Publications by authors named "Morten Blinkenberg"

35 Publications

Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial.

Lancet Neurol 2021 Nov;20(11):917-929

Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address:

Background: Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis.

Methods: MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18-50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2-15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5-6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit.

Findings: From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58-1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study.

Interpretation: Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair.

Funding: Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors' Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l'aide à la recherche sur la sclérose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).
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http://dx.doi.org/10.1016/S1474-4422(21)00301-XDOI Listing
November 2021

Ocrelizumab treatment in Multiple Sclerosis: A Danish population-based cohort study.

Eur J Neurol 2021 Oct 13. Epub 2021 Oct 13.

The Danish Multiple Sclerosis Registry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Background: Real-world evidence regarding effectiveness and safety of ocrelizumab for treatment of multiple sclerosis (MS) are limited. We aimed to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting.

Methods: We conducted a nationwide population-based cohort study where we analyzed clinical and MRI data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry (DMSR) who initiated ocrelizumab treatment between January 2018 and November 2020.

Results: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale (EDSS) score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24-week confirmed disability worsening. Conversely, 16.7% showed a 24-week confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of MRI activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients and mostly consisting of infusion-related reactions and infections.

Conclusions: We show that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.
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http://dx.doi.org/10.1111/ene.15142DOI Listing
October 2021

Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial.

Neurol Neuroimmunol Neuroinflamm 2021 09 24;8(5). Epub 2021 Aug 24.

From the Danish Multiple Sclerosis Center (H.H.C., J.T., L.M., M.M., S.B., R.H.H., M.B., J.R.C., P.S.S., M.E., F.S.), Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup; Danish Research Centre for Magnetic Resonance (H.L., C.G.M., H.R.S.), Copenhagen University Hospital Hvidovre, Hvidovre; Section of Biostatistics (T.L.), Department of Public Health, University of Copenhagen, Copenhagen K; Department of Neurology (H.R.S.), Copenhagen University Hospital Bispebjerg, Copenhagen; and Institute for Clinical Medicine (H.R.S.), University of Copenhagen, Copenhagen N, Denmark.

Background And Objective: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS).

Methods: In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set.

Results: Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups.

Discussion: Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment.

Trial Registration Information: Clinicaltrials.gov identifier NCT02959658.

Classification Of Evidence: This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.
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http://dx.doi.org/10.1212/NXI.0000000000001037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407149PMC
September 2021

Magnetic resonance imaging at baseline and follow-up to differentiate between pediatric monophasic acquired CNS demyelination and MS.

Mult Scler Relat Disord 2020 Nov 21;46:102590. Epub 2020 Oct 21.

Department of Radiology, Diagnostic Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: It is essential to distinguish acute disseminated encephalomyelitis (ADEM) from MS early. Our aim was to determine MRI features at baseline and follow-up to distinguish pediatric ADEM from MS stratified according to age at onset.

Methods: Using hospital ICD-10 codes for acquired demyelinating syndromes from a nationwide register and subsequent chart review, we identified 52 children (<18 years) with ADEM and 66 children with MS. We undertook a retrospective analysis of MRI scans at onset and at follow-up. The MRI rater was a senior neuroradiologist blinded to clinical characteristics.

Results: At baseline, children with ADEM had more diffuse poorly demarcated lesions, particularly in the basal ganglia/thalamus (p = 0.001) and cerebellar peduncles (p < 0.0001). Further, longitudinal extensive transverse myelitis was strongly associated with ADEM (p<0.0001). Children with ADEM had fewer contrast-enhancing lesions (p = 0.0004), occipital lesions (p = 0.01), optic nerve lesions (p = 0.01), periventricular lesions, well-defined lesions only (p<0.0001), and fewer fulfilled dissemination in time according to the McDonald 2017 criteria (p = 0.005). On baseline MRI, dissemination in space and time was fulfilled in 17% of children with ADEM and in 34% of children with MS (p = 0.06), and 60% of children with ADEM fulfilled the criterion for dissemination in space. The mean time from baseline MRI to follow-up MRI was 1.0 year for children with ADEM and 2.1 years for children with MS. On follow-up MRI, 85% of children with ADEM had partial or complete T2 lesion resolution, but in the 58% without complete resolution lesions were predominantly frontal. Only 47% of children with MS had partial or complete T2 lesion resolution, and therefore more MRI features differed between children with ADEM and MS on follow-up. MRI had the greatest distinguishing value after age 11 years because MS is exceptional in the first decade of life.

Conclusion: Age at onset and the timing of MRI in relation to disease onset are critical in the interpretation of MRI to distinguish between ADEM and MS.
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http://dx.doi.org/10.1016/j.msard.2020.102590DOI Listing
November 2020

School performance, psychiatric comorbidity, and healthcare utilization in pediatric multiple sclerosis: A nationwide population-based observational study.

Mult Scler 2021 02 25;27(2):259-267. Epub 2020 Sep 25.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark/Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Pediatric multiple sclerosis (MS) may hamper educational achievements due to psychiatric comorbidity and cognitive impairment. Our aims were to investigate school performance, psychiatric comorbidity, and healthcare utilization following pediatric MS and to differentiate between disability in MS and that arising from a non-brain-related chronic disease.

