Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.

INTRODUCTION: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. OBJECTIVE: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). METHODS: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects. RESULTS: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. CONCLUSIONS: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.

Deep neural networks learn general and clinically relevant representations of the ageing brain.

The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data - the brain age delta - has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

International consensus on quality standards for brain health-focused care in multiple sclerosis.

BACKGROUND: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. OBJECTIVES: We sought to develop internationally applicable quality standards for timely, brain health-focused MS care. METHODS: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define 'core', 'achievable' and 'aspirational' time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. RESULTS: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. CONCLUSION: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis.

PURPOSE: The utility of perfusion-weighted imaging in multiple sclerosis (MS) is not well investigated. The purpose of this study was to compare baseline normalized perfusion measures in subgroups of newly diagnosed MS patients. We wanted to test the hypothesis that this method can differentiate between groups defined according to disease severity and disease activity at 1 year follow-up. METHODS: Baseline magnetic resonance imaging (MRI) including a dynamic susceptibility contrast perfusion sequence was performed on a 1.5-T scanner in 66 patients newly diagnosed with relapsing-remitting MS. From the baseline MRI, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were generated. Normalized (n) perfusion values were calculated by dividing each perfusion parameter obtained in white matter lesions by the same parameter obtained in normal-appearing white matter. Neurological examination was performed at baseline and at follow-up approximately 1 year later to establish the multiple sclerosis severity score (MSSS) and evidence of disease activity (EDA). RESULTS: Baseline normalized mean transit time (nMTT) was lower in patients with MSSS >3.79 (p = 0.016), in patients with EDA (p = 0.041), and in patients with both MSSS >3.79 and EDA (p = 0.032) at 1-year follow-up. Baseline normalized cerebral blood flow and normalized cerebral blood volume did not differ between these groups. CONCLUSION: Lower baseline nMTT was associated with higher disease severity and with presence of disease activity 1 year later in newly diagnosed MS patients. Further longitudinal studies are needed to confirm whether baseline-normalized perfusion measures can differentiate between disease severity and disease activity subgroups over time.

Bone mineral density in patients with multiple sclerosis, hereditary ataxia or hereditary spastic paraplegia after at least 10 years of disease - a case control study.

BACKGROUND: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA). METHODS: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years. RESULTS: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers. CONCLUSION: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis.

BACKGROUND: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. OBJECTIVE: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. METHODS: Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708). RESULTS: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P << 10(-22)). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. CONCLUSION: The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

Environmental exposures and the risk of multiple sclerosis investigated in a Norwegian case-control study.

BACKGROUND: Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis. METHODS: A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated. RESULTS: Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR = 1.79, 95% CI: 1.12-2.87, p = 0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR = 0.56, 95% CI: 0.40-0.78, p = 0.001). More patients than controls reported smoking and fewer patients reported snuff use. CONCLUSIONS: In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard.

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway.

OBJECTIVE: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient. METHODS: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose. RESULTS: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98-1.24), in Middle Norway 1.11 (0.97-1.27) and in Northern Norway 1.28 (1.0-1.63) compared with the other months. CONCLUSIONS: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

The instrumented single leg stance test detects early balance impairment in people with multiple sclerosis.

Balance impairment is frequent in people with multiple sclerosis (pwMS) and affects risk of falls and quality of life. By using inertial measurement units (IMUs) on the Single Leg Stance Test (SLS) we aimed to discriminate healthy controls (HC) from pwMS and detect differences in balance endurance and quality. Thirdly, we wanted to test the correlation between instrumented SLS parameters and self-reported measures of gait and balance. Fifty-five pwMS with mild (EDSS<4) and moderate disability (EDSS≥4) and 20 HC performed the SLS with 3 IMUs placed on the feet and sacrum and filled the Twelve Item Multiple Sclerosis Walking Scale (MSWS-12) questionnaire. A linear mixed model was used to compare differences in the automated balance measures. Balance duration was significantly longer in HC compared to pwMS (p < 0.001) and between the two disability groups (p < 0.001). Instrumented measures identified that trunk stability (normalized mediolateral and antero-posterior center of mass stability) had the strongest association with disability (R2 marginal 0.30, p < 0.001) and correlated well with MSWS-12 (R = 0.650, p < 0.001). PwMS tended to overestimate own balance compared to measured balance duration. The use of both self-reported and objective assessments from IMUs can secure the follow-up of balance in pwMS.

"No association between disease modifying treatment and fatigue in multiple sclerosis".

