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

Background. Different disease-modifying therapies (DMT) for multiple sclerosis (MS) have disparate effects on disability outcomes. Sweden has a leading position globally in initiating high-efficacy DMT instead of escalating DMT from 1st-line to high-efficacy DMT. With optical coherence tomography (OCT), retinal changes can be measured at a few micrometer level. OCT has been increasingly applied in diagnosing MS and monitoring disease course and therapeutic effect. Objective. We investigate the effects of 1st-line versus high-efficacy DMT for MS on retinal and brain atrophy and on functional outcomes during 6.8 years of escalating DMT. Materials and Methods. In this prospective longitudinal observational study, 18 MS patients were followed up for 6.8 years. Twelve of the patients were untreated at baseline. All patients underwent 1st-line DMT for median duration of 2.4 years and then switched to high-efficacy DMT for a median duration of 2.9 years. Findings from neurological examinations, MRI, and OCT measures were registered 2-4 times per year. Results. Ganglion cell-inner plexiform layer (GCIPL) thickness was significantly reduced during 1st-line DMT (73.75 μm, p < 0.01 ) compared to baseline (76.38 μm). During high-efficacy DMT, thickness reduction was slower (73.27 μm, p < 0.05 ), and MRI contrast-loading lesions vanished ( p < 0.01 ). However, brain parenchymal fraction (BPF) decreased during high-efficacy DMT compared to 1st-line DMT. Estimated models showed similar results. Conclusion. GCIPL decline was most profound during 1st-line DMT and diminished during high-efficacy DMT. MRI contrast lesions vanished during high-efficacy DMT. However, brain atrophy continued regardless of high-efficacy DMT.

The afferent visual pathway provides a unique opportunity to monitor clinical and subclinical optic neuritis and features of neuroaxonal degeneration in secondary progressive MS.To investigate the usefulness of visual evoked potentials (VEP) and optical coherence tomography (OCT) in evaluating SPMS, and the association between these modalities and clinical course and lesion load on the magnetic resonance imaging (MRI) in patients with SPMS with or without a history of optic neuritis (ON).SPMS patients (n = 27) underwent clinical assessment with Expanded Disability Status Scale (EDSS) grading, visual acuity, OCT, and VEP examination. MRI of the brain and spinal cord were evaluated. Ordinal scores of VEP and MRI findings were used in the statistical analyses.The ganglion cell and inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness correlated with VEP latency. VEP P100 score correlated with EDSS. Linear regression showed an association between GCIPL thickness and EDSS as well as VEP P100 latency and EDSS. The MRI analyses were negative.VEP latency and GCIPL thickness correlated with disability measured as EDSS in patients with SPMS and are useful in monitoring SPMS patients.

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.

Objectives Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization. Methods Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan-Meier and Mann-Whitney U test. Cox regression was used for risk estimation. Results Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units. Conclusion Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours. Funding Agencies|Gustav Lindholm Foundation for malignant brain tumours

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

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

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing–remitting multiple sclerosis (RRMS). Methods: In this nested case–control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1–1.9) and in all men (OR = 1.4, 95% CI = 1.0–2.0). In contrast, for women aged 30–39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54–1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

Background: High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals. Objective: Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent. Methods: Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry. Results: High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93). Conclusion: These findings further support a role for vitamin D in MS aetiology.

Although oxylipins are involved in inflammation, data on these lipid mediators in multiple sclerosis are sparse. In this study, a panel of oxylipins were analysed swith liquid chromatography tandem mass spectrometry in cerebrospinal fluid (CSF) from 41 treatment naive patients with clinically isolated syndrome (CIS) or relapsing remitting MS (RRMS) and 22 healthy controls. CSF levels of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE) were significantly higher in patients than in healthy controls (9-HODE median 380 nM (interquartile range 330-450 nM) in patients and 290 nM (interquartile range 250-340 nM) in controls, 13-HODE median 930 nM (interquartile range 810-1080 nM) in patients and 690 nM (interquartile range 570-760 nM) in controls, p amp;lt; 0.001 in Mann-Whitney U tests). 9-HODE and 13-HODE performed well for separation of patients and healthy controls (AUC 0.85 and 0.88, respectively, in ROC curve analysis). However, baseline CSF levels of the oxylipins did not differ between patients with signs of disease activity during one, two and four years of follow-up and patients without. In conclusion, this study indicates that 9-HODE and 13-HODE levels are increased in CSF from CIS and RRMS patients compared with healthy controls, but does not support 9-HODE or 13-HODE as prognostic biomarkers of disease activity in patients during follow-up.

ObjectivesIdiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of ostergotland, Sweden. Material and MethodsWe reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented. ResultsFour of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of ostergotland was 7.3 per million/year. ConclusionsThe results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM. Funding Agencies|Linkoping University; Region Ostergotland

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.

BACKGROUND A seizure as the only symptom before diagnosing glioblastoma improves survival rate. Apart from seizures, the main presenting symptom of glioma in adults is cognitive dysfunction. The effect of generalized symptoms or loss of function on lead times and survival of glioblastoma has not been studied. Generalized symptoms include cognitive dysfunction, headache, dizziness and fatigue. Loss of function comprise paresis, sensory deficit and speech aberrations. The objective of this study was to evaluate the influence of different presenting symptoms regarding health care level, lead times and survival. MATERIAL AND METHOD Medical case notes regarding 189 consecutive patients with histopathologically verified glioblastoma, were reviewed for information about the date and level of care of the first medical appointment, presenting symptom/s, and date of the diagnostic radiology. The extent of surgery was noted. Data on oncologic treatment was retrieved. Summary statistics were provided for patient demographics and treatment factors. The estimates of overall survival were calculated using the Kaplan-Meier method. Survival time was calculated from the date of radiological diagnosis. RESULTS The majority of patients (66%) presented with generalized symptoms, which significantly reduced survival compared to not having generalized symptoms (mean survival 10.5 months vs 19.9 months, p=0.001). The most common generalized symptom was cognitive dysfunction which further reduced survival (mean survival 9.0 months, p=0.0001). Among the different cognitive aberrations, personality change and memory impairment were associated with a significantly poorer survival, (mean survival 7.9 months, p=0.015 and 8.0 months p=0.010, respectively). Disorientation also significantly reduced survival (mean survival 8.2 months p=0.001). Presenting with loss of function (58%) did not influence survival (mean survival 12.3 months). 32% of patients with an epileptic seizure as initial symptom had significantly prolonged survival compared to those not having an epileptic seizure (mean 18.9 months vs 11.0 months p=0.002). When comparing focal and secondary generalized epileptic seizures, focal epileptic seizures were more favorable. The first medical appointment was evenly distributed between primary health care and the emergency units. 8.4% of patients had multiple contacts in primary health care without being admitted to radiology or specialized care. All but one of them presented with generalized symptoms. CONCLUSION Glioblastoma patients presenting with generalized symptoms such as cognitive dysfunction are difficult to identify and have significantly poorer survival than other glioblastoma patients. Patients presenting with an epileptic seizure have shorter leadtime and longer survival.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care. Funding Agencies|Swedish Multiple Sclerosis Association

Background and purpose Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing–remitting MS. Methods Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing–remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing–remitting MS and supports its use as a predictive biomarker of disease activity.

Background: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). less thanbrgreater than less thanbrgreater thanObjective: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. less thanbrgreater than less thanbrgreater thanMethods: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. less thanbrgreater than less thanbrgreater thanResults: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). less thanbrgreater than less thanbrgreater thanConclusion: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given. Funding Agencies|Swedish||Gothenburg Multiple Sclerosis Societies||Bayer Schering Pharma||Biogen Idec||Novartis||Sanofi-Aventis||BiogenIdec||Merck-Serono||Bayer-Schering||Teva||Swedish Research Council||Gothenburg Societies of the Neurologically Disabled

Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS. The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1 beta, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-alpha, IL-6 and IL-10) also decreased after one year of treatment. This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment. Original Publication: Johan Mellergård, Måns Edström, Magnus Vrethem, Jan Ernerudh and Charlotte Dahle, Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid, 2010, MULTIPLE SCLEROSIS, (16), 2, 208-217. http://dx.doi.org/10.1177/1352458509355068 Copyright: SAGE Publications http://www.uk.sagepub.com/

Background and purpose Brain atrophy is related to clinical deterioration in multiple sclerosis (MS) but its association with intrathecal markers of inflammation or neurodegeneration is unclear. Our aim was to investigate whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration are associated with brain volume change in natalizumab-treated MS and whether this change is reflected in non-lesional white matter metabolites. Methods About 25 patients with natalizumab-treated MS were followed for 3 years with assessment of percentage brain volume change (PBVC) and absolute quantification of metabolites with proton magnetic resonance spectroscopy (1H MRS). Analyses of inflammatory [interleukin 1β (IL-1β), IL-6, C-X-C motif chemokine 8 (CXCL8), CXCL10, CXCL11, C-C motif chemokine 22] and neurodegenerative [neurofilament light protein (NFL), glial fibrillary acidic protein, myelin basic protein, tau proteins] markers were done at baseline and 1-year follow-up. Results The mean decline in PBVC was 3% at the 3-year follow-up, although mean 1H MRS metabolite levels in non-lesional white matter were unchanged. CSF levels of NFL and tau at baseline correlated negatively with PBVC over 3 years (r = −0.564, P = 0.012, and r = −0.592, P = 0.010, respectively). Conclusions A significant 3-year whole-brain atrophy was not reflected in mean metabolite change of non-lesional white matter. In addition, our results suggest that CSF levels of NFL and tau correlate with brain atrophy development and may be used for evaluating treatment response in inflammatory active MS. Funding agencies: Medical Research Council [K2013-61X-22310-01-4]; Swedish Society of Neurologically Disabled; Swedish Society of Medicine; National Research Council (VR/NT); Linkoping University; Linkoping University Hospital; County Council of Ostergotland

BACKGROUNDComputer-processed algorithms of encephalographic signals are widely used to assess the depth of anaesthesia. However, data indicate that the bispectral index (BIS), a processed electroencephalography monitoring system, may not be reliable for assessing the depth of anaesthesia.OBJECTIVEThe aim of this study was to evaluate the ability of the BIS monitoring system to assess changes in the level of unconsciousness, specifically during the transition from consciousness to unconsciousness, in patients undergoing total intravenous anaesthesia with propofol. We compared BIS with the electroencephalogram (EEG), and clinical loss of consciousness (LOC) defined as loss of verbal commands and eyelash reflex.DESIGNThis was an observational cohort study.SETTINGUniversity Hospital Linkoping, University Hospital orebro, Finspang Hospital and Kalmar Hospital, Sweden from October 2011 to April 2013.PATIENTSA total of 35 ASA I patients aged 18 to 49 years were recruited.INTERVENTIONSThe patients underwent total intravenous anaesthesia with propofol and remifentanil for elective day-case surgery. Changes in clinical levels of consciousness were assessed by BIS and compared with assessment of stage 3 neurophysiological activity using the EEG. The plasma concentrations of propofol were measured at clinical LOC and 20 and 30min after LOC.MAIN OUTCOME MEASURESThe primary outcome was measurement of BIS, EEG and clinical LOC.RESULTSThe median BIS value at clinical LOC was 38 (IQR 30 to 43), and the BIS values varied greatly between patients. There was no correlation between BIS values and EEG stages at clinical LOC (r=-0.1, P=0.064). Propofol concentration reached a steady state within 20min.CONCLUSIONThere was no statistically significant correlation between BIS and EEG at clinical LOC. BIS monitoring may not be a reliable method for determining LOC.CLINICAL TRIALS REGISTRYThis trial was not registered because registration was not mandatory at the time of the trial. Funding Agencies|Medical Research Council of Southeast Sweden; Swedish Research Council; County Council in Ostergotland

Background Multiple sclerosis (MS) often causes a reduced ability to work. Improved disease control as well as adjustment of working conditions may improve work ability in MS. Objectives The objective of this article is to compare the degree of sickness absence in two MS populations that either have or have not received disease-modifying drug (DMD) treatments or active work-promoting measures. Methods We investigated the occurrence of sickness absence in MS patients living in Västerbotten County, Sweden, in 2013, in which the majority of MS patients receive DMD treatment. The result was compared with a previous survey in the same area during a period when no DMD was available and no work-promoting measures for MS patients were practiced. Results The proportion of MS patients active in the labor market or studying increased from 38% to 70% in the contemporary compared with the historic population ( p Conclusions Our data indicate that treatment with DMDs combined with active work-promoting measures lead to improved work ability in MS.

Bent spine syndrome : a phenotype of dysferlinopathy or a symptomatic DYSF gene mutation carrier

SummaryMonoclonal expansion of B cells and plasma cells, producing antibodies against ‘self’ molecules, can be found not only in different autoimmune diseases, such as peripheral neuropathy (PN), but also in malignancies, such as Waldenström’s macroglobulinaemia and B-type of chronic lymphocytic leukaemia (B-CLL), as well as in precancerous conditions including monoclonal gammopathy of undetermined significance (MGUS). About 50% of patients with PN-MGUS have serum antibodies against peripheral nerve myelin, but the specific role of these antibodies remains uncertain. The aims of the study were to establish, and characterize, myelin-specific B cell clones from peripheral blood of patients with PN-MGUS, by selection of cells bearing specific membrane Ig-receptors for myelin protein P0, using beads coated with P0. P0-coated magnetic beads were used for selection of cells, which subsequently were transformed by Epstein–Barr virus. The specificity of secreted antibodies was tested by ELISA. Two of the clones producing anti-P0 antibodies were selected and expanded. The magnetic selection procedure was repeated and new clones established. The cells were CD5+ positive, although the expression declined in vitro over time. The anti-P0 antibodies were of IgM-λ type. The antibodies belonged to the VH3 gene family with presence of somatic mutations. The IgM reacted with P0 and myelin-associated glycoprotein (MAG), and showed no evidence for polyreactivity, in contrast to other IgM CD5+ clones included in the study as controls. The expanded clones expressed CD80 and HLA-DR, which is compatible with properties of antigen-presenting cells. The immunomagnetic selection technique was successfully used for isolation of antimyelin protein P0-specific clones. The cell lines may provide useful tools in studies of monoclonal gammopathies, leukaemia, and autoimmune diseases, including aspects of antigen-presentation by these cells followed by T cell activation.

Background and PurposezzThe etiology of small fiber neuropathy (SFN) often remains unclear. Since SFN may be the only symptom of late-onset Fabry disease, it may be underdiagnosed in patients with idiopathic polyneuropathy. We aimed to uncover the etiological causes of seemingly idiopathic SFN by applying a focused investigatory procedure, to describe the clinical phenotype of true idiopathic SFN, and to elucidate the possible prevalence of late-onset Fabry disease in these patients. MethodszzForty-seven adults younger than 60 years with seemingly idiopathic pure or predominantly small fiber sensory neuropathy underwent a standardized focused etiological and clinical investigation. The patients deemed to have true idiopathic SFN underwent genetic analysis of the alpha-galactosidase A gene (GLA) that encodes the enzyme alpha-galactosidase A (Fabry disease). ResultszzThe following etiologies were identified in 12 patients : impaired glucose tolerance (58.3%), diabetes mellitus (16.6%), alcohol abuse (8.3%), mitochondrial disease (8.3%), and hereditary neuropathy (8.3%). Genetic alterations of unknown clinical significance in GLA were detected in 6 of the 29 patients with true idiopathic SFN, but this rate did not differ significantly from that in healthy controls (n=203). None of the patients with genetic alterations in GLA had significant biochemical abnormalities simultaneously in blood, urine, and skin tissue. ConclusionszzA focused investigation may aid in uncovering further etiological factors in patients with seemingly idiopathic SFN, such as impaired glucose tolerance. However, idiopathic SFN in young to middle-aged Swedish patients does not seem to be due to late-onset Fabry disease.

SUMMARY Polyneuropathy associated with monoclonal gammopathy is usually regarded as an immune-mediated disorder with autoantibody activity against myelin glycoproteins. The pathogenic mechanisms are, however, not fully understood. Several reports have indicated an additional involvement of T cells. We investigated the occurrence of myelin-specific T cells as well as their functional characteristics. Cytokine responses generated after stimulation of peripheral blood mononuclear cells with selected peptides of myelin proteins P0 and P2 were investigated with an ELISPOT method. Three P0 peptides caused significantly elevated levels of interferon-gamma (IFN-γ)-secreting cells in patients with polyneuropathy associated with monoclonal gammopathy (n=8) compared with controls (n=8), whereas none of the peptides caused elevated levels of IL-4-secreting cells. Patients with non-immunological types of neuropathy (n=4) did not reveal any cytokine responses to myelin peptides. Our results indicate that a Th1-like response against myelin proteins occurs in polyneuropathy associated with monoclonal gammopathy.