Methods: We included all children (<18 years) with MS onset during 2008-2015 in Denmark with a medical record-validated MS diagnosis. The control groups were children from the general population or children with non-brain-related chronic diseases. Outcomes were register-based on 9-12 grade point average, psychiatric comorbidity, and healthcare visits.

Results: Cohorts were children with MS ( = 92), control children matched to children with MS ( = 920), children with non-brain-related chronic diseases ( = 9108), and "healthy" children with neither MS nor brain-related chronic disease ( = 811,464). School performance in grades 9-12 was similar, but children with MS compared to those with non-brain-related chronic disease had an almost doubled hazard for psychiatric comorbidity (hazard ratio = 1.87; 95% confidence interval = 1.38-2.53;  < 0.0001) and a higher rate of all hospital visits ( < 0.0001) but a lower rate of hospital admissions ( = 0.001).

Conclusion: Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.
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http://dx.doi.org/10.1177/1352458520959673DOI Listing
February 2021

Disentangling white-matter damage from physiological fibre orientation dispersion in multiple sclerosis.

Brain Commun 2020 8;2(2):fcaa077. Epub 2020 Jun 8.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark.

Multiple sclerosis leads to diffuse damage of the central nervous system, affecting also the normal-appearing white matter. Demyelination and axonal degeneration reduce regional fractional anisotropy in normal-appearing white matter, which can be routinely mapped with diffusion tensor imaging. However, the standard fractional anisotropy metric is also sensitive to physiological variations in orientation dispersion of white matter fibres. This complicates the detection of disease-related damage in large parts of cerebral white matter where microstructure physiologically displays a high degree of fibre dispersion. To resolve this ambiguity, we employed a novel tensor-valued encoding method for diffusion MRI, which yields a microscopic fractional anisotropy metric that is unaffected by regional variations in orientation dispersion. In 26 patients with relapsing-remitting multiple sclerosis, 14 patients with primary-progressive multiple sclerosis and 27 age-matched healthy controls, we compared standard fractional anisotropy mapping with the novel microscopic fractional anisotropy mapping method, focusing on normal-appearing white matter. Mean microscopic fractional anisotropy and standard fractional anisotropy of normal-appearing white matter were significantly reduced in both patient groups relative to healthy controls, but microscopic fractional anisotropy yielded a better reflection of disease-related white-matter alterations. The reduction in mean microscopic fractional anisotropy showed a significant positive linear relationship with physical disability, as reflected by the expanded disability status scale. Mean reduction of microscopic fractional anisotropy in normal-appearing white matter also scaled positively with individual cognitive dysfunction, as measured with the symbol digit modality test. Mean microscopic fractional anisotropy reduction in normal-appearing white matter also showed a positive relationship with total white-matter lesion load as well as lesion load in specific tract systems. None of these relationships between normal-appearing white-matter microstructure and clinical, cognitive or structural measures emerged when using mean fractional anisotropy. Together, the results provide converging evidence that microscopic fractional anisotropy mapping substantially advances the assessment of cerebral white matter in multiple sclerosis by disentangling microstructure damage from variations in physiological fibre orientation dispersion at the stage of data acquisition. Since tensor-valued encoding can be implemented in routine diffusion MRI, microscopic fractional anisotropy mapping bears considerable potential for the future assessment of disease progression in normal-appearing white matter in both relapsing-remitting and progressive forms of multiple sclerosis as well as other white-matter-related brain diseases.
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http://dx.doi.org/10.1093/braincomms/fcaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472898PMC
June 2020

Motor fatigue is associated with asymmetric connectivity properties of the corticospinal tract in multiple sclerosis.

Neuroimage Clin 2020 25;28:102393. Epub 2020 Aug 25.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark.

Multiple Sclerosis (MS) is characterized by demyelination and neurodegeneration of the central nervous system and causes excessive fatigue in more than 80% of the patients. The pathophysiologic mechanisms causing fatigue are still largely unknown. In 46 right-handed patients with relapsing-remitting MS and 25 right-handed controls, we performed diffusion MRI and applied streamline based probabilistic tractography to derive unilateral anatomical connectivity maps for the white matter of the right and left hemispheres. The maps provide an indication how often a streamline has passed through a given voxel. Since tractography based anatomical connectivity mapping (ACM) is sensitive to disease-induced changes in anatomical connectivity, we used ACM to test whether motor fatigue is associated with altered ipsi-hemispherical anatomical connectivity in the major motor output pathway, the corticospinal tract (CST). Patients had higher mean ACM values in the CST than healthy controls. This indicated that a higher number of streamlines, starting from voxels in the same hemisphere, travelled through the CST and may reflect an accumulated disease-induced disintegration of CST. The motor subscale of the Fatigue Scale for Motor and Cognitive functions (FSMC) was used to define sub-groups with (n = 29, FSMC score ≥ 27) and without motor fatigue (n = 17, FSMS score ≤ 26). Patients without fatigue only showed higher ACM values in right CST, while mean ACM values were unaltered in left CST. The higher the mean ACM values in the left relative to the right CST, the more patients reported motor fatigue. Left-right asymmetry in anatomical connectivity outside the CST did not scale with individual motor fatigue. Our results link lateralized changes of tractography-based microstructural properties in the CST with motor fatigue in relapsing-remitting MS.
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http://dx.doi.org/10.1016/j.nicl.2020.102393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490847PMC
June 2021

Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: A prospective Danish cohort study.

Mult Scler Relat Disord 2020 May 17;40:101956. Epub 2020 Jan 17.

The Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup 2600, Denmark; Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup 2600, Denmark. Electronic address:

Background: A consensus of early treatment with disease-modifying therapies (DMT) in multiple sclerosis (MS) has been reached based on several observational and experimental studies in adults. However, paediatric onset (PO)MS appears phenotypically different from adult onset MS, characterized by increased relapse rate and pronounced radiological activity on MRI. The objective of this study was to investigate the long-term consequences of delayed treatment start in POMS on disability in a real-world, population-based setting.

Methods: Based on prospectively collected data from The Danish Multiple Sclerosis Registry, we defined a cohort of MS patients with onset before the age of 18 years, who were born in 1980 or later, and started treatment with a DMT between 1998 and 2018. The POMS cohort was stratified according to treatment start within 2 years of onset (N = 140) or later (N = 151). Annualised relapse rate in each study group was compared using a negative binomial regression; and Cox proportional hazard model was used to estimate hazard ratios (HR) of time to sustained Expanded Disability Status Scale (EDSS) score 4, 6-month confirmed EDSS worsening and 6-month confirmed EDSS improvement, respectively, according to disease duration.

Results: The POMS cohort had a total median follow-up time of 7.7 years (interquartile range 4.6-11.6). There was no association between risk of relapses in patients with delayed treatment start compared to earlier treatment start. Patients starting on a DMT later than 2 years after onset had a 2.52-fold increased risk of reaching sustained EDSS 4 compared to those starting within 2 years of onset (HR=2.52, 95% confidence interval (CI)=1.01-6.34). For every year increment from onset to start of first DMT, the risk of reaching sustained EDSS 4 increased by 17% (HR=1.17, 95% CI=1.05-1.30). In line with this, the risk of reaching confirmed EDSS worsening was increased by 44% compared to those starting earlier, although not statistically significant (HR=1.44, 95% CI=0.95-2.19). Starting on a DMT later was associated with 61% decreased chance of confirmed EDSS improvement compared to those starting earlier (HR=0.39, 95% CI=0.26-0.59). For every year increment from onset to starting DMT, the risk of confirmed EDSS improvement decreased by 10% (HR=0.90, 95% CI=0.84-0.96).

Conclusions: Delayed treatment start in this POMS cohort was associated with shorter time to reach sustained EDSS 4 and confirmed EDSS worsening, and decreased chance of reaching confirmed EDSS improvement, and thus support early treatment start in POMS patients.
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http://dx.doi.org/10.1016/j.msard.2020.101956DOI Listing
May 2020

Anti-CD20 Monoclonal Antibodies for Relapsing and Progressive Multiple Sclerosis.

CNS Drugs 2020 03;34(3):269-280

Danish Multiple Sclerosis Clinic, Department of Neurology 2082, University of Copenhagen, Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark.

Multiple sclerosis (MS) was previously thought to be a T-cell-mediated, demyelinating disease of the central nervous system. Disease-modifying therapies targeting T cells have, indeed, shown remarkable efficacy in patients with relapsing-remitting MS. However, these therapies do also target B cells, and a B-cell-depleting monoclonal antibody (ocrelizumab) has recently been approved for MS therapy and is efficacious not only in relapsing forms of MS but also in some patients with primary progressive MS. This suggests that B cells may play a more important role in the pathogenesis of MS than previously appreciated. We review the potential roles of B cells, which are the precursors of antibody-secreting plasma cells in the pathogenesis of MS. Furthermore, we provide an overview of the characteristics and clinical data for the four monoclonal antibodies (ocrelizumab, ofatumumab, rituximab, and ublituximab) that have been approved, are currently been used off-label or are being investigated as treatments for MS. These antibodies all target the cluster of differentiation (CD)-20 molecule and bind to distinct or overlapping epitopes on B cells and a subset of T cells that express CD20. This leads to B-cell depletion and, possibly, to depletion of CD20-positive T cells. The net result is strong suppression of clinical and radiological disease activity as well as slowing of the development of persisting neurological impairment.
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http://dx.doi.org/10.1007/s40263-020-00704-wDOI Listing
March 2020

Clinical characteristics and use of disease modifying therapy in the nationwide Danish cohort of paediatric onset multiple sclerosis.

Mult Scler Relat Disord 2020 Jan 8;37:101431. Epub 2019 Oct 8.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark; Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Tagensvej 22, 2200 Copenhagen, Denmark. Electronic address:

Background: Several disease-modifying therapies (DMT) are being used in paediatric patients with multiple sclerosis (MS) despite the limited number of randomised controlled clinical trials leading to approved indication in children.

Objectives: The aim of this study was to describe clinical characteristics of the Danish population of paediatric onset MS, and the patterns of DMT utilisation in patients who started treatment before the age of 18 years.

Methods: We conducted a nationwide population-based cohort study, including 347 children with paediatric-onset MS (<18 years). Subjects were followed until their 25 birthday or end of follow-up.

Results: Median age at onset and diagnosis was 15.8 years and 17.2, respectively. The majority of the children had monosymptomatic presentation. In total, 140 children received DMT before the age of 18. Most started treatment with a moderate-efficacy drug (90%) of which interferon-beta was the most used (80%). However, since oral treatments became available, these have increasingly been used. During follow-up, 108 children switched or discontinued DMT. Fingolimod was prescribed more frequently than natalizumab as escalation therapy.