BACKGROUND: Fatigue affects 60-90% of people with multiple sclerosis (MS). It reduces quality of life and the ability to work. The cause of fatigue in MS remains unknown. Several disease-modifying treatments (DMTs) slow the disease process in relapsing MS by suppressing neuroinflammation. We aimed to investigate if treatment with a DMT is associated with lower rates of fatigue. METHODS: In this cross-sectional study of the MS population in three counties in Norway, we used the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Hospital Anxiety and Depression Scale (HADS) to assess patient-reported fatigue, anxiety and depression. Clinical data were retrieved from the electronic patient record system. We categorized DMTs as high-efficacy therapy or moderate-efficacy therapy. High-efficacy drugs included fingolimod, natalizumab, ocrelizumab, rituximab, alemtuzumab, daclizumab, and autologous hematopoietic stem cell transplantation. Moderate-efficacy drugs included interferons, glatiramer acetate, dimethyl fumarate, and teriflunomide. We included persons with relapsing MS only. RESULTS: Of 1142 patients, 80% had fatigue. Fifty-six percent of the patients were on DMTs (25% on moderate-efficacy treatment and 30% on high-efficacy treatment), 18% had discontinued treatment and 26% had never received any DMT. Sex, level of disability as measured by the Multiple Sclerosis Severity Score, anxiety and depression were independently associated with fatigue. Moderate-efficacy treatment was associated with less fatigue, but not after adjustment for other variables. There was no association between high-efficacy treatment and fatigue. CONCLUSION: We found no independent relationship between the use of disease-modifying treatment and fatigue in MS.

Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis.

BACKGROUND: A sudden onset of extensive disease activity, including severe clinical relapse and extensive brain or spinal magnetic resonance imaging (MRI) lesions, termed "rebound" disease activity has been reported after withdrawal of fingolimod in patients with multiple sclerosis (MS). OBJECTIVE: To compare the risk of rebound after switching from fingolimod to cladribine or rituximab in MS. METHODS: All patients switching from fingolimod to cladribine or rituximab were included in a retrospective cohort study utilizing prospectively collected data from two university hospitals with different treatment strategies. RESULTS: A total of 73 patients with at least 6 months follow-up after switching were identified, 33 patients had switched from fingolimod to cladribine and 40 patients to rituximab. No patients in the rituximab group and seven (21.1%) in the cladribine group qualified for rebound disease activity. Ten (30.3%) of the patients using cladribine and five (12.5%) of the patients using rituximab experienced a relapse. MRI disease activity was seen in 18 (54.5%) and eight (20.0%) of the patients using cladribine and rituximab, respectively. Younger age and previous high relapse rate were associated with increased risk of rebound in the cladribine group. CONCLUSIONS: We identify a lower risk of rebound during the first year after switching from fingolimod to rituximab compared to cladribine, indicating a better initial clinical outcome with the former treatment strategy.

Fatigue in multiple sclerosis is associated with socioeconomic factors.

OBJECTIVES: Fatigue is one of the leading causes of reduced quality of life and inability to work in people with multiple sclerosis (pwMS). Currently, no treatment effectively ameliorates fatigue. We still know little about what causes fatigue and which factors may contribute to fatigue. Knowledge about socioeconomic factors' role in fatigue might help us recognize strategies for the management of fatigue. Our aim was to explore whether socioeconomic factors are associated with the presence or level of perceived fatigue. METHODS: This is a cross-sectional study of the MS population in three Norwegian counties. We used the Fatigue Scale for Motor and Cognitive Functions to assess self-reported fatigue, and obtained socioeconomic data from Statistics Norway and questionnaires. To assess self-reported anxiety and depression, we employed the Hospital Anxiety and Depression Scale. Clinical data were gathered from the hospital record system. RESULTS: The response rate was 64% (1599/2512). Seventy percent of the respondents were female, and the mean age was 52 years. Higher levels of education were associated with lower levels of fatigue. Receiving a disability pension, being divorced and having children were all factors associated with higher levels of fatigue, as were low parental education, low income, current smoking, and autoimmune comorbidities. We found a higher prevalence of anxiety and depression in pwMS with fatigue compared to those without fatigue CONCLUSION: Female sex, high level of disability, anxiety, depression and socioeconomic factors were independently associated with fatigue in contemporary patients with MS. These factors should be considered when devising management strategies.

Sensor-based gait analyses of the six-minute walk test identify qualitative improvement in gait parameters of people with multiple sclerosis after rehabilitation.