Background Changes in the peripheral blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks. Objectives To assess changes in circulating lymphocyte subpopulation compositions and T-cell responses during natalizumab treatment. Material and methods A broad panel of markers for blood lymphocyte populations, including states of activation and co-stimulation as well as T-cell responses to recall antigens and mitogens, was assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment. Results Absolute numbers of all major populations of lymphocytes increased after treatment, most markedly for NK- and B-cells. The fraction of both memory and presumed regulatory B-cell subsets increased, as did CD3-CD56dim cytotoxic NK-cells, whereas CD3-CD56bright regulatory NK-cells decreased. Treatment was also associated with a restored T-cell responsiveness to recall antigens and mitogens. Conclusions Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK- and B-cells. This supports reduction of lymphocyte extravasation as a main mode of action, although the differential composition of lymphocyte subpopulations suggests cell-signalling effects may also be operative. The systemic increase in T-cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses become correspondingly decreased.

Background 2,5-hexanedione (2,5-HD) is the main neurotoxic metabolite of methyl-n-butyl ketone (MBK) and n-hexane, and known to cause polyneuropathy. The aim of our study was to compare the urinary levels of 2,5-HD between cases with cryptogenic polyneuropathy and the general Swedish population, and to elucidate the role of certain external factors. Methods Morning urine samples were collected from 114 cases with cryptogenic polyneuropathy (77 men and 37 women) and 227 referents (110 men and 117 women) randomly selected from the population registry. None had any current occupational exposure to n-hexane or MBK. The urine samples were analysed by a gas chromatographic method based on acidic hydrolysis. Results Cases had statistically higher urinary levels of 2,5-HD (0.48 mg/L) than the general population (0.41 mg/L) and men higher excretion than women (0.48 mg/L and 0.38 mg/L, respectively). There was no difference in 2,5-HD levels between current smokers and non-smokers. Occupational exposure to xylene, alcohol consumption and ever exposed to general anaesthesia were associated with lower excretion in men while for occupational exposure to nitrous oxide in women higher excretion was seen. Higher excretion of 2,5 HD was inversely related to increasing age. Conclusions Significantly higher levels of urinary 2,5-HD were seen in men and cryptogenic polyneuropathy cases seemingly unexposed to n-hexane. Hypothetically, this might be due to either differences in metabolic patterns or some concealed exposure. The difference in means between cases and the general population is small and can therefore not allow any firm conclusions of the causality, however.

SUMMARYLate stages of borrelia Lyme disease infections may be difficult to diagnose because of unspecific symptoms and unreliable laboratory tests, being too unspecific or insensitive. The T cell immune response was thus evaluated in these patients by using a sensitive ELISPOT T cell assay that detects the secretion of IFN-γ, i.e. a T helper 1 (Th1) response on the single-cell level. Three subcellular fractions of the Lyme borreliosis strain Borrelia afzelii were used for antigenic stimulation. The outer surface protein (Osp) fraction elicited the strongest response, discriminating between borrelia infections (n= 15) compared with other neurological diseases (n= 10) and normal controls (n= 12) (P= 0.0001). The more heterogeneous sonicated borrelia fraction also elicited a strong response, however, also in some of the controls. The flagellin fraction did not have a similar T cell-stimulating effect. When looking at subgroups of borrelia infections, central nervous system (CNS) infections (n= 7) revealed a lower T cell response in blood (P= 0.0128) compared with other borrelia manifestations (n= 8). Cerebrospinal fluid (CSF) lymphocytes were available from three patients with CNS borreliosis, and all showed a compartmentalization with higher responses to the Osp fraction in CSF compared with blood, also in the two patients without any intrathecal-specific antibody synthesis. The ELISPOT method is feasible for detecting a specific IFN-γ T cell response in borrelia infections. This Th1 response may well be of pathogenic relevance.

