Search

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 selfreported 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. [ABSTRACT FROM AUTHOR]

This article discusses the use of ecological momentary assessment (EMA) in capturing real-time data on individuals' behaviors and experiences in their natural environments. EMA has been utilized in various research domains, including studies on multiple sclerosis (MS), to evaluate neurological symptoms and explore associations between physical activity and MS symptoms. However, the integration of EMA into routine care raises concerns about over-medicalization, increased stress levels, unnecessary clinical examinations, and the reliability of self-reported data. Careful consideration is needed to balance the benefits of EMA with its potential psychological impact and overutilization of healthcare resources. [Extracted from the article]

Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation. Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort. Methods: MS patients (n = 309) were prospectively enrolled at four centres and re-examined after 2 years (n = 226). NfL concentration was measured by single molecule array assay in serum. The patients' phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up. Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5–5.3), p = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening. Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting. [ABSTRACT FROM AUTHOR]

We aimed to determine whether retinal vessel diameters and retinal oxygen saturation in newly diagnosed patients with multiple sclerosis (pwMS) are different from those of a healthy population. Retinal blood vessel diameters were measured using imaging with a spectrophotometric non-invasive retinal oximeter. Twenty-three newly diagnosed untreated relapsing-remitting MS (RRMS) patients (mean age: 32.2 ± 7.5 years, age range = 18–50 years, 56.5% female) were measured and compared to 23 age- and sex-matched healthy controls (HCs) (mean age: 34.8 ± 8.1 years). Patients with Optic Neuritis were excluded. Retinal venular diameter (143.8 µm versus 157.8 µm: mean; p = 0.0013) and retinal arteriolar diameter (112.6 µm versus 120.6 µm: mean; p = 0.0089) were smaller in pwMS when compared with HCs, respectively. There was no significant difference in the oxygen saturation in retinal venules and arterioles in pwMS (mean: 60.0% and 93.7%; p = 0.5980) compared to HCs (mean: 59.3% and 91.5%; p = 0.8934), respectively. There was a significant difference in the median low contrast visual acuity (2.5% contrast) between the pwMS and the HC groups (p = 0.0143) Retinal arteriolar and venular diameter may have potential as objective biomarkers for MS. [ABSTRACT FROM AUTHOR]

Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B‐cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single‐cell full‐length RNA‐seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy‐ and light‐chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody‐secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy‐chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4‐39 gene was most used and showed the highest frequency of pairing with IGKV1‐5 and IGKV1(D)‐33. These results link IgG constant region polymorphisms to stereotyped B‐cell responses in MS and indicate that the intrathecal B‐cell response in these patients could be directed against structurally similar epitopes. [ABSTRACT FROM AUTHOR]

Background: Moderate and high efficacy disease modifying therapies (DMTs) have a profound effect on disease activity. The current treatment guidelines only recommend high efficacy DMTs for patients with highly active MS. The objective was to examine the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2. Methods: Using a real-world population-based registry with limited selection bias from the southeast of Norway, we determined how many patients achieved NEDA on moderate and high efficacy DMTs. Results: 68.0% of patients who started a high efficacy DMT as the first drug achieved NEDA at year 1 and 52.4% at year 2 as compared to 36.0 and 19.4% of patients who started a moderate efficacy DMT as a first drug. The odds ratio (OR) of achieving NEDA on high efficacy drugs compared to moderate efficacy drugs as a first drug at year 1 was 3.9 (95% CI 2.4–6.1, p < 0.001). The OR for high efficacy DMT as the second drug was 2.5 (95% CI 1.7–3.9, p < 0.001), and was not significant for the third drug. Patients with a medium or high risk of disease activity were significantly more likely to achieve NEDA on a high efficacy therapy as a first drug compared to moderate efficacy therapy as a first drug. Conclusions: Achieving NEDA at year 1 and 2 is significantly more likely in patients on high-efficacy disease modifying therapies than on moderate efficacy therapies, and the first choice of treatment is the most important. The immunomodulatory treatment guidelines should be updated to ensure early, high efficacy therapy for the majority of patients diagnosed with MS. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of multiple sclerosis (MS)-related fatigue may have changed due to new diagnostic criteria and new disease modifying drugs. We aimed to assess the prevalence of fatigue in a contemporary MS cohort, and to explore associations between fatigue and clinical and demographic factors. Methods: This is a cross-sectional study of the MS population in three Norwegian counties. Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC). We also assessed self-reported anxiety, depression and daytime sleepiness. Results: The response rate was 64% (1599/2512). The mean age of the participants was 52 ± 13 years, median EDSS was 2.5 (IQR 1.5-3.0) and median disease duration from onset was 16 years (IQR 8-25). We found a prevalence of fatigue of 81%. Women had a higher prevalence of fatigue than men (83% vs 78%, p = 0.02). The prevalence increased with age (p < 0.001) and with increasing disease severity (p < 0.001), but in multivariate analyses, only sex and disease severity remained independent determinants of fatigue. Anxiety, depression, and daytime sleepiness were more prevalent in patients with fatigue than in those without fatigue (all p-values < 0.001). Conclusion: The prevalence of fatigue is high in contemporary patients with MS. Fatigue is associated with female sex and level of disability, as well as with anxiety, depression and excessive daytime sleepiness. [ABSTRACT FROM AUTHOR]

Background and Goals: Multiple sclerosis (MS) is a central nervous system inflammatory disease where magnetic resonance imaging (MRI) is an important tool for diagnosis and disease monitoring. Quantitative measurements of lesion volume, lesion count, distribution of lesions, and brain atrophy have a potentially significant value for evaluating disease progression. We hypothesize that utilizing software designed for evaluating MRI data in MS will provide more accurate and detailed analyses compared to the visual neuro-radiological evaluation. Methods: A group of 56 MS patients (mean age 35 years, 70% females and 96% relapsing-remitting MS) was examined with brain MRI one and 5 years after diagnosis. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. These data were compared with data from structured visual evaluations of the MRI scans performed by neuro-radiologists, including assessments of atrophy, and lesion count. The data from LQ were also compared with data from other validated research methods for brain segmentation, including assessments of whole brain volume and lesion volume. Correlations with clinical tests like the timed 25-foot walk test (T25FT) were performed to explore additional value of LQ analyses. Results: Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor = 0.92, p = 2.2 × 10−16) and 5 years (cor = 0.84, p = 2.7 × 10−16) after diagnosis. Analyzes of the intra- and interrater variability also correlated significantly (cor = 0.96, p < 0.001, cor = 0.97, p < 0.001). Significant positive correlation was found between lesion volume measured by LQ and by the software Cascade (cor = 0.7, p < 0.001. LQ detected a reduction in whole brain percentile >10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8–28) in the LQ analysis. Significant positive correlation was identified between lesion volume measured by LQ and test performance on the T25FT both at 1 and 5 years after diagnosis. Conclusion: For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radiologist. Lesion volume evaluated with LQ correlated with T25FT performance. LQ-analyses classified more patients to have brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions in MS patients and also detecting early signs of atrophy in both a longitudinal and cross-sectional setting. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Structural and physiological abnormalities have been reported in the retina of people with multiple sclerosis (pwMS). We aimed to investigate whether change in the peripapillary retinal nerve fibre layer (RNFL) thickness is associated with difference in retinal oxygen (O2) saturation in newly diagnosed pwMS. Methods: Retinal oxygen saturation was measured using imaging by spectrophotometric non‐invasive retinal oximeter. RNFL thickness was acquired by RS‐3000 NIDEK OCT. Twenty‐five newly diagnosed pwMS were included. The measurements were performed primarily on the right eye; 25 healthy individuals (HCs) were age‐ and gender‐ matched with the pwMS. Arterio‐venular difference (A‐V diff) was calculated from the mean arteriolar and venular O2 saturation values based on measurements obtained from all vessels. Data were analysed by Spearman correlation. Results: There was a significant positive correlation between RNFL and A‐V diff in pwMS (p = 0.0014; rho = 0.4949), and no significant difference in the O2 saturation in retinal venules and arterioles in pwMS (mean: 60.0% and 93.7%; p = 0.5980) compared to HCs (mean: 59.3% and 91.5%; p = 0.8934), respectively. Conclusions: Our findings indicate that early in MS, changes in RNFL and A‐V diff are detectable, before patients develop any apparent/severe disease. We recommend inclusion of the peripapillary RNFL and A‐V diff in MS monitoring and research. [ABSTRACT FROM AUTHOR]

