higher SDMT scores, compared to patients with SPMS and lower SDMT scores. The QoL impact of CD manifested itself in the encounter between individual symptoms, expectations, coping and meaningful activities. All patients supported an introduction of routine cognitive testing, but patients with RRMS and SPMS had different main reasons to do so. These were related to supporting research, optimising treatment decisions, and providing documentation of this invisible MS symptom. CONCLUSION: All aspects of MS patients' QoL may be affected by CD. Introducing routine cognitive testing was widely supported by patients in all phases of MS calling for comprehensive care taking both physical and cognitive difficulties into account.

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis.

OBJECTIVE: To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT). METHODS: Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks. RESULTS: We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0-5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5-10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01). CONCLUSION: Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.

[Natalizumab can induce progressive multifocal leucoencephalopathy].

A 41-year-old woman with relapsing-remitting multiple sclerosis came to the outpatient-clinic, prior to a scheduled infusion with natalizumab. She had been treated with natalizumab for four years. Prior to treatment she did not wish to have her John Cunningham virus status tested. At the consultation she appeared disoriented and answered questions inadequately. An MRI was consistent with progressive multifocal leucoencephalopathy, and treatment with plasmapheresis was startet immediatly. The patient deceased four months later.