The aim of this work was to determine whether wearable inertial measurement units (IMUs) could detect gait improvements across different disability groups of people with Multiple Sclerosis (pwMS) by the six-minute walk test (6MWT) during a rehabilitation stay in a specialized rehabilitation center. Forty-six pwMS and 20 healthy controls (HC) were included in the study. They performed the 6MWT with two inertial measurement units (IMUs) placed on the feet. Thirty-two of the pwMS were retested at the end of the stay. PwMS were divided in a mild-disability and a moderate-disability group. The 6MWT was divided in six sections of 1 min each for technical analysis, and linear mixed models were used for statistical analyses. The comparison between the two disability groups and HC highlighted significant differences for each gait parameter (all p < 0.001). The crossing effect between the test-retest and the two disability groups showed greater improvement for the moderate-disability group. Finally, the gait parameter with the higher effect size, allowing the best differentiation between the disability groups, was the foot flat ratio (R2 = 0.53). Gait analyses from wearable sensors identified different evolutions of gait patterns during the 6MWT in pwMS with different physical disability. The measured effect of a short-time rehabilitation on gait with 6MWT was higher for pwMS with higher degree of disability. Using IMUs in a clinical setting allowed to identify significant changes in inter-stride gait patterns. Wearable sensors and key parameters have the potential as useful clinical tools for focusing on gait in pwMS.

The influence of socioeconomic factors on access to disease modifying treatment in a Norwegian multiple sclerosis cohort.

OBJECTIVE: Several studies report an impact of socioeconomic factors on access to disease modifying treatment (DMT) in multiple sclerosis (MS), with a trend of less access to more deprived persons. We investigated the impact of socioeconomic status (SES) on access to treatment in a well-defined Norwegian MS cohort. METHODS: This is a study of a population-based Norwegian MS cohort. We collected detailed information on disease development, progression, and DMT administered. Socioeconomic data was obtained from Statistics Norway and a questionnaire. RESULTS: We included 1314 persons with relapsing remitting MS at the prevalence date 01/01/2018. The population ever treated with DMTs is younger at onset, has shorter time from onset to diagnosis and lower expanded disability status score (EDSS) at diagnosis. The persons with MS (pwMS) with the highest levels of education, and those who are married are more likely to be ever treated with DMT. In the subgroup treated with a high efficacy DMT as a first drug, the pwMS are younger at prevalence date (39.9 years (SD 12.1)) compared with those who are not treated with a high efficacy DMT as first drug (43.8 years (SD 10.3)). The subgroup treated with a high efficacy DMT as a first drug has a 0.5 point higher EDSS at diagnosis compared to those not treated with a high efficacy DMT as a first drug. The level of education, household income and marital status are inversely related to access to high efficacy DMT as a first drug. None of the above differences persist when analyzing the subgroup diagnosed within the last six years (2012-2017). CONCLUSIONS: Since 2012, the pwMS in this Norwegian cohort are treated equally with DMT in terms of different measures of socioeconomic position.

Rebaseline no evidence of disease activity (NEDA-3) as a predictor of long-term disease course in a Norwegian multiple sclerosis population.

Introduction: No evidence of disease activity with three components (NEDA-3) is achieved if the person with MS (pwMS) has no new MRI lesions, no new relapses and no change in Expanded disability status scale (EDSS) over 1 year. Whether NEDA-3 is a good tool in measuring disease activity is up for discussion, but it is superior to the individual parameters separately and user-friendly. There is disagreement on whether NEDA-3 is a good predictor of long-term disability. Methods: This is a retrospective cohort study using real-world data with limited selection bias from the complete MS population at two hospitals in the southeast of Norway. We included pwMS diagnosed between 2006 and 2017 who had enough information to determine time to failure of NEDA-3 after diagnosis. Results: Of 536 pwMS, only 38% achieved NEDA 1 year after diagnosis. PwMS achieving NEDA were more likely to be started on a high efficacy drug as the initial drug, but there were no demographic differences. Mean time to NEDA failure was 3.3 (95% CI 2.9-3.7) years. Starting a high efficiacy therapy was associated with an increased risk of sustaining NEDA as compared to those receiving moderate efficacy therapy. PwMS who achieved NEDA at year one had a mean time to EDSS 6 of 33.8 (95% CI 30.9-36.8) years vs. 30.8 (95% CI 25.0-36.6) years in pwMS who did not achieve NEDA, p < 0.001. When rebaselining NEDA 1 year after diagnosis, 52.2% achieved NEDA in the 1st year after rebaseline, mean time to NEDA failure was 3.4 (95% CI 3.0-3.7) years and mean time to EDSS 6 was 44.5 (95% CI 40.4-48.5) years in pwMS achieving NEDA vs. 29.6 (95% CI 24.2-35.0) years in pwMS not achieving NEDA, p < 0.001. After rebaseline, pwMS with a high efficacy therapy as the initial drug had a mean time from diagnosis to NEDA fail of 4.8 years (95% CI 3.9-5.8) vs. 3.1 years (95% CI 2.7-3.5) in pwMS started on a moderate efficacy therapy, p < 0.001. In pwMS with NEDA failure at year one, 70% failed one, 28% failed two and 2% failed three components. New MRI lesions were the most common cause of NEDA failure (63%), followed by new relapses (50%) and EDSS change (25%). Conclusion: NEDA-3 from rebaseline after 1 year, once treatment is stabilized, can predict the long-term disease course in MS. Starting a high efficacy DMT is associated with longer time to NEDA failure than moderate therapies. Finally, most pwMS only fail one component and new MRI lesions are the most likely cause of NEDA failure.

