High Risk For Multiple Sclerosis Research Articles

Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis

Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Prevalence and Incidence of Multiple Sclerosis in the City of Biancavilla

Background: It is common that the epidemiology of multiple sclerosis (MS) varies with geography and ethnicity. Recent studies show a continuous growth of incidence and prevalence in Sicily, despite the controversial “latitude gradient theory.” Objectives: The aim of our study is to ascertain incidence and prevalence rates of MS in the city of Biancavilla, Sicily, Southern Italy. Method: Case ascertainment approach and a clinical database collecting data of MS cases to Biancavilla, according to McDonald 2011 and Thompson 2018 criteria, from 1992 to 2018, have been used to the study. We further collected information regarding the familiarity of patients with Mesothelioma, highly incident in this geographic area. Results: The results showed an increase of the mean annual incidence for the period 2012–2018 (16.8/100,000) compared to 1992–1996 (4.5/100,000), and a standardized incidence ratio of 1.41 (95% CI 0.74–2.45). On December 31, 2018, 70 patients suffering from definite MS and living in Biancavilla yielded a crude prevalence of 292.3 per 100,000 (198.2/100,000 for men; 380.7/100,000 for women) with a standardized morbidity ratio of 2.3 (95% CI 1.8–2.9). Conclusions: Our data confirmed Biancavilla is an area at high risk for MS, ascribable to increased survival, improved ascertainment, or maybe related to a genetic or environmental risk. At the time, any relation with mesothelioma was excluded.

GP.01 Childhood obesity and multiple sclerosis susceptibility: a Mendelian randomization study

Background: Observational studies have reported an association between childhood obesity and a higher risk of multiple sclerosis (MS). However, the difficulties to fully account for confounding and long recall periods make causal inference from these studies challenging. The objective of this study was to assess the contribution of childhood obesity to the development of MS through Mendelian randomization, which uses genetic associations to minimize the risk of confounding. Methods: We selected 23 independent genetic variants strongly associated with childhood body mass index (BMI) in a genome-wide association study (GWAS) which included 47,541 children. The corresponding effects of these variants on risk of MS were obtained from a GWAS of 14,802 MS cases and 26,703 controls. Standard two-sample Mendelian randomization methods were performed, with additional sensitivity analyses to assess the likelihood of bias from genetic pleiotropy. Results: The inverse-variance weighted MR analysis revealed that one standard deviation increase in childhood BMI increased odds of MS by 26% (odds ratio=1.26, 95% confidence interval 1.10-1.45, p=0.001). There was no significant heterogeneity across the individual estimates. Sensitivity analyses were consistent with the main findings and provided no evidence of pleiotropy. Conclusions: This study provides genetic support of a role for increased childhood BMI in the development of MS.

Prevalence of multiple sclerosis in an urban population of Sivas province in Turkey

Background/aimMultiple sclerosis (MS) is a common neurological disorder that can be a leading cause of nontraumatic disability in several countries. Recent reports have indicated a moderate to high risk of MS in European countries. In this study, we examined the prevalence of MS in a well-defined urban population of provincial center in Sivas Province in Turkey.Materials and methodsThis study sampled all registered residents of urban areas of provincial center in Sivas Province in April 2017 and 2018 January. All the included patients met the McDonald 2010 criteria. Medical records were reviewed, including all available previously acquired magnetic resonance imaging data. All patients were subsequently subjected to neurologic examination to confirm the MS diagnosis.ResultsWe identified 21 possible MS patients, with MS diagnosis confirmed in 19. The prevalence of MS was 288 per 100,000 inhabitants. ConclusionFor future studies, these high ratio results can be used in regional and national comparisons to determine cofactors contributing to the high prevalence of MS in our region and can help health-decision makers to better plan healthcare policies to improve neurological services and awareness about multifaceted clinical presentations of MS.

Multiple Sclerosis in Italy: A 40-Year Follow-Up of the Prevalence in Ferrara

Background: To assess a longitudinal follow-up of the prevalence of multiple sclerosis (MS) through 4 decades in the province of Ferrara, northern Italy, and reappraise the current rates on December 31, 2016. Methods: We conducted a community-based intensive prevalence study, by adopting a complete enumeration approach. MS cases were identified from administrative health data and medical records from the Units of Neurology and Motor Rehabilitation, Ferrara University Hospital, from other provincial neurological structures and from archives of the National Pension Institute and National Health Insurance scheme of the study area. Case ascertainment method and case definition are analogous to those adopted in previous surveys in the same area of study. Results: On December 31, 2016, 685 patients (478 women and 207 men) affected by definite or probable MS (Poser’s criteria) were living in the province of Ferrara (population 386,896), yielding a crude prevalence ratio of 194.91 (95% CI 180.4–209.6) per 100,000, 260.8 (95% CI 238.10–285.82) for women and 123.1 (95% CI 106.98–141.21) for men The prevalence ratio was 26.9 per 100,000 in 1978, increased to a value of 46.1 per 100,000 in 1981, 69.4 per 100,000 in 1993, 120.9 per 100,000 in 2004. Female to male ratio was 2.31 (1.2 on December 31, 1978). The mean duration of the disease at prevalence day was 17.5 ± 11.9 years (13.9 ± 10.8 years in 1978). The mean age at prevalence day was 52.04 ± 10.8 years (13.8 ± 10.8 years in 1978). Conclusion: Our study has confirmed the province of Ferrara is an area at high risk for MS, in line with epidemiological data from the regions of continental and insular Italy. The sharp increase in MS prevalence over time in this population can be imputed in part to a greater exposition to risk factors in genetically susceptible subjects but also to an increased survival and improved ascertainment. So, the results suggest that both methodologic and environmental factors are essential in determining the real distribution of MS. The need to get reliable estimates of MS prevalence must be highlighted as a public health and research priority, essential to support planning and prioritization of care services and to reduce the overall burden of chronic disease.

A healthy dietary pattern associates with a lower risk of a first clinical diagnosis of central nervous system demyelination

Background: The evidence associating diet and risk of multiple sclerosis is inconclusive. Objective: We investigated associations between dietary patterns and risk of a first clinical diagnosis of central nervous system demyelination, a common precursor to multiple sclerosis. Methods: We used data from the 2003–2006 Ausimmune Study, a case–control study examining environmental risk factors for a first clinical diagnosis of central nervous system demyelination, with participants matched on age, sex and study region. Using data from a food frequency questionnaire, dietary patterns were identified using principal component analysis. Conditional logistic regression models (n = 698, 252 cases, 446 controls) were adjusted for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, race, education, body mass index and dietary misreporting. Results: We identified two major dietary patterns – healthy (high in poultry, fish, eggs, vegetables, legumes) and Western (high in meat, full-fat dairy; low in wholegrains, nuts, fresh fruit, low-fat dairy), explaining 9.3% and 7.5% of variability in diet, respectively. A one-standard deviation increase in the healthy pattern score was associated with a 25% reduced risk of a first clinical diagnosis of central nervous system demyelination (adjusted odds ratio 0.75; 95% confidence interval 0.60, 0.94; p = 0.011). There was no statistically significant association between the Western dietary pattern and risk of a first clinical diagnosis of central nervous system demyelination. Conclusion: Following healthy eating guidelines may be beneficial for those at high risk of multiple sclerosis.

Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity.

Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in CD4 T effector cells, but not CD4 regulatory T cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T effector cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype dependent, whereby high VitD: (1) was protective, (2) had no effect, and (3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex specific and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation. Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype dependent and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.

Multiple sclerosis in the Republic of San Marino, Italian peninsula: an incidence and prevalence study from a high-risk area.

Epidemiological studies on multiple sclerosis (MS) carried out in Southern Europe in the last years have shown a significant increase in the disease frequency. Previous surveys conducted in the Republic of San Marino, Northern Italian peninsula, identifiedthat the population is at high risk for MS, with a prevalence of 51.6 per 100,000 population in 1982 and of 166.7 in 2005 and with a mean annual incidence of 7.9 per 100,000 for the period 1990-2005. The present work is a community-based intensive prevalence and incidence survey, by a complete enumeration approach,to update the prevalence and incidence of MS in the Republic of San Marino. The mean annual incidence for the period 2005-14 was 7.7 (95% CI 4.9-11.4) per 100,000, 3.3 (95% CI 1.1-7.6) for men and 11.9 (95% CI 7.2-18.6) for women. On 31 December 2014, 67 patients (19 men and 48 women), suffering from definite or probable MS and living in the Republic of San Marino, yielded a crude prevalence of 204.3 (95% CI 158.4-259.5) per 100,000, 117.8 (95% CI 70.9-183.7) for men and 288.2 (95% CI 212.4-383.3) for women. Our study has confirmed San Marino is an area at high risk for MS, in line with epidemiological data from continental Italy. The marked increase in MS prevalence over time in this population can be ascribable to increased survival and improved ascertainment, in the presence of a substantially stable, yet high, incidence rate.

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10−5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35–2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13–1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

Environmental Risk Factors for Multiple Sclerosis: A Case-control Study in Kerman, Iran.

Background:Several studies have addressed the environmental risk factors for multiple sclerosis (MS). Concerning contradictory results and change of epidemiologic patterns and the role of environmental factors, in the present study, some risk factors, especially environmental factors, on MS were studied.Materials and Methods:This was a retrospective case-control study conducted among 120 patients with MS and 360 healthy individuals in Kerman, Iran. Inclusion criteria included (1) MS disease, diagnosed by a neurologist according to the McDonald criteria, and (2) tendency to participation in the study. Exclusion criteria included (1) suffering from cognitive disorders; (2) incomplete questionnaire; and (3) continuous migration. Data were collected using a questionnaire consisting of personal information and some environmental factors. Data were analyzed using descriptive and inferential statistics.Results:The results showed that diet was associated with a higher risk of MS with the odds ratio (OR) of 14.46 and 95% confidence interval (CI) of 3.02–69.21 (p < 0.001) for vegetarian and OR of 11.74, 95% CI of 4.66–29.57 (p < 0.001) for animal diets. Similarly, vitamin D supplementation contributed to MS risk (OR: 2.27, 95% CI: 1.32–3.89; p < 0.001). In contrast, history of using cow's milk during infancy resulted in a lower risk of MS (OR: 0.33, 95% CI: 0.20–0.52, p < 0.001).Conclusions:This study suggests that different lifestyles including using cow's milk during infancy and avoiding only vegetarian and animal diets may reduce MS risk in southeastern Iran. More studies are suggested to investigate the controversial finding of the negative effect of vitamin D supplementation in this area.

The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults

BackgroundWhile common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. MethodsGenotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. ResultsFor pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18–2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05–3.03, p = 0.026). ConclusionsOur results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.

Diffusion Tensor Imaging as a Biomarker to Differentiate Acute Disseminated Encephalomyelitis From Multiple Sclerosis at First Demyelination

BackgroundThere are no clinical features or biomarkers that can reliably differentiate acute disseminated encephalomyelitis from multiple sclerosis at the first demyelination attack. Consequently, a final diagnosis is sometimes delayed by months and years of follow-up. Early treatment for multiple sclerosis is recommended to reduce long-term disability. Therefore, we intend to explore neuroimaging biomarkers that can reliably distinguish between the two diagnoses. MethodsWe reviewed prospectively collected clinical, standard MRI and diffusion tensor imaging data from 12 pediatric patients who presented with acute demyelination with and without encephalopathy. Patients were followed for an average of 6.5 years to determine the accuracy of final diagnosis. Final diagnosis was determined using 2013 International Pediatric MS Study Group criteria. Control subjects consisted of four age-matched healthy individuals for each patient. ResultsThe study population consisted of six patients with central nervous system demyelination with encephalopathy with a presumed diagnosis of acute disseminated encephalomyelitis and six without encephalopathy with a presumed diagnosis of multiple sclerosis or clinically isolated syndrome at high risk for multiple sclerosis. During follow-up, two patients with initial diagnosis of acute disseminated encephalomyelitis were later diagnosed with multiple sclerosis. Diffusion tensor imaging region of interest analysis of baseline scans showed differences between final diagnosis of multiple sclerosis and acute disseminated encephalomyelitis patients, whereby low fractional anisotropy and high radial diffusivity occurred in multiple sclerosis patients compared with acute disseminated encephalomyelitis patients and the age-matched controls. ConclusionsFractional anisotropy and radial diffusivity measures may have the potential to serve as biomarkers for distinguishing acute disseminated encephalomyelitis from multiple sclerosis at the onset.

25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort.

To determine whether and to what extent vitamin D deficiency is associated with multiple sclerosis (MS) risk. We conducted a prospective nested case-control study among women in the Finnish Maternity Cohort (FMC). The FMC had 1.8 million stored serum samples taken during the pregnancies of over 800,000 women at the time of this study. Through linkages with hospital and prescription registries, we identified 1,092 women with MS diagnosed between 1983 and 2009 with at least 1 serum sample collected prior to date of MS diagnosis; ≥2 serum samples were available for 511 cases. Cases were matched to up to 3 controls (n = 2,123) on date of birth (±2 years) and area of residence. 25-Hydroxyvitamin D (25[OH]D) levels were measured using a chemiluminescence assay. We used conditional logistic regression adjusted for year of sample collection, gravidity, and parity to estimate relative risks (RRs) and 95% confidence intervals (CIs). A 50 nmol/L increase in 25(OH)D was associated with a 39% reduced risk of MS (RR 0.61, 95% CI 0.44-0.85), p = 0.003. Women with 25(OH)D levels <30 nmol/L had a 43% higher MS risk (RR 1.43, 95% CI 1.02-1.99, p = 0.04) as compared to women with levels ≥50 nmol/L. In women with ≥2 samples, MS risk was 2-fold higher in women with 25(OH)D <30 nmol/L as compared to women with 25(OH)D ≥50 nmol/L (RR 2.02, 95% CI 1.18-3.45, p = 0.01). These results directly support vitamin D deficiency as a risk factor for MS and strengthen the rationale for broad public health interventions to improve vitamin D levels.

Cognitive impairment and structural brain changes in patients with clinically isolated syndrome at high risk for multiple sclerosis.

Patients with clinically isolated syndrome (CIS), unlike those with multiple sclerosis (MS), have a selective cognitive impairment which is not consistently related to structural brain changes. Our objective was to characterize a profile of cognitive impairment and its association with structural brain changes in patients with CIS who are at high risk of developing MS. Patients with CIS at high risk for MS on interferon-beta (n=51) and age-, gender-, and education-matched controls (n=44) underwent comprehensive neuropsychological testing and MRI brain scan with voxel-based morphometry. The CIS group had lower cognitive performance in verbal and nonverbal memory, information processing speed/attention/working memory, and executive and visuo-spatial functions compared to controls (p≤0.040). Lower cognitive performance was present in 18-37 and 14-26% of patients with CIS at high risk for MS depending on the criteria used. Brain volume was reduced predominantly in fronto-temporal regions and the thalamus in the CIS group (p≤0.019). Cognitive performance was not associated with structural brain changes except for the association between worse visuo-spatial performance and lower white matter volume in the CIS group (β=0.29; p=0.042). Our results indicated that patients with CIS at high risk for MS may have a pattern of lower cognitive performance and regional brain atrophy similar to that found in patients with MS. Lower cognitive performance may be present in up to one-third of patients with CIS at high risk for MS, but, unlike patients with MS, variability in their cognitive performance may lead to a lack of consistent associations with structural brain changes.

Disease course after clinically isolated syndrome in children versus adults: a prospective cohort study.

Clinically isolated syndrome (CIS) is a first demyelinating event of the central nervous system and can be a single event. After CIS, a chronic disease course with ongoing inflammation and relapses might occur, resulting in a diagnosis of multiple sclerosis (MS). As yet, there has been no prospective exploration of whether children and adults with CIS have the same disease course. Patients with CIS, whose age ranged from 1 to 50 years, were prospectively followed. We divided the patients into three different age groups, i.e. 1-10, 11-17 and 18-50 years old. Demographic data, disease course, time to MS diagnosis and annualized relapse rates (ARRs) were compared among these groups. We included 383 patients with CIS, of whom 218 (56.9%) were diagnosed with MS. Children of between 11 and 17 years old had the highest rate of MS conversion (83.5% vs. 50.0% in the other age groups together, P < 0.01) and the shortest time to MS diagnosis [median time 2.6 months (interquartile range, 0.6-6.0) vs. 8.2 months (interquartile range, 1.9-28.2) in the other age groups together, P < 0.01). ARRs corrected for follow-up were higher in children of <18 years old than in adults of ≥18 years old with MS (mean ARR, 0.65 vs. 0.43, P < 0.01). Children with CIS tend to have a more inflammatory disease course appearing from higher ARRs in all children and the highest rate of MS conversion in 11-17-year-old children. This supports early initiation of disease-modifying therapy in children, perhaps even at the first event in children at high risk for MS in line with clinical practice in adults.

Dietary Inflammatory Index and Risk of Multiple Sclerosis in a Case-Control Study from Iran

Background: Diet and inflammation have been suggested to be important risk factors for multiple sclerosis (MS). Objectives: In this study, we examined the ability of the dietary inflammatory index (DII) to predict MS in a case-control study conducted in Iran. Methods: This study included 68 MS cases and 140 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a previously validated food frequency questionnaire. Logistic regression models were used to estimate ORs adjusted for age, energy, sex, body mass index, season of birth, rubella history, history of routine exercise before MS, smoking and history of consumption of cow's milk in the first 2 years of life. Results: Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of MS, with the DII being used both as a continuous variable (OR_continuous 1.66; 95% CI 1.19-2.31; 1 unit increase corresponding to ≈15% of its range in the current study) and a categorical variable (OR_{DII (>1.43 vs.}_≤_1.43) 2.68; 95% CI 1.15-6.26). Conclusions: These results indicate that a pro-inflammatory diet is associated with increased risk of MS.

The risk of smoking on multiple sclerosis: a meta-analysis based on 20,626 cases from case-control and cohort studies.

Background. Multiple sclerosis (MS) has become a disease that represents a tremendous burden on patients, families, and societies. The exact etiology of MS is still unclear, but it is believed that a combination of genetic and environmental factors contribute to this disease. Although some meta-analyses on the association between smoking and MS have been previously published, a number of new studies with larger population data have published since then. Consequently, these additional critical articles need to be taken into consideration.Method. We reviewed articles by searching in PubMed and EMBASE. Both conservative and non-conservative models were used to investigate the association between smoking and the susceptibility to MS. We also explored the effect of smoking on the susceptibility to MS in strata of different genders and smoking habits. The association between passive smoking and MS was also explored.Results.The results of this study suggest that smoking is a risk factor for MS (conservative model: odds ratio (OR) 1.55, 95% CI [1.48–1.62], p < 0.001; non-conservative model: 1.57, 95% CI [1.50–1.64], p < 0.001). Smoking appears to increase the risk of MS more in men than in women and in current smokers more than in past smokers. People who exposed to passive smoking have higher risk of MS than those unexposed.Conclusion.This study demonstrated that exposure to smoking is an important risk factor for MS. People will benefit from smoking cessation, and policymakers should pay attention to the association between smoking and MS.

Epidemiology of multiple sclerosis

Multiple sclerosis (MS) is the most frequently seen demyelinating disease, with a prevalence that varies considerably, from high levels in North America and Europe (>100/100,000 inhabitants) to low rates in Eastern Asia and sub-Saharan Africa (2/100,000 population). Knowledge of the geographical distribution of the disease and its survival data, and a better understanding of the natural history of the disease, have improved our understanding of the respective roles of endogenous and exogenous causes of MