Publications by authors named "Anders Svenningsson"

62 Publications

Metabolomics of Cerebrospinal Fluid from Healthy Subjects Reveal Metabolites Associated with Ageing.

Metabolites 2021 Feb 23;11(2). Epub 2021 Feb 23.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, 751 85 Uppsala, Sweden.

To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing of the brain and CNS that could be reflected in CSF. In the present study the CSF metabolomes of healthy subjects aged 30-74 years ( = 23) were studied using liquid chromatography high-resolution mass spectrometry (LC-HRMS), and investigated in relation to age. Ten metabolites were identified with high confidence as significantly associated with ageing, eight with increasing levels with ageing: isoleucine, acetylcarnitine, pipecolate, methionine, glutarylcarnitine, 5-hydroxytryptophan, ketoleucine, and hippurate; and two decreasing with ageing: methylthioadenosine and 3-methyladenine. To our knowledge, this is the first time the CSF metabolomes of healthy subjects are assessed in relation to ageing. The present study contributes to the field of ageing metabolomics by presenting a number of metabolites present in CSF with potential relevance for ageing and the results motivate further studies.
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http://dx.doi.org/10.3390/metabo11020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927110PMC
February 2021

Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension.

J Neurol 2021 Feb 8;268(2):651-657. Epub 2020 Sep 8.

Department of Clinical Science, Umeå University, Umeå, Sweden.

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period.

Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter.

Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study.

Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression.

Classification Of Evidence: This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression.

Eu Clinical Trial Register: EudraCT; 2008-002626-11 and 2012-000721-53.
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http://dx.doi.org/10.1007/s00415-020-10210-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880973PMC
February 2021

Location matters: highly divergent protein levels in samples from different CNS compartments in a clinical trial of rituximab for progressive MS.

Fluids Barriers CNS 2020 Jul 29;17(1):49. Epub 2020 Jul 29.

Department of Neurosciences, Uppsala University, Uppsala, Sweden.

Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared.

Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively.

Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman's rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF.

Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.
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http://dx.doi.org/10.1186/s12987-020-00205-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390226PMC
July 2020

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address:

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients.

Ann Neurol 2020 05 9;87(5):688-699. Epub 2020 Mar 9.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.

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. ANN NEUROL 2020;87:688-699.
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http://dx.doi.org/10.1002/ana.25701DOI Listing
May 2020

Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry.

Metabolomics 2020 02 12;16(2):26. Epub 2020 Feb 12.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala University Hospital, Entrance 61, 3rd Floor, Dag Hammarskjölds Väg 18, 751 85, Uppsala, Sweden.

Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma.

Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls.

Methods: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS).

Results: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls.

Conclusion: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS.
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http://dx.doi.org/10.1007/s11306-020-1648-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015966PMC
February 2020

Serum sickness following rituximab therapy in multiple sclerosis.

Neurol Clin Pract 2019 Dec;9(6):519-521

Department of Neurology (TH), Akershus University Hospital, Lørenskog; Institute of Clinical Medicine (TH), University of Oslo, Norway; Karolinska Institutet (AF-H), Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska University Hospital Solna; and Department of Clinical Sciences (AF-H, AS), Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1212/CPJ.0000000000000685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927430PMC
December 2019

Reply to Sun et al.

Pain 2019 12;160(12):2898-2899

Department of Medical Sciences, Chemical Chemistry, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1097/j.pain.0000000000001699DOI Listing
December 2019

Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies.

JAMA Neurol 2020 02;77(2):184-191

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1001/jamaneurol.2019.3365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784753PMC
February 2020

[Diagnostic challenge in a man with intractable hiccups and vomiting: a case of neuromyelitis optica spectrum disorder (NMOSD)].

Lakartidningen 2019 Aug 13;116. Epub 2019 Aug 13.

Danderyds sjukhus - Röntgenavd Stockholm, Sweden Danderyds sjukhus - Röntgenavd Stockholm, Sweden.