Conclusion: We present that use of DMT in POMS varies over the observed period concurrently with the availability of disease modifying drugs with progressive use of oral and high-efficacy therapies.
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http://dx.doi.org/10.1016/j.msard.2019.101431DOI Listing
January 2020

School performance and psychiatric morbidity 6 years after pediatric acute disseminated encephalomyelitis: A nationwide population-based cohort study.

Mult Scler Relat Disord 2019 Nov 3;36:101425. Epub 2019 Oct 3.

Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark. Electronic address:

Background: Acute disseminated encephalomyelitis (ADEM) can cause cognitive impairment in children. However, long-term consequences for school performance and psychiatric morbidity have never been characterized. Our aim was to investigate long-term school performance and psychiatric morbidity after pediatric ADEM (<18 years).

Methods: We identified all children with ADEM 2008-2015 in Denmark using hospital diagnostic codes for acquired demyelinating syndromes. We reviewed all medical records to validate ADEM including blinded MRI review. Reference children were the entire pediatric (<18 years) population or randomly sampled sex and age-matched reference children. Outcomes were from nationwide population-based registers on special needs assistance, grade point average, highest completed education, in-hospital psychiatric hospital diagnoses, out-of-hospital psychiatric consultations or psychopharmacological drug prescriptions.

Results: 52 children had ADEM (median onset age: 5.5 years; median age at follow-up end: 13.4 years). Secondary school grade point average was similar among children with ADEM and reference children; however, children with ADEM had increased psychiatric morbidity (hazard ratio = 2.4; 95% confidence interval = 1.2-5.1; p = 0.02), primarily due to increased drug prescriptions for sleep problems and depression.

Conclusion: Children with prior ADEM have increased sleep problems and possibly also depression; however, school performance is seemingly unaffected. Clinicians should consider problems with sleep and mood at follow-up.
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http://dx.doi.org/10.1016/j.msard.2019.101425DOI Listing
November 2019

[Autologous haematopoietic stem cell transplantation of patients with multiple sclerosis].

Ugeskr Laeger 2019 Sep;181(36)

Immunosuppression with chemotherapy followed by autologous haematopoietic stem cell transplantation has proven to be an effective long-term treatment for younger patients with relapsing-remitting multiple sclerosis and clinical as well as radiological evidence of high disease activity. The conditioning regimen can be of either high, intermediate or low intensity. Due to the safety profile and favourable efficacy measures, the low intensity regimen cyclophosphamide + anti-thymocyte globulin is currently used in Denmark as standard regimen.
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September 2019

Incidence of pediatric neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease in Denmark 2008‒2018: A nationwide, population-based cohort study.

Mult Scler Relat Disord 2019 Aug 5;33:162-167. Epub 2019 Jun 5.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

Background: The incidence of pediatric neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease have not been reported previously. Our aim was to estimate the incidence of pediatric NMOSD and the occurrence of anti-MOG antibody-associated disease in Denmark during 2008-18, and to evaluate the diagnostic usefulness of antibodies against MOG and aquaporin-4 (AQP4) in children <18 years.

Methods: We undertook a nationwide, population-based, multicenter cohort study using data from the Danish National Patient Register, the Danish Multiple Sclerosis Registry, and laboratories providing anti-AQP4 and anti-MOG antibody analyses. Diagnoses were confirmed by review of the medical records, including blinded MRI review in most children with acute disseminated encephalomyelitis (ADEM).

Results: In children with acquired demyelinating syndromes, anti-AQP4 antibodies were detected in 4% and anti-MOG antibodies in 18%, including in the two children with ADEM who relapsed. We identified four children with NMOSD, equivalent to an incidence of 0.031/100,000 (95% confidence interval = 0.011‒0.082). In anti-MOG antibody-positive children, 32% relapsed during follow-up.

Conclusions: Pediatric NMOSD and MOG antibody-associated disease are rare, but one-third of anti-MOG-positive children relapsed. In pediatric ADEM, only anti-MOG antibody-positive children relapsed, but the overall risk of relapse after pediatric ADEM was low.
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http://dx.doi.org/10.1016/j.msard.2019.06.002DOI Listing
August 2019

Predictors of treatment outcome in patients with paediatric onset multiple sclerosis.

Mult Scler 2020 07 13;26(8):964-975. Epub 2019 May 13.

The Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark/Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults.

Objective: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs.

Methods: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 ( = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models.

Results: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years.

Conclusions: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.
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http://dx.doi.org/10.1177/1352458519846100DOI Listing
July 2020

Diagnostic Value of Oligoclonal Bands in Children: A Nationwide Population-Based Cohort Study.

Pediatr Neurol 2019 08 13;97:56-63. Epub 2019 Mar 13.

Department of Pediatrics, Rigshospitalet, University of Copenhagen, Denmark.

Objective: We evaluated the diagnostic value of cerebrospinal fluid oligoclonal bands in individuals less than 18 years of age.

Methods: In a nationwide population-based setting, we retrieved data on 2055 children's oligoclonal band examination, including concordant cerebrospinal fluid biomarkers, during 1994 to 2017. Case ascertainment was by review of medical records and diagnostic codes. We used Fisher's exact test to explore distribution differences of oligoclonal band positivity in acquired demyelinating syndromes (ADS) before and after age 12 years and calculated the sensitivity, specificity, positive predictive value, and negative predictive value of oligoclonal bands to distinguish ADS from the other diagnostic groups.