Background: Restriction spectrum imaging (RSI) is a recently introduced magnetic resonance imaging diffusion technique. The utility of RSI in multiple sclerosis (MS) is unknown. Objective: To investigate the association between RSI-derived parameters and neurological disability in MS. Methods: Seventy-seven relapsing–remitting MS patients were scanned with RSI on a 3-T scanner. RSI-derived parameters: fast and slow apparent diffusion coefficient (sADC), fractional anisotropy, restricted fractional anisotropy, neurite density (ND), cellularity, extracellular water fraction, and free water fraction, were obtained in white matter lesions (WML) and normal appearing white matter (NAWM). Patients were divided into three groups according to their expanded disability status scale (EDSS): with minimal, low, and substantial disability (<2.5, 2.5–3, and >3, respectively). Group comparisons and correlation analyses were performed. Results: All tested RSI-derived parameters differed between WML and NAWM (p < 0.001 for all pairwise comparisons). The sADC in WML showed largest difference across disability subgroups (analysis of variance (ANOVA): F = 5.1, η2 = 0.12, p = 0.008). ND in NAWM showed strongest correlation with disability (ϱ = –0.39, p < 0.001). Conclusion: The strongest correlation with EDSS of ND obtained in NAWM indicates that processes outside lesions are important for disability in MS. Our study suggests that RSI-derived parameters may help understand the "clinico-radiological paradox" and improve disease monitoring in MS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis-associated genetic variants indicate that the adaptive immune system plays an important role in the risk of developing multiple sclerosis. It is currently not well understood how these multiple sclerosis-associated genetic variants contribute to multiple sclerosis risk. CD4+ T cells are suggested to be involved in multiple sclerosis disease processes. Objective: We aim to identify CD4+ T cell differential gene expression between multiple sclerosis patients and healthy controls in order to understand better the role of these cells in multiple sclerosis. Methods: We applied RNA sequencing on CD4+ T cells from multiple sclerosis patients and healthy controls. Results: We did not identify significantly differentially expressed genes in CD4+ T cells from multiple sclerosis patients. Furthermore, pathway analyses did not identify enrichment for specific pathways in multiple sclerosis. When we investigated genes near multiple sclerosis-associated genetic variants, we did not observe significant enrichment of differentially expressed genes. Conclusion: We conclude that CD4+ T cells from multiple sclerosis patients do not show significant differential gene expression. Therefore, gene expression studies of all circulating CD4+ T cells may not result in viable biomarkers. Gene expression studies of more specific subsets of CD4+ T cells remain justified to understand better which CD4+ T cell subsets contribute to multiple sclerosis pathology. [ABSTRACT FROM AUTHOR]

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS. [ABSTRACT FROM AUTHOR]

• Fatigue is a frequent symptom which has a major impact on the quality of life in people with MS. • Socioeconomic factors are associated with fatigue in MS. • Considering socioeconomic factors may help us recognize persons at risk of having fatigue. 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. 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. 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 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. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the prevalence of multiple sclerosis (MS) in immigrants in Norway. The study used standardized prevalence ratio (SPR) to compare the prevalence of MS in different ethnic groups. The study concluded that the prevalence of MS among immigrants in the country reflects the uneven distribution worldwide.

• The paper present the study of a population-based Norwegian MS cohort, including 1314 persons with MS (pwMS). Detailed information on disease development and use of disease modifying treatment (DMT) was combined with data on socioeconomic factors. • The pwMS treated with DMT were younger at onset, had shorter time from onset to diagnosis and lower EDSS at diagnosis. • The subgroup treated with a high efficacy DMT as a first drug was younger and had 0.5 point higher EDSS score than those not treated with a high efficacy DMT as a first drug. • Level of education, household income and marital status were inversely related to access to high efficacy DMT as first drug. • We describe a change over time to current pattern where the pwMS are treated equally with DMT in term of different measures of socioeconomic position. 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. 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. 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). Since 2012, the pwMS in this Norwegian cohort are treated equally with DMT in terms of different measures of socioeconomic position. [ABSTRACT FROM AUTHOR]

The article focuses on the research which discusses the impact of established multiple sclerosis (MS) genetic variants on MS phenotypes. It states that the scores of total human leukocyte antigen (HLA) and non-HLA MS Genetic Burden (MSGB in MS patients were higher compared to control groups. It mentions that the MSGB score was linked with specific clinical MS characteristics.

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10−15) and rs3817963 (p = 5.7×10−10) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10−7). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied. [ABSTRACT FROM AUTHOR]

• The duration and features of the multiple sclerosis (MS) prodrome are not well defined. • We did not find a difference in days of absence or grades achieved in upper secondary school in the four years leading up to disease onset in cases compared to controls. • Nor did we find an association between time to disease onset and days of absence or grades. • A potential prodrome may not affect cognition enough to impact school achievements. The duration and features of the multiple sclerosis (MS) prodrome are not well defined. We aimed to ascertain whether people with a future MS diagnosis have more days of absence and perform worse in upper secondary school than age, gender and county-matched controls. Using registry data from the southeast of Norway, we identified people with MS born ≥1978. Statistics Norway provided information on grades and days of absence in cases and matched controls. We looked at absence in the three years of upper secondary school and grades in the compulsory subjects Norwegian, English, mathematics and physical education. We identified 107 cases with disease onset one year or more after graduation and 626 controls. There were no significant differences in absence or grades achieved in the population as a whole or in those with disease onset within four years of diagnosis, and no association between time to disease onset and days of absence or grades. There was no difference in days of absence or grades achieved in upper secondary school in the four years leading up to disease onset in cases compared to controls. A potential prodrome may not affect cognition enough to impact school achievements. [ABSTRACT FROM AUTHOR]

• The paper presents information on disease progression combined with socioeconomic factors in 1598 patients with multiple sclerosis recruited from a well-defined population in Norway. • High parental level of education at patient's age 16 was significantly associated with younger age and lower EDSS at disease onset, and shorter time from onset to diagnosis. • Maternal level of education has an impact on disease progression measured by MSSS similar to that of disease modifying treatment. The identification of potential risk factors for disease severity is of great importance in the treatment of multiple sclerosis. The influence of socioeconomic status on progression in multiple sclerosis (MS) is sparsely investigated. Our aim was to investigate how socioeconomic status in adolescence influences disease progression in later life. A total of 1598 patients with multiple sclerosis from a well-defined population in Norway were included. Detailed information on disease progression, measured by expanded disability status scale (EDSS) and multiple sclerosis severity score (MSSS), were combined with data on socioeconomic factors. We used residency and parental level of education at patients' age 16 and exposure to second-hand smoking as a measure of socioeconomic status in adolescence, adjusting for the same variables as well as use of disease modifying treatments at prevalence date 01.01.18. High maternal level of education at patients' age 16 was significantly associated with less pronounced disease progression measured by MSSS (β-coefficient -0.58, p = 0.015), younger age and lower EDSS at disease onset, and shorter time from onset to diagnosis. No significant associations were found for paternal education level and MSSS. The use of any disease modifying treatment before prevalence date was significantly associated with disease progression (β-coefficient -0.49, p=0.004), while residence, current and second-hand smoking were not. This study on a population-based, real-world cohort shows that the parental level of education has a significant impact on a timely diagnosis of MS. In addition to disease modifying treatment, maternal level of education also had an impact on disease progression in later life. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions We need more knowledge on clinical presentations, time course, biomarkers, and prognosis in European Lyme neuroborreliosis (LNB).A prospective 12‐month follow‐up of predetermined clinical and laboratory parameters was undertaken in 105 patients with LNB.At presentation, 79% had radiculopathy, 49% had facial palsy, and 13% had solely subjective symptoms (predominately pain). Intrathecally produced Borrelia burgdorferi (Bb) antibodies were demonstrated and cerebrospinal fluid (CSF) CXCL13 was positive in 85% and 82% pretreatment, in 73% and 10% at 6 months, and in 58% and 14% at 12 months, respectively. CSF Bb polymerase chain reaction (PCR) was positive in 40% pretreatment. In four patients who tested negative for Bb antibodies in both serum and CSF, the diagnosis was supported by typical clinical features, pleocytosis, CSF Bb‐PCR (n = 1), or CSF CXCL13 (n = 2). The proportion with symptoms influencing daily life was 91% pretreatment, 25% at 10 weeks, 20% at 6 months, and 15% at 12 months. Fatigue was the most common complaint at 12 months. A high burden of symptoms before and after treatment was associated with residual complaints at 12 months, whereas background data, other clinical features, and laboratory features were not.LNB can present with solely subjective symptoms, especially pain. Many LNB patients have persistent Bb antibodies in serum and CSF. In seronegative LNB, CSF Bb‐PCR and CXCL13 may give diagnostic support. CXCL13 may be persistently positive after treatment in some patients. Most of the clinical improvement occurs during the first 10 weeks. High initial clinical score is associated with poorer outcome. [ABSTRACT FROM AUTHOR]