Neuromyelitis optica is an inflammatory CNS syndrome that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). According to the new diagnostic criteria the term NMO is replaced by the term NMOSD and for the first time criteria allow diagnosis in patients who have not experienced clinical involvement of either optic nerves or spinal cord. Area postrema, the emetic reflex center, may be a selective target of the disease. We report a case of a 74-year-old man who presented with intractable hiccups and vomiting. He underwent medical and surgical evaluation but the neurological consultation was delayed one month because these symptoms are usually not appreciated as the possible initial manifestation of NMOSD. Missing diagnosis at this early stage leads to a delay in the treatment and a risk of more severe manifestations, such as transverse myelitis.
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August 2019

Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS.

Mult Scler 2020 10 8;26(12):1532-1539. Epub 2019 Aug 8.

Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.

Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited.

Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden.

Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF ( = 641) or interferons/glatiramer acetate (IFN/GA;  = 555) as the initial therapy, or DMF ( = 703) or fingolimod (FGL;  = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016.

Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58,  < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09,  < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13;  < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04;  = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy ( < 0.05 and  = 0.20, respectively).

Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.
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http://dx.doi.org/10.1177/1352458519866600DOI Listing
October 2020

Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression.

Pain 2019 11;160(11):2603-2611

Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.

Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN, and TN can exist without a neurovascular contact. A common observation during microvascular decompression surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology to analyse the levels of 92 protein biomarkers related to inflammation in lumbar cerebrospinal fluid from patients with TN (n = 27) before and after microvascular decompression compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the cerebrospinal fluid from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins seemed to be of specific interest for TN: TRAIL and TNF-β. Thus, inflammatory activity might be one important mechanism in TN.
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http://dx.doi.org/10.1097/j.pain.0000000000001649DOI Listing
November 2019

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.

JAMA Neurol 2019 Jun 17. Epub 2019 Jun 17.

UCL Institute of Neurology, Queen Square, London, United Kingdom.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction And Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome And Measure: The cNfL levels adjusted for age and sex across diagnoses.

Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions And Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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http://dx.doi.org/10.1001/jamaneurol.2019.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580449PMC
June 2019

Lower risk of multiple sclerosis in patients with chronic hepatitis C: a nationwide population-based registry study.

J Neurol 2019 Sep 31;266(9):2208-2215. Epub 2019 May 31.

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Multiple sclerosis (MS) is an immune-mediated neurological disease that causes demyelination. The etiology is unknown, but patients with a previous viral infection, such as Epstein-Barr virus, have been shown to be at a higher risk of developing MS. In contrast, people living with HIV have a lower risk of developing MS. Hepatitis C virus (HCV) mainly infects the liver, but patients with HCV can experience several extrahepatic manifestations and studies have shown an association with several autoimmune conditions such as neuropathy and myelitis. The present study aimed to investigate the risk of MS in patients with chronic HCV infection compared with matched comparators.

Methods: Patients were identified using the nationwide Swedish inpatient (2001-2013) and outpatient care registers (2001-2013) for HCV (B18.2) and MS (G35) according to the International Classification of Diseases-10. Up to five comparators (matched on age/sex/place of residency) were drawn from the general population for each HCV patient. Follow-up started at the first HCV visit from 2001 and the patients' accrued person-time until death, emigration or 31 December 2013. Risk of MS diagnosis was calculated as standardized incidence ratio (SIR) with 95% confidence intervals (CIs).

Results: HCV patients were at lower risk of MS diagnosis (SIR 0.37; 95% CI 0.26-0.50). The incidence of MS during the study in the HCV cohort was 0.087% compared with 0.27% in the matched comparator cohort.

Conclusion: Surprisingly, these data suggest HCV patients to have a lower risk of MS diagnosis.
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http://dx.doi.org/10.1007/s00415-019-09397-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687702PMC
September 2019

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

J Neuroimmunol 2019 07 25;332:31-36. Epub 2019 Mar 25.

Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden. Electronic address:

Background: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

Methods: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

Results: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

Conclusions: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.
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http://dx.doi.org/10.1016/j.jneuroim.2019.03.015DOI Listing
July 2019

Inflammatory activity and vitamin D levels in an MS population treated with rituximab.

Mult Scler J Exp Transl Clin 2019 Jan-Mar;5(1):2055217319826598. Epub 2019 Feb 11.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden.

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;  = 0.030). Levels of 25-hydroxy-vitamin D were associated with self-perceived health ( = 0.18,  = 0.041,  = 130) and C-reactive protein ( = -0.13,  = 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.
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http://dx.doi.org/10.1177/2055217319826598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378455PMC
February 2019

Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial.

Acta Neurol Scand 2019 May 5;139(5):462-468. Epub 2019 Mar 5.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.

Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

Materials And Methods: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance.

Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials.
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http://dx.doi.org/10.1111/ane.13078DOI Listing
May 2019

Serum neurofilament light and prediction of multiple sclerosis in clinically isolated syndrome.

Neurology 2019 02 11;92(7):313-314. Epub 2019 Jan 11.

From the Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Department of Clinical Sciences (A.S.), Danderyd Hospital, Karolinska Institutet, Danderyd Hospital AB, Stockholm, Sweden.

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http://dx.doi.org/10.1212/WNL.0000000000006906DOI Listing
February 2019

Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study.

Neurology 2018 11 10;91(20):e1893-e1901. Epub 2018 Oct 10.

From the Department of Pharmacology and Clinical Neuroscience (J. Bergman, J.D.G., T.B., A.S.), Umeå University; Department of Neurosciences (J. Burman, E.J.), Uppsala University; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Department of Clinical Sciences (A.S.), Karolinska Institute Danderyd Hospital, Stockholm, Sweden.

Objectives: To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period.

Methods: Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months.

Results: Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers.

Conclusions: Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy.

Clinicaltrialsgov Identifier: NCT01719159.

Classification Of Evidence: This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.
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http://dx.doi.org/10.1212/WNL.0000000000006500DOI Listing
November 2018

Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls.

PLoS One 2018 8;13(2):e0192516. Epub 2018 Feb 8.

Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.

Objective: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

Method: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

Results: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

Conclusion: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805315PMC
April 2018

Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis.

JAMA Neurol 2018 03;75(3):320-327

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Importance: Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.

Objective: 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.

Design, Setting, And Patients: 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.

Main Outcomes And Measures: 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.

Results: 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).

Conclusions And Relevance: 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.
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http://dx.doi.org/10.1001/jamaneurol.2017.4011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885857PMC
March 2018

Cortico-juxtacortical and periventricular lesions and MS diagnostic criteria.

Neurology 2017 12 3;89(23):2308-2309. Epub 2017 Nov 3.

From the Department of Clinical Sciences (A.S.), Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden; and Queen Square MS Centre (O.C.), UCL Institute of Neurology, London, UK.

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http://dx.doi.org/10.1212/WNL.0000000000004725DOI Listing
December 2017

Monitoring disease activity in multiple sclerosis using serum neurofilament light protein.

Neurology 2017 Nov 27;89(22):2230-2237. Epub 2017 Oct 27.

From the Department of Clinical Neuroscience (L.N., M.A., C.M., J.L.) and Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; Department of Pharmacology and Clinical Neuroscience (P.S.), Umeå University; University Department of Clinical Neuroscience (M.K., T.O., F.P.), Neuroimmunology Unit, and Department of Clinical Sciences (A.S.), Danderyd Hospital, Karolinska Institutet, Stockholm; and Department of Neurology (M.G.), Faculty of Medicine and Health, Örebro University, Sweden.

Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).

Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.

Results: In MS, the correlation between serum and CSF NFL was = 0.62 ( < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, < 0.001 and < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L ( < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission ( < 0.001) or those without new lesions on MRI ( < 0.001).

Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
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http://dx.doi.org/10.1212/WNL.0000000000004683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705244PMC
November 2017

Brain Parenchymal Fraction in Healthy Adults-A Systematic Review of the Literature.

PLoS One 2017 17;12(1):e0170018. Epub 2017 Jan 17.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.

Brain atrophy is an important feature of many neurodegenerative disorders. It can be described in terms of change in the brain parenchymal fraction (BPF). In order to interpret the BPF in disease, knowledge on the BPF in healthy individuals is required. The aim of this study was to establish a normal range of values for the BPF of healthy individuals via a systematic review of the literature. The databases PubMed and Scopus were searched and 95 articles, including a total of 9269 individuals, were identified including the required data. We present values of BPF from healthy individuals stratified by age and post-processing method. The mean BPF correlated with mean age and there were significant differences in age-adjusted mean BPF between methods. This study contributes to increased knowledge about BPF in healthy individuals, which may assist in the interpretation of BPF in the setting of disease. We highlight the differences between post-processing methods and the need for a consensus gold standard.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170018PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240949PMC
August 2017

How to minimize the risk for headache? A lumbar puncture practice questionnaire study.

Ideggyogy Sz 2016 Nov;69(11-12):397-402

Umeå University, Department of Pharmacology and Clinical Neuroscience, Section for Neurology Umeå, Sweden.

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.
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http://dx.doi.org/10.18071/isz.69.0397DOI Listing
November 2016

Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS.

Mult Scler 2017 Aug 25;23(9):1249-1257. Epub 2016 Oct 25.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden/Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.

Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.

Method: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.

Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.

Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.
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http://dx.doi.org/10.1177/1352458516676643DOI Listing
August 2017

Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy.

Neurology 2016 Nov 19;87(20):2074-2081. Epub 2016 Oct 19.

From the Department of Pharmacology and Clinical Neuroscience (J.S., R.S., P.I.-J., M.V., P.S., A.S.), Umeå University; Departments of Clinical Neuroscience (R.S., P.A., A.B., K.F., F.P.) and Clinical Sciences, Danderyd Hospital (A.S.), Karolinska Institutet, Stockholm; and Department of Clinical Neuroscience (L.N., C.M., M.A., J.L.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.

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.
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http://dx.doi.org/10.1212/WNL.0000000000003331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109942PMC
November 2016

Brain parenchymal fraction in an age-stratified healthy population - determined by MRI using manual segmentation and three automated segmentation methods.

J Neuroradiol 2016 Dec 5;43(6):384-391. Epub 2016 Oct 5.

Department of Pharmacology and Clinical Neuroscience, Section of Neuroscience, Umeå University, 90185 Umeå, Sweden.

Background And Purpose: Brain atrophy is a prominent feature in many neurodegenerative diseases, such as multiple sclerosis, but age-related decrease of brain volume occurs regardless of pathological neurodegeneration. Changes in brain volume can be described by use of the brain parenchymal fraction (BPF), most often defined as the ratio of total brain parenchyma to total intracranial space. The BPF is of interest both in research and in clinical practice. To be able to properly interpret this variable, the normal range of BPF must be known. The objective of this study is to present normal values for BPF, stratified by age, and compare manual BPF measurement to three automated methods.

Materials And Methods: The BPFs of 106 healthy individuals aged 21 to 85 years were determined by the automated segmentation methods SyMap, VBM8 and SPM12. In a subgroup of 54 randomly selected individuals, the BPF was also determined by manual segmentation.

Results: The median (IQR) BPFs of the whole study population were 0.857 (0.064), 0.819 (0.028) and 0.784 (0.073) determined by SyMap, VBM8 and SPM12, respectively. The BPF decreased with increasing age. The correlation coefficients between manual segmentation and SyMap, VBM8 and SPM12 were 0.93 (P<0.001), 0.77 (P<0.001) and 0.56 (P<0.001), respectively.

Conclusions: There was a clear relationship between increasing age and decreasing BPF. Knowledge of the range of normal BPF in relation to age group will help in the interpretation of BPF data. The automated segmentation methods displayed varying degrees of similarity to the manual reference, with SyMap being the most similar.
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http://dx.doi.org/10.1016/j.neurad.2016.08.002DOI Listing
December 2016

Reply.

Ann Neurol 2016 11 27;80(5):791-792. Epub 2016 Sep 27.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

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http://dx.doi.org/10.1002/ana.24767DOI Listing
November 2016

Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.

Neurol Neuroimmunol Neuroinflamm 2016 Oct 2;3(5):e271. Epub 2016 Aug 2.

Department of Pharmacology and Clinical Neuroscience (J.B., A.D., J.G., T.B., A.S.), Umeå University; Institute of Neuroscience and Physiology (H.Z., K.B.), Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK; UmanDiagnostics AB (N.N.), Umeå; and Department of Clinical Sciences (A.S.), Danderyd Hospital, Karolinska Institutet, Danderyd Hospital AB, Stockholm, Sweden.

Objective: In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.

Methods: Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point.

Results: One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum.

Conclusions: The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.

Clinicaltrialsgov Identifier: NCT01719159.
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http://dx.doi.org/10.1212/NXI.0000000000000271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972001PMC
October 2016