Results: Median age at oligoclonal band examination was 15.2 years (range = 1.8 to 18.0), and 10% had presence of cerebrospinal fluid oligoclonal bands. Oligoclonal band positivity was the highest in ADS (52%), but it was age dependent: 21% in children with ADS before age 12 years and 68% in children aged 12 through 17 years (P < 0.0001) owing to the higher incidence of multiple sclerosis in the latter. Cerebrospinal fluid oligoclonal bands were not predictive of ADS before age 12 years compared with the other diagnostic groups. However, cerebrospinal fluid oligoclonal bands in children aged 12 through 17 years were highly predictive of ADS compared with central nervous system infections and non-ADS immune-mediated central nervous system diseases (positive predictive value: 0.89; 95% confidence interval = 0.82 to 0.94; P < 0.0001), but negative oligoclonal bands were not discriminatory (negative predictive value: P = 0.17).

Conclusions: In a clinical setting, cerebrospinal fluid oligoclonal band examination may be of higher yield in children aged 12 through 17 years if there is clinical suspicion of multiple sclerosis, and in such circumstances a positive test supports a diagnosis of multiple sclerosis.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.002DOI Listing
August 2019

Cerebellar and premotor activity during a non-fatiguing grip task reflects motor fatigue in relapsing-remitting multiple sclerosis.

PLoS One 2018 24;13(10):e0201162. Epub 2018 Oct 24.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Fatigue is a common and highly disabling symptom of multiple sclerosis. Patients experience an effort-independent general subjective feeling of fatigue as well as excessive fatigability when engaging in physical or mental activity. Previous research using functional magnetic resonance imaging (fMRI) has revealed heterogeneous findings, but some evidence implicates the motor system. To identify brain correlates of fatigue, 44 mildly impaired patients with relapsing-remitting multiple sclerosis and 25 age- and gender-matched healthy controls underwent functional magnetic resonance imaging at 3 Tesla, while they performed alternating blocks of rest and a non-fatiguing precision grip task. We investigated neural correlates of fatigue using the motor subscore of Fatigue Scale for Motor and Cognitive Functions (FSMCMOTOR) using the bilateral motor cerebellum, putamen, and dorsal premotor cortex as regions of interest. Patients and healthy controls performed the grip force task equally well without being fatigued. In patients, task-related activity in lobule VI of right motor cerebellum changed in proportion with individual FSMCMOTOR scores. In right dorsal premotor cortex, linear increases in activity across consecutive task blocks scaled with individual FSMCMOTOR scores in healthy controls, but not in patients. In premotor and dorsomedial prefrontal areas, patients were impaired at upscaling task-related activity the more they were affected by motor fatigue. The results support the notion that increased sensorimotor processing in the cerebellum contributes to the experience of motor fatigue and fatigability in multiple sclerosis. Additionally, downscaling of motivational input or sensorimotor processing in prefrontal and premotor areas may constitute an additional pathophysiological factor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201162PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200185PMC
March 2019

Clinical utility of anti-MOG antibody testing in a Danish cohort.

Mult Scler Relat Disord 2018 Nov 11;26:61-67. Epub 2018 Sep 11.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark.

Background: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet.

Methods: In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy.

Results: We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy.

Conclusion: A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated.
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http://dx.doi.org/10.1016/j.msard.2018.09.010DOI Listing
November 2018

Increased cerebrospinal fluid chitinase 3-like 1 and neurofilament light chain in pediatric acquired demyelinating syndromes.

Mult Scler Relat Disord 2018 Aug 11;24:175-183. Epub 2018 Jun 11.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark.

Background: Chitinase 3-like 1 (CHI3L1), neurofilament light chain (NFL) and oligoclonal bands (OCB) in cerebrospinal fluid are associated with central nervous system demyelination in adults. CHI3L1 and OCB are markers of central nervous system inflammation, whereas NFL is a marker of white-matter axonal injury. The aim was to examine whether CHI3L1 and NFL in cerebrospinal fluid are associated with acquired demyelinating syndromes at disease onset in a pediatric population.

Methods: Children (<18 years) referred to hospital for possible neuroinflammatory disease were retrospectively included from 2010 to 2016. Case ascertainment was by review of medical records. NFL and CHI3L1 were measured by enzyme-linked immunosorbent assays. Endpoints were differences in concentrations of cerebrospinal fluid NFL and CHI3L1.

Results: We included 193 children who all underwent cerebrospinal fluid OCB examination as part of their diagnostic work-up and classified these children into 5 groups: acquired demyelinating syndromes (n = 33), normal diagnostic work-up (n = 36), inflammatory neurological disease (n = 50), other neurological disease (n = 55), and systemic inflammatory diseases (n = 19). NFL and CHI3L1 in cerebrospinal fluid differed significantly between the five groups (p = 0.0001). CHI3L1 was significantly higher in acquired demyelinating syndromes than in all other groups, and NFL was significantly higher in acquired demyelinating syndromes than in the other groups except systemic inflammatory disease. Children with acute disseminated encephalomyelitis had significantly higher concentrations of CHI3L1 than did children with multiple sclerosis.