We describe a patient with apparently sporadic amyotrophic lateral sclerosis (SALS) with a novel g>c point mutation at position 382 in the SOD1 gene, leading to a substitution of glycine for arginine in amino acid position 127 (G127R). The disease presented with flaccid leg paresis, and progressed rapidly with generalized paresis resulting in respiratory failure after seven months. In addition to a predominating lower motor neuron syndrome, the phenotype was characterized by a severe lower back and leg pain syndrome which was treated successfully with spinal anaesthesia. [ABSTRACT FROM AUTHOR]

Background: Diagnostic criteria for multiple sclerosis have been developed to guide the diagnostic process. In the latest revision of the McDonald criteria, the presence of oligoclonal bands may replace the need for dissemination in time. The aim of this study is to investigate if the less time-consuming analysis of immunoglobulin G index in cerebrospinal fluid can safely predict the findings of oligoclonal bands. Methods: This is a retrospective study of patients with multiple sclerosis at three hospitals in South-East Norway where lumbar puncture is performed routinely. We included patients diagnosed with multiple sclerosis after 2005 with known oligoclonal band status and an immunoglobulin G index score. Results: Of 1295 patients diagnosed during or after 2005, 93.8% were oligoclonal band positive at diagnosis. Of 842 multiple sclerosis patients with known immunoglobulin G index and oligoclonal band status, 93.3% were oligoclonal band positive and 76.7% had an elevated immunoglobulin G index. The positive predictive value of a high immunoglobulin G index when oligoclonal bands are positive was 99.4% (95% confidence interval 98.4–99.8%). The negative predictive value of a normal immunoglobulin G index when oligoclonal bands are negative was 26.5% (95% confidence interval 23.5–29.9%). Conclusion: An immunoglobulin G index >0.7 has a positive predictive value >99% for oligoclonal bands. An elevated immunoglobulin G index adds diagnostic value versus oligoclonal bands and saves time in the diagnostic process. [ABSTRACT FROM AUTHOR]

Purpose: Structural and physiological abnormalities have been reported in the retina in patients with multiple sclerosis (MS). Retinal oximetry has recently detected changes in retinal oxygen metabolism in Alzheimer's disease, mild cognitive impairment and in a small cohort of MS patients with history of optic neuritis. Our goal was to determine whether oxygen saturation in retinal blood vessels of newly diagnosed MS patients is different from that of a healthy population. Methods: Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric non‐invasive retinal oximeter. Six newly diagnosed MS patients were measured and compared to six healthy individuals that were age‐ and gender‐matched with the MS patients. Results: Venular oxygen saturation was increased in patients with MS compared to healthy individuals (mean: 61.9% versus 56.3%). Retinal venular diameter (138.2 µm versus 160.2 µm: mean) and retinal arteriolar diameter were smaller in MS patients (111.8 µm versus 131.3 µm: mean) when compared to healthy individuals. No big difference could be measured in the oxygen saturation in arterioles when patients with MS (mean: 91.2%) and healthy individuals (mean: 92.3%) were compared. Conclusion: Increased venular oxygen saturation and smaller retinal venular and arteriolar diameter in patients with MS may indicate reduced oxygen uptake in the retina. This may be due to less oxygen demand following axonal loss and may be a useful objective biomarker for MS. Further studies are needed to confirm and expand these findings. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood–brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset. Methods: In the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography–tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing–remitting MS and 14 age- and sex-matched healthy controls. Results: An overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes. Conclusion: Our study provides evidence for proteomic differences in T cells from relapsing–remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Author CS has received personal compensation for lectures and/or serving on scientific advisory boards from Sanofi, Merck, Novartis, BMS, and Biogen Idec and received unrestricted research grants from Sanofi and Novartis. Author HF has received unrestricted research grants from Biogen Idec and Novartis. Author KB has received personal compensation for lectures and/or serving on advisory boards from Biogen, Novartis, and Merck. Author LB has received unrestricted research grants from Sanofi, and advisory board honoraria from Sanofi, Merck, and Biogen. Author PB-H has received advisory board and/or speaker honoraria from Novartis, UCB, Teva, Merck, and Biogen Idec. Author EC has received personal compensation for lectures and / or serving on scientific advisory boards for Almirall, Biogen, BMS, Janssen, Genzyme, Merck, Novartis, Roche, and Teva. Her department has received unrestricted research grants from Biogen, Novartis, Merck, and Genzyme. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Simonsen, Flemmen, Broch, Brekke, Brunborg, Berg-Hansen and Celius.)

Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation., Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort., Methods: MS patients ( n  = 309) were prospectively enrolled at four centres and re-examined after 2 years ( n  = 226). NfL concentration was measured by single molecule array assay in serum. The patients' phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up., Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5-5.3), p  = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening., Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting.

Background: Multiple sclerosis-associated genetic variants indicate that the adaptive immune system plays an important role in the risk of developing multiple sclerosis. It is currently not well understood how these multiple sclerosis-associated genetic variants contribute to multiple sclerosis risk. CD4 + T cells are suggested to be involved in multiple sclerosis disease processes., Objective: We aim to identify CD4 + T cell differential gene expression between multiple sclerosis patients and healthy controls in order to understand better the role of these cells in multiple sclerosis., Methods: We applied RNA sequencing on CD4 + T cells from multiple sclerosis patients and healthy controls., Results: We did not identify significantly differentially expressed genes in CD4 + T cells from multiple sclerosis patients. Furthermore, pathway analyses did not identify enrichment for specific pathways in multiple sclerosis. When we investigated genes near multiple sclerosis-associated genetic variants, we did not observe significant enrichment of differentially expressed genes., Conclusion: We conclude that CD4 + T cells from multiple sclerosis patients do not show significant differential gene expression. Therefore, gene expression studies of all circulating CD4 + T cells may not result in viable biomarkers. Gene expression studies of more specific subsets of CD4 + T cells remain justified to understand better which CD4 + T cell subsets contribute to multiple sclerosis pathology.

Background: Restriction spectrum imaging (RSI) is a recently introduced magnetic resonance imaging diffusion technique. The utility of RSI in multiple sclerosis (MS) is unknown., Objective: To investigate the association between RSI-derived parameters and neurological disability in MS., Methods: Seventy-seven relapsing-remitting MS patients were scanned with RSI on a 3-T scanner. RSI-derived parameters: fast and slow apparent diffusion coefficient (sADC), fractional anisotropy, restricted fractional anisotropy, neurite density (ND), cellularity, extracellular water fraction, and free water fraction, were obtained in white matter lesions (WML) and normal appearing white matter (NAWM). Patients were divided into three groups according to their expanded disability status scale (EDSS): with minimal, low, and substantial disability (<2.5, 2.5-3, and >3, respectively). Group comparisons and correlation analyses were performed., Results: All tested RSI-derived parameters differed between WML and NAWM ( p < 0.001 for all pairwise comparisons). The sADC in WML showed largest difference across disability subgroups (analysis of variance (ANOVA): F = 5.1, η 2  = 0.12, p = 0.008). ND in NAWM showed strongest correlation with disability (ϱ = -0.39, p < 0.001)., Conclusion: The strongest correlation with EDSS of ND obtained in NAWM indicates that processes outside lesions are important for disability in MS. Our study suggests that RSI-derived parameters may help understand the "clinico-radiological paradox" and improve disease monitoring in MS.

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS., Competing Interests: Dipen P. Sangurdekar and Paola G. Bronson are employees at Biogen, Inc. Stine Marit Moen reports an unrestricted travel grant from Biogen Idec and speaker's fees from Biogen Idec and Novartis. Hanne F. Harbo reports personal fees from Biogen Norway, Merck Norway, and Genzyme Norway, and grants and personal fees from Novartis Norway. Pål Berg-Hansen reports grants and personal fees from Novartis and personal fees from Biogen Idec and Teva. Jeannette Lechner-Scott reports grants and personal fees from Biogen, Novartis, and TEVA, and personal fees from Sanofi Genzyme, Roche, and Merck. Tone Berge reports unrestricted grants from Biogen Idec and Sanofi Genzyme. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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.

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.