SUMMARY B cells expressing the CD5 marker belong to a subpopulation with potential autoreactive properties. Increased proportions of CD5+ B cells have been reported in autoimmune diseases. In patients with monoclonal gammopathy and demyelinating polyneuropathy, the M-component often consists of autoantibodies reacting with myelin components. We therefore investigated if CD5+ B cells were involved in the production of anti-myelin antibodies. There was no difference of mean value of CD5+ B cells between patients and controls. However, the proportion of CD5+ B cells was significantly correlated with the amount of anti-myelin antibodies. In seven patients, CD5+ B cells were enriched using an immunomagnetic technique. The number of CD5+ and CD5− B cells secreting anti-myelin antibodies was determined by ELISPOT. In two patients with high levels of antibodies, antibody-secreting cells were mainly, but not exclusively, CD5+ B cells. In five patients with low levels of antibodies, most cells secreting anti-myelin antibodies were CD5−. We conclude that CD5 expressed on B cells may be an activation marker, reflecting B cells producing high amounts of anti-myelin antibodies in patients with polyneuropathy associated with monoclonal gammopathy.

Background: Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM. Methods: Quantitative proton magnetic resonance spectroscopy (1H-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in 1H-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients. Results: The group levels of 1H-MRS metabolite concentrations were unchanged pre-to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43–0.67, pfunding agencies|Swedish Society of Neurologically Disabled||Swedish Society of Medicine||National Research Council (VR/NT)||University Hospital of Linkoping||County Council of Ostergotland||Teva||Biogen Idec

The diagnosis of neuroborreliosis is not always straightforward. Intrathecal immunoglobulin (Ig) synthesis against Borrelia antigen may not be detected, at least early in the disease course. Also other neurological and infectious diagnoses have to be considered. We have studied patients with clinical possible neuroborreliosis without intrathecal Ig synthesis against Borrelia antigen in the cerebrospinal fluid (CSF) (n=17). Diagnosis was based on typical clinical history and at least one of the following findings; mononuclear leucocytosis in the CSF (n=4); typical erythema migrans >5 cm in diameter in relation to debut of symptoms (n=8); prompt clinical response to antibiotic teratment (n=14). Also other possible diagnoses had to be excluded. Seventeen patients first investigated because of suspected neuroborreliosis but later confirmed with other diagnoses were used as controls. All patients had a lumbar puncture. Borrelia specific IFN-γ and IL-4 secretion was investigated in peripheral blood (PBL) and CSF with an ELISPOT assay. Polymerase chain reaction (PCR) was used to reveal any Borrelia antigen in the CSF. Six of 17 patients with possible neuroborreliosis showed high IFN-g secretion in peripheral blood, otherwise we found no statistically significant differences between the groups. PCR did not reveal any Borrelia antigen in CSF. The diagnosis and treatment of possible but not confirmed neuroborreliosis is a clinical challenge. The clinical response to treatment may be the best option in these cases.

The aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), Glutathione S-Transferase Theta-1 (GSTT1), and a low-activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. Seventy-nine patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (ORs) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased OR for GSTT1, which was strongest if the patients had the low-activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.

Seven different formulae and agarose isoelectrofocusing (AIF) using immunolabelling for IgG were compared for their ability to discriminate between intrathecally produced IgG and transudated IgG in cerebrospinal fluid. All reference limits were set to a specificity of 97·5% (reference group, n = 211). The probability of a positive test ( p+) was evaluated for 112 patients with multiple sclerosis (MS), 42 with meningitis, 114 with noninflammatory diseases affecting the central nervous system (CNS), 23 with Guillain-Barré syndrome, and 56 with various diseases not affecting the CNS. Agarose isoelectrofocusing had the best diagnostic sensitivity (93%) for MS, combined with a low p+ (0–19%) for other diseases. Among the formulae, the IgG extended index and Reiber's hyperbolic formula were equivalent, giving high (75–79%) diagnostic sensitivity for MS combined with low p+ (4–22%) for other diseases. All other formulae, although sensitive for MS, had a higher rate of false positive results.

D-dimer levels in plasma, a degradation product of fibrin, have been shown to correlate with the severity of ischemic stroke. In order to investigate the outcome of patients with elevated D-dimer we have carried out a follow-up study of patients of 65 years of age and younger with acute ischemic stroke or transient ischemic attacks (TIA) admitted to our stroke unit from 1991 to 1992. Twenty-two of the 57 patients had elevated D-dimer levels in the plasma. High levels were associated with cardioembolic stroke. On follow-up after a mean of 12 years, 15 patients had died and six patients had suffered another stroke or TIA (three of whom were dead). Ten patients had suffered other cardiovascular events and seven of them were dead. We concluded that high levels of D-dimer in acute ischemic stroke patients on admission were associated with cardioembolic stroke and might have prognostic value for the development of further cardio- or cerebrovascular events. Advanced age was found to be an independent risk factor.

The Borrelia-specific interferon (IFN)- gamma and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN- gamma (P

Background: Lyme borreliosis is a tick-borne infectious disease caused by the spirochete Borrelia burgdorferi sensu lato. The disease is characterised by several disease stages, where multiple organ systems might be affected, e.g. the skin, nervous system, heart or joints. The disease might lead to chronic symptoms of e.g. the nervous system, so called chronic neuroborreliosis (NB). The clinical features are often less severe in children, as compared to adults. The mechanisms responsible for the development of chronic symptoms are not fully established, but several factors might be involved. Probably the type of immune response elicited against the Borrelia spirochete during infection has implications on the clinical outcome, including development of chronic symptoms. Pro-inflammatory and type 1 responses are known to be efficient for elimination of pathogens, but may also be disease generating, whereas anti-inflammatory and type 2 responses are believed to regulate inflammation and possible tissue-harm, and have been reported in relation to resolution of symptoms in inflammatory diseases. In human Lyme borreliosis, mostly pro-inflammatory and type 1 responses have been reported previously.Aim: To examine selected aspects of the immune response- i.e. type 1/type 2 responses and pro-/anti-inflammatory responses - during the course of human Lyme borreliosis in patients with chronic and non-chronic manifestations, and in children vs. adults with NB, and to relate the type of immune response to the clinical outcome.Material and methods: Adult patients with the non-chronic manifestations erythema migrans and non-chronic NB or the chronic manifestations chronic NB and acrodermatitis chronica atrophicans (ACA), and children with NB were included in the study. Some of the adult patients were followed during the course of the disease. The Borrelia-specific cytokine production of interferon (IFN)-γ and interleukin (IL)-4 and the Borrelia-specific IgG subclass distribution were analysed as a measure of type 1 and type 2 responses, and the cytokinelevels of tumour necrosis factor (TNF)-α, IL-6 and transforming growth factor (TGF)-s1 were analysed as a measure of the pro- and anti-inflammatory responses. IFN-γ and IL-4 were measured as number of cytokine secreting cells, using the sensitive method ELISPOT. Mononuclear cells were separated from blood and cerebrospinal fluid (CSF) and stimulated with a Borrelia antigen containing outer surface protein (Osp)A and OspB. Borrelia-specific IgG subclasses were measured in serum and CSF by ELISA using a flagellin-containing antigen. Levels of TNF-α, IL-6 and total TGF-s1 were measured in serum and CSF by ELISA.Results: Adult patients with non-chronic NB showed a strong initial TNF-α and IFN-γ response in the CSF with production of the complement-activating and opsonizing IgG1 and IgG3. Subsequently, this inflammatory response seemed to be down-regulated by an upregulation of IL-4. TGF-s1 was expressed during the entire follow-up period. Patients with EM showed the same pattern, with an early IFN-γ response, elevated levels of TGF-s1 and a late up-regulation of IL-4. In addition, the children with early stage NB had elevated production of both IFN-γ and IL-4. The chronic NB patients, however, lacked early TNF-α in CSF and the subsequent up-regulation of IL-4, but showed persistent expression of IFN-γ. Furthermore, they did not show IgG3 or early TGF-s1 in serum. Furthermore, ACA patients showed elevated IFN-γ late in disease.Conclusions: Altogether, the results suggest that good prognosis of human Lyme borreliosis is associated with a strong initial pro-inflammatory type 1 response, effective for elimination of Borrelia spirochetes, which is subsequently down-regulated by up-regulation of a type-2 response, and whose possible harmful effects might also be limited by TGF-s1. Chronic manifestations, on the contrary, seem to be associated with lack of early pro-inflammatory responses, plausibly limiting their ability to eradicate the pathogen, followed by persistent inflammatory type 1 response, which might be self-destructive and disease-generating. In addition, the relative absence of type-2 responses in chronic manifestations may reduce the ability to limit the possibly harmful effects generated by long-standing IFN-γ. The results may have implications on future development of immuomodulatory treatments of chronic Lyme neuroborreliosis.