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Notes how a female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients has been demonstrated in many countries around the world, but without a direct comparison of sex ratio time-trends among MS populations from different geographical areas. Assesses and compares sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. Includes a cohort with definite MS, and birth years ranging from 1930 to 1989, extracted from the New Zealand MS database. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

BackgroundPrimary progressive multiple sclerosis (PPMS) is an infrequent clinical form of multiple sclerosis (MS). Scarce information is available about PPMS in Latin America. The aim of this work is to describe the clinical and demographic characteristics of PPMS patients in Argentina.Material and methodsRelevarEM is a longitudinal, strictly observational registry in Argentina. Clinical and epidemiological data from PPMS patients were described.ResultsThere were 144 cases of PPMS. They represented 7% of MS patients. The mean age was 44.1 years. The female:male ratio was 1.08. The mean Expanded Disability Status Scale (EDSS) score was 5.5 and the mean disease evolution time was 10.6 years. Oligoclonal bands were found in 72.9%. At the time of diagnosis, magnetic resonance imaging showed spinal cord lesions in 82.6% and contrast-enhancing brain lesions in 18.1% of patients. Almost one third of patients were treated with a disease-modifying drug, and ocrelizumab was the most frequently used (55.8%).ConclusionsPPMS is an infrequent subtype of MS and its recognition is of the highest importance as it has its own evolution, treatment, and prognosis. The importance of our research resides in providing local data and contributing to a better understanding of PPMS and its treatment in Latin America.

The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients’ access to medical facilities and MS specialists. •The mean time from clinical symptoms onset to diagnosis of MS was 13.42 months.•in cases registered in the National MS Registry of Iran.•More than half of the MS cases were diagnosed within one-month interval.•Age at symptoms onset, age at the time of diagnosis, male sex and type of MS.•were associated factors to a late diagnosis in Iranian MS subjects.

ObjectiveInvestigate the incidence of multiple sclerosis during 1953–2013 and estimate the prevalence rate of MS on 1 January 2003 and 2013 in Hordaland County, Western Norway.MethodsAll patients with onset of disease in Hordaland 1953–2013 were identified in files from previous studies until 2003 and from patient records at the departments of Neurology, Haukeland University Hospital and Haugesund Hospital during 2003–2013. 1558 patients were assessed and 1402 of these were included, of whom 1035 were alive and living in Hordaland at prevalence day 1 January 2013. Annual incidence rates were calculated for 1953–2013.ResultsOn 1 January 2003, the crude prevalence rate was 191/100 000 population and on 1 January 2013, the crude prevalence rate was 211.4 (95% CI 198.3 to 224.2) per 100 000; 270.9 (95% CI 250.6 to 292.3) for women and 151.8 (95% CI 136.8 to 167.9) for men. Prevalence peaked at ages 55–59 years for women and 60–64 years for men. The annual incidence rate increased from 1.9 (95% CI 1.2 to 2.6) per 100 000 during 1953–1957 to 7.2 (95% CI 6.0 to 8.5) during 1978–1982 and to 8.5 (95% CI 7.3 to 9.7) during 2003–2007, thus indicating a stabilising incidence over the past 35 years. The female/male ratio ranged from 1.2:1 to 1.8:1 (p=0.381) during the period.ConclusionsStabilising rather than increasing incidence combined with the stable female/male ratio are indicative of non-fluctuating environmental factors in a geographical area otherwise characterised by lack of vitamin D effective sun exposure. The rising prevalence of MS could result from improved survival and follow-up methodology.

BackgroundStress is a potential trigger for clinical and radiological activity in Multiple Sclerosis (MS). COVID-19 pandemic has been a relevant source of mental distress in people with MS (pwMS) and deeply impacted on disease management.ObjectiveTo investigate the association between stress, anxiety, depression, and risk of relapse during the COVID-19 pandemic.MethodsFrom an electronic database used for clinical practice, we extracted data of relapsing–remitting (RR) or relapsing-progressive (RP) MS patients and calculated the annualized relapse rate (ARR) during 2019 and 2020. From 01/12/2020 to 30/12/2020, enrolled patients were invited to fill in a Google Forms survey to investigate depression, anxiety, stress, and Post-Traumatic Stress Disorder (PTSD).ResultsWe selected 216 patients with RR or RP-MS to calculate ARR: compared to 2019, in 2020 there was a significant increase in ARR (p = 0.0142).Over 216 selected pwMS, 154 completed the survey. Matching the survey responses and incidence of relapses in 2020, there was a significant association between relapses and stress (p = 0.030) and relapses and depression (p = 0.011), but not between relapses and anxiety (p = 0.130) or PTSD (p = 0.279).ConclusionsOur results support the hypothesis that pandemic-related stress is associated to clinical exacerbations, both as a possible consequence of the COVID-19 impact on MS care.

To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades. We define the \"genetically-susceptible\" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive \"non-susceptible\" subset (G-). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure. We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men. The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.

ABSTRACT Background Epstein–Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that HLA‐E*01:03, in contrast to HLA‐E*01:01, may protect against MS through more effective immune responses against EBV‐infected B cells. However, the role of HLA‐E*01 in MS remains unclear. Methods We investigated if HLA‐E*01:01 was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between HLA‐E*01:01 and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS‐related HLA alleles (e.g., HLA‐DRB1*15:01). Results HLA‐E*01:01 allele alone was not significantly associated with IM or MS (p > 0.05). However, a significant interaction between HLA‐E*01:01 and IM history was observed in relation to MS risk (p < 0.001). Specifically, MS risk was significantly higher in both HLA‐E*01:01 heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], p < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], p < 0.001) with IM history, compared to HLA‐E*01:03 homozygotes. Conversely, these associations were non‐significant in individuals without IM history (p > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in HLA‐E*01:01 heterozygotes and 65% in HLA‐E*01:01 homozygotes. Conclusions HLA‐E*01:01 carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS‐related HLA alleles. This supports the hypothesis that HLA‐E*01:01 may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating HLA‐E*01:01 into existing MHC‐based MS risk models could then enhance personalized risk assessments in individuals with IM history.

Summary Introduction Multiple sclerosis (MS) is an autoimmune disease of the CNS, which predominantly affects women. Studies investigating the sex distribution in MS are sparse. We aim to analyze the female‐to‐male ratio (F/M ratio) in different MS phenotypes in association with age at diagnosis and year of birth. Methods We performed a retrospective cross‐sectional analysis by cumulating data (sex, year of birth, age at diagnosis, and MS phenotypes) from unpublished and published studies of the participating centers. Results Datasets of 945 patients were collected. The overall F/M ratio was 1.9:1.0 and female preponderance was present in all phenotypes except for primary progressive MS (PPMS), in which men were predominantly affected (F/M ratio: 0.5:1.0). Female preponderance declined with increasing age at diagnosis and was no longer present in relapsing‐remitting MS (RRMS) patients > 58 years of age. Conclusion Our data demonstrate an age dependency of female preponderance in MS except for PPMS. This could be influenced by the lifecycle of sex hormone secretion in women. In PPMS, a male preponderance was observed in all age‐groups, which might point to pathophysiological mechanisms being less influenced by sex hormones.

ABSTRACT Background We aimed to provide updated evidence from the current literature regarding pediatric environmental factors associated with the risk of developing multiple sclerosis (MS). Methods Articles were searched in PubMed, SciVerse ScienceDirect, and Web of Science. We included all clinical studies assessing the occurrence of MS at any age in association with the exposure to any environmental risk factor during childhood or adolescence. The main outcome was the occurrence of MS. The quality assessment was performed with the critical appraisal checklist for case–control studies. Pooled unadjusted effect sizes (OR) were calculated and reported with a 95% CI from random‐effects meta‐analysis. Results The review included 87 studies conducted across 20 countries. The studies analyzed diverse environmental risk factors, including infections, vaccinations, tobacco exposure, body mass index, and other pediatric exposures. EBV infection showed a significant positive association with MS risk (ES = 2.38, 95% CI = 1.80–3.15). Breastfeeding showed limited protective associations, and various adverse social experiences like bullying and sexual abuse were linked to increased MS risk. Active smoking during childhood/adolescence and obesity during these periods were associated with higher MS risk, while normal body mass index was protective. Antibiotic and chemical exposures, as well as vitamin D deficiency, were linked to higher MS risk. The review highlighted substantial heterogeneity and identified publication bias in studies on infections and vaccinations. Conclusions Environmental risk factors for MS are important during childhood and adolescence. The first 20 years are a key window for prevention and should be seen as an opportunity. The review analyzed 87 studies from 20 countries on environmental risk factors for MS. EBV infection increased MS risk, while breastfeeding showed limited protection. Adverse social experiences, active smoking, and obesity in childhood/adolescence raised risk, whereas normal BMI was protective. Antibiotic and chemical exposures, along with vitamin D deficiency, were also linked to higher MS risk.

Objectives To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution. Methods Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan–Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression. Results The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p<0.001). Shorter latency to SP was associated with shorter times to severe disability. The same association was found even when patients were grouped by number of total relapses before progression. However, the evolution of the SP phase was not influenced by the duration of the RR phase. Male sex (HR=1.41; p<0.001), older age at onset (age ≤20 and 21–30 vs >30 HR=0.52 (p<0.001), 0.65 (p<0.001), respectively) and high early relapse frequency (1–2 attacks vs ≥3 HR=0.63 (p<0.001), 0.75 (p=0.04), respectively) predicted significantly higher risk of SP MS and shorter latency to progression. Times to DSS 8 from onset of progression were significantly shorter among those with high early relapse frequency (≥3 attacks), and among those presenting with cerebellar and brainstem symptoms. Conclusions The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.