Effect of desire for pregnancy on decisions to escalate treatment in multiple sclerosis care: Differences between MS specialists and non-MS specialists.

BACKGROUND: Therapeutic inertia (TI) is a worldwide phenomenon that affects 60 to 90% of neurologists and up to 25% of daily treatment decisions during management of multiple sclerosis (MS) patients. A large volume of MS patients are women of childbearing age, and desire for pregnancy is a complex variable often affecting MS care. The objective of this study was to determine the effect of desire for pregnancy on decisions to escalate treatment during management of MS patients. METHODS: 300 neurologists with expertise in MS from 20 countries were invited to participate in the study. Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. Disaggregated discrete choice experiments were used to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. An excel calculator that provides estimates as the percentage of participants that would escalate treatment for a simulated case-scenario was constructed. RESULTS: 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per month by each neurologist was 18 (±16). Non-MS specialists were significantly less likely to escalate treatment than MS specialists across mild, moderate, and severe patient cases. These differences were accentuated when case scenarios introduced a desire for pregnancy. The findings were consistent when MRI-lesions, severity of symptoms, and number of relapses were included. CONCLUSIONS: Desire for pregnancy differentially influences decisions to escalate treatment, suggesting knowledge-to-action gaps between MS and non-MS specialists. Our findings indicate the need for educational strategies to overcome these gaps and improve clinical outcomes for MS patients who desire pregnancy.

[Development of new therapies for multiple sclerosis]. / Utvikling av ny behandling for multippel sklerose.

BACKGROUND: Current first line treatment for multiple sclerosis is only moderately effective and is associated with frequent and disturbing side effects. We here describe opportunities and challenges related to drugs under development. MATERIAL AND METHODS: Non-systematic search in PubMed and congress abstracts. RESULTS AND INTERPRETATION: Monoclonal antibodies (e.g. natalizumab, alemtuzumab, rituximnab and dacklizumab) and oral agents (e.g. fingolimod and cladribine) target molecules or cells which are important in the immunopathogenesis of multiple sclerosis. These agents seem to have a considerable effect on relapsing-remitting multiple sclerosis, but may also be associated with serious side effects. Natalizumab is licensed as second line treatment for relapsing-remitting multiple sclerosis, and also as first line treatment in especially serious cases. Cladribine and fingolimod may be available in Norway in 2011. INTERPRETATION: Treatment of exacerbations in multiple sclerosis is changing. Indication for the drugs under development is not yet clear.

[New gene map for multiple sclerosis]. / Nytt genkart for multippel sklerose.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating, inflammatory disease of the central nervous system which affects young adults with a relapsing or progressive disease course. The etiology of the disease is unknown, but both environmental and genetic factors contribute to the risk of developing MS. MATERIAL AND METHODS: We give an overview of new knowledge of the genetic risk factors for MS, based on our own work as well as on literature in this field. RESULTS: Through genome-wide association studies and subsequent replication studies a series of novel MS genes have recently been identified, in addition to the HLA association previously described. The International MS Genetics Consortium in collaboration with the Wellcome Trust Case Control Consortium recently published a genome-wide study of 9,722 MS patients and 17,376 controls. Genome-wide significant association (p < 10-8) was observed for 29 new as well as 23 previously identified gene regions, in addition to the HLA-DRB1 and -A loci .The majority of these MS-associated regions encode immune-related molecules. CONCLUSION: Genetic studies of large patient and control samples obtained through international and national collaborations have identified a list of more than 50 MS risk-gene regions, in addition to HLA-DRB1 and -A loci. The risk associated with each of these loci is low, however, they collectively point to the importance of immune-related pathways in the etiology of MS.