Conclusion: We provide class II evidence that CHI3L1 and NFL are associated with pediatric acquired demyelinating syndromes. CHI3L1 may help distinguishing between acute disseminated encephalomyelitis and multiple sclerosis, but this needs further confirmation.
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http://dx.doi.org/10.1016/j.msard.2018.05.017DOI Listing
August 2018

Infections seem to be more frequent before onset of pediatric multiple sclerosis: A Danish nationwide nested case-control study.

Mult Scler 2019 05 17;25(6):783-791. Epub 2018 May 17.

The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark/Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated.

Objectives: To investigate whether childhood infections contribute to pediatric MS.

Methods: A nationwide nested case-control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression.

Results: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6-17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01-1.22, p = 0.04); having 5+ infections compared with 0-4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12-4.30, p = 0.02).

Conclusion: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.
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http://dx.doi.org/10.1177/1352458518771871DOI Listing
May 2019

Implications of the International Paediatric Multiple Sclerosis Study Group consensus criteria for paediatric acute disseminated encephalomyelitis: a nationwide validation study.

Dev Med Child Neurol 2018 11 10;60(11):1123-1131. Epub 2018 May 10.

Department of Paediatrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: The International Paediatric Multiple Sclerosis Study Group (IPMSSG) has proposed criteria for acute disseminated encephalomyelitis (ADEM) not evaluated in clinical practice. Our objective was to assess epidemiological implications of the IPMSSG criteria for ADEM in a cohort study using prospectively collected data.

Method: We identified all diagnosed cases of ADEM in Denmark between 2008 and 2015 from the Danish National Patient Register by International Classification of Diseases 10 codes assigned to acute demyelinating episodes, and we reviewed all medical records to validate ADEM.

Results: We found 52 children up to the age of 18 years with a verified clinical diagnosis of ADEM (incidence rate 0.54/100 000 person-years; all had abnormal brain magnetic resonance imaging). Only 18 (35%) fulfilled the IPMSSG criteria regarding encephalopathy and polyfocal neurological deficits. Among all 52 children with ADEM, 33 per cent had clinical sequelae after a median follow-up of 4 years 6 months (range: 10mo-8y 3mo). Surprisingly, none progressed to multiphasic ADEM or multiple sclerosis, but median age at end of follow-up was only 10 years 9 months (range: 2y-24y 3mo).

Interpretation: Among 52 children with ADEM, none converted to multiphasic ADEM or multiple sclerosis (median follow-up: 4y 6mo; range: 10mo-8y 3mo). Applying the IPMSSG criteria to all children with a diagnosis of ADEM leaves 65 per cent of the cases without a diagnosis and lowers the incidence rate of paediatric ADEM.

What This Paper Adds: The incidence of paediatric acute disseminated encephalomyelitis (ADEM) was 0.54 per 100 000 person-years in children younger than 18 years. Only 35 per cent of children with ADEM fulfilled the International Paediatric Study Group consensus criteria. ADEM in clinical practice was primarily based on magnetic resonance imaging findings. Paediatric neurologists diagnosed ADEM in the absence of encephalopathy. None of the children with ADEM progressed to multiple sclerosis/multiphasic ADEM during follow-up.
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http://dx.doi.org/10.1111/dmcn.13798DOI Listing
November 2018

Psychiatric morbidity develops after onset of pediatric multiple sclerosis: A Danish nationwide population-based study.

Mult Scler Relat Disord 2018 Jan 31;19:30-34. Epub 2017 Oct 31.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark; The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

Background: Pediatric-onset multiple sclerosis (MS) affects life at a stage vital for social and educational achievements and psychiatric co-morbidity is common after MS onset. Few studies have examined psychiatric morbidity before MS onset.

Methods: In this nationwide study, detailed case ascertainment was performed in all children with pediatric MS, including chart review. For each MS patient, we selected five controls using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data as a nested case-control study with psychiatric morbidity as exposure and MS as outcome, and a matched cohort study with MS as exposure and psychiatric co-morbidity as outcome. Hazard ratios (HR) including 95% confidence intervals (CI) were estimated using Cox regression.

Results: We identified 212 children with MS and 1060 controls. No association between psychiatric morbidity and the rate of MS was found before MS onset. After MS onset, children with MS had two times higher hazard for psychiatric co-morbidity compared with children without MS (HR=2.0; 95% CI=1.3-3.1; p<0.001).

Conclusion: Psychiatric morbidity seems to commence after MS onset, making screening for neuropsychiatric conditions pertinent in newly-diagnosed children with MS.
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http://dx.doi.org/10.1016/j.msard.2017.10.018DOI Listing
January 2018

Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: A nationwide population-based incidence study.

Mult Scler 2018 07 13;24(8):1077-1086. Epub 2017 Jun 13.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population.

Objectives: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS.

Methods: Data were sourced from the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses.

Results: We identified 364 cases of pediatric MS occurring during 1977-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable through the study period. During 2008-2015, we identified 219 ADS cases. The incidence was 2.29 per 100,000 person-years with considerable differences in the age peaks for the separate ADS.

Conclusion: The incidence rates of MS and other ADS in Denmark were higher than those reported for some other European countries. Referral bias and classification differences may account for this disparity, in particular the age-intervals and the definition of onset.
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http://dx.doi.org/10.1177/1352458517713669DOI Listing
July 2018

Monoclonal Antibodies for Relapsing Multiple Sclerosis: A Review of Recently Marketed and Late-Stage Agents.

CNS Drugs 2017 May;31(5):357-371

Danish Multiple Sclerosis Center, Department of Neurology 2082, Rigshospitalet and University of Copenhagen, 2100, Copenhagen, Denmark.

Treatment of multiple sclerosis (MS) has improved considerably over the last decade because of new insights into MS pathology and biotechnological advances. This has led to the development of new potent pharmaceutical compounds targeting different processes in the complex autoimmune pathology leading to chronic central nervous system (CNS) demyelination, neural loss, and, finally, neurological disability. Although a number of disease-modifying treatments are available for the treatment of the inflammatory phase of MS, there is still a need for highly efficacious therapies with an acceptable safety profile in order to gain therapeutic control early in the disease course. Monoclonal antibodies have proven to be some of the most efficacious disease-modifying therapies in the field of MS, and recent developments in clinical research hold promise for new compounds fulfilling the need for improved safety and high efficacy. We review recent developments in the field of therapeutic monoclonal antibodies used for the treatment of MS and current information on the mode of action, efficacy, and safety of existing and emerging therapeutic monoclonal antibodies as well as their place within the context of different treatment strategies. Finally, we consider the most important future developments.
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http://dx.doi.org/10.1007/s40263-017-0414-3DOI Listing
May 2017

The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.

Ther Adv Neurol Disord 2016 Jan;9(1):44-52

Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

B cells play a central role in the pathogenesis in multiple sclerosis (MS), being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin. Hence, the usage of B-cell-depleting monoclonal antibodies as therapy for autoimmune diseases including MS lay near at hand. Rituximab was the first therapeutic B-cell-depleting chimeric monoclonal antibody to be used successfully in MS. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large phase II, randomized, placebo-controlled multicentre trial in patients with relapsing-remitting disease. Compared with placebo, two doses of ocrelizumab (600 and 2000 mg on days 1 and 15) showed a pronounced effect on disease activity seen in magnetic resonance imaging (MRI) as gadolinium-enhanced lesions (89% and 96% relative reduction, both p < 0.001) and also had a significant effect on relapses. In exploratory analyses, both doses of ocrelizumab had better effect on gadolinium-enhanced lesions than interferon beta-1a intramuscularly that was used as a reference arm. Adverse effects were mainly infusion-related reactions, in particular during the first infusion. Serious infections occurred at similar rates in ocrelizumab and placebo-treated patients, and no opportunistic infections were reported. However, progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with anti-CD20 monoclonal antibodies for other indications. Other anti-CD20 monoclonal antibodies have been tested as treatments for MS, including ofatumumab that has shown beneficial results in placebo-controlled phase II trials in patients with relapsing-remitting MS. Ocrelizumab is now in phase III development for the treatment of relapsing-remitting MS, as well as primary progressive MS, and the results of ongoing clinical trials are eagerly awaited and will determine the place of ocrelizumab in the armamentarium of MS therapies.
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http://dx.doi.org/10.1177/1756285615601933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710102PMC
January 2016

Recovery from an acute relapse is associated with changes in motor resting-state connectivity in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2016 08 14;87(8):912-4. Epub 2015 Dec 14.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark Cognitive Systems, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark.

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http://dx.doi.org/10.1136/jnnp-2015-311375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975821PMC
August 2016

Onset symptoms in paediatric multiple sclerosis.

Dan Med J 2014 Apr;61(4):A4800

Dansk Multipel Sclerose Center, Neurologisk Klinik N2082, Rigshospitalet, 2100 Copenhagen, Denmark.

Introduction: Paediatric multiple sclerosis (MS) carries a relatively higher mortality and morbidity than adult MS. Paediatric MS symptoms and paraclinical findings at the first demyelinating event have never before been characterised in a Danish setting. The aim of this study was to compare symptoms and paraclinical findings at the first demyelinating event in paediatric MS with those of an adult MS population.

Material And Methods: A total of 18 subjects with onset of MS relapse before 16 years of age were retrospectively included in the study. Case records were reviewed for symptoms at disease onset, cerebrospinal fluid findings, magnetic resonance imaging (MRI) and evoked potentials at the first demyelinating event. These data were compared with similar nationwide data from adults in Denmark.

Results: The median age was 14 (range 10-15) years at the first demyelinating event and the mean time to MS diagnosis was 1.7 years. The majority of children had sensory symptoms (47%; 95% confidence interval (CI): 23-72%) or optic neuritis (35%; CI: 14-62%) as their presenting symptoms. These results did not differ from the findings in adult MS subjects. Pleocytosis was present in 93% (CI: 66-100%) of paediatric MS subjects, 77% (CI: 46-95%) had an elevated IgG index and 85% (CI: 55-98%) had oligoclonal bands in the cerebrospinal fluid. MRI showed characteristic white matter lesions in all children (CI: 80-100%).

Conclusion: MS symptoms at the first demyelinating event and diagnostic delay in paediatric MS subjects do not differ significantly from those seen in an adult MS population.

Funding: not relevant.

Trial Registration: not relevant.
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April 2014

Secondary progressive and relapsing remitting multiple sclerosis leads to motor-related decreased anatomical connectivity.

PLoS One 2014 18;9(4):e95540. Epub 2014 Apr 18.

Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Multiple sclerosis (MS) damages central white matter pathways which has considerable impact on disease-related disability. To identify disease-related alterations in anatomical connectivity, 34 patients (19 with relapsing remitting MS (RR-MS), 15 with secondary progressive MS (SP-MS) and 20 healthy subjects underwent diffusion magnetic resonance imaging (dMRI) of the brain. Based on the dMRI, anatomical connectivity mapping (ACM) yielded a voxel-based metric reflecting the connectivity shared between each individual voxel and all other brain voxels. To avoid biases caused by inter-individual brain-shape differences, they were estimated in a spatially normalized space. Voxel-based statistical analyses using ACM were compared with analyses based on the localized microstructural indices of fractional anisotropy (FA). In both RR-MS and SP-MS patients, considerable portions of the motor-related white matter revealed decreases in ACM and FA when compared with healthy subjects. Patients with SP-MS exhibited reduced ACM values relative to RR-MS in the motor-related tracts, whereas there were no consistent decreases in FA between SP-MS and RR-MS patients. Regional ACM statistics exhibited moderate correlation with clinical disability as reflected by the expanded disability status scale (EDSS). The correlation between these statistics and EDSS was either similar to or stronger than the correlation between FA statistics and the EDSS. Together, the results reveal an improved relationship between ACM, the clinical phenotype, and impairment. This highlights the potential of the ACM connectivity indices to be used as a marker which can identify disease related-alterations due to MS which may not be seen using localized microstructural indices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095540PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991654PMC
May 2015

Cortical N-acetyl aspartate is a predictor of long-term clinical disability in multiple sclerosis.

Neurol Res 2014 Aug 21;36(8):701-8. Epub 2014 Jan 21.

Objective: To evaluate the prognostic value of the cortical N-acetyl aspartate to creatine ratio (NAA/Cr) in early relapsing-remitting multiple sclerosis (RRMS).

Methods: Sixteen patients with newly diagnosed RRMS were studied by serial MRI and MR spectroscopic imaging (MRSI) once every 6 months for 24 months. Clinical examinations, including the expanded disability status scale (EDSS), were performed at baseline, month 24, and at year 7.

Results: Baseline cortical NAA/Cr correlated inversely with EDSS at month 24 (r  =  -0·61, P < 0·05), and patients with EDSS ≧ 4 had a lower baseline cortical NAA/Cr compared to those with EDSS less than 4 (P < 0·05). Baseline cortical NAA/Cr also correlated inversely with EDSS at the 7-year follow-up (r  =  -0·56, P < 0·05), and patients with EDSS ≧ 4 had a lower baseline cortical NAA/Cr compared to those with EDSS less than 4 (P < 0·05). Baseline brain parenchymal fraction (BPF) correlated inversely with EDSS at month 24 (r  =  -0·61, P < 0·05), but not with EDSS at year 7.

Discussion: Cortical NAA/Cr in early RRMS correlated with clinical disability after 2 and 7 years and may be used as a predictor of long-term disease outcome.
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http://dx.doi.org/10.1179/1743132813Y.0000000312DOI Listing
August 2014

Multiple sclerosis impairs regional functional connectivity in the cerebellum.

Neuroimage Clin 2014 27;4:130-8. Epub 2013 Nov 27.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Kettegaard Allé 30, 2650 Hvidovre, Denmark.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been used to study changes in long-range functional brain connectivity in multiple sclerosis (MS). Yet little is known about how MS affects functional brain connectivity at the local level. Here we studied 42 patients with MS and 30 matched healthy controls with whole-brain rs-fMRI at 3 T to examine local functional connectivity. Using the Kendall's Coefficient of Concordance, regional homogeneity of blood-oxygen-level-dependent (BOLD)-signal fluctuations was calculated for each voxel and used as a measure of local connectivity. Patients with MS showed a decrease in regional homogeneity in the upper left cerebellar hemisphere in lobules V and VI relative to healthy controls. Similar trend changes in regional homogeneity were present in the right cerebellar hemisphere. The results indicate a disintegration of regional processing in the cerebellum in MS. This might be caused by a functional disruption of cortico-ponto-cerebellar and spino-cerebellar inputs, since patients with higher lesion load in the left cerebellar peduncles showed a stronger reduction in cerebellar homogeneity. In patients, two clusters in the left posterior cerebellum expressed a reduction in regional homogeneity with increasing global disability as reflected by the Expanded Disability Status Scale (EDSS) score or higher ataxia scores. The two clusters were mainly located in Crus I and extended into Crus II and the dentate nucleus but with little spatial overlap. These findings suggest a link between impaired regional integration in the cerebellum and general disability and ataxia.
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http://dx.doi.org/10.1016/j.nicl.2013.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871286PMC
May 2015

Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab.

Mult Scler 2013 Aug 18;19(9):1226-9. Epub 2013 Mar 18.

Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark.

We report the case of a woman with natalizumab-treated multiple sclerosis (MS) and clinically silent progressive multifocal leukoencephalopathy (PML) with an unusually long preclinical phase, followed by acute symptoms due to development of immune reconstitution inflammatory syndrome (IRIS). Furthermore, the course of the IRIS was prolonged and continued to progress even five months after natalizumab treatment was ceased. This case shows that PML and IRIS can have a considerably variable course in natalizumab-treated MS patients and underlines the need for PML screening in JC virus antibody-positive patients in order to detect clinically silent cases.
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http://dx.doi.org/10.1177/1352458513481010DOI Listing
August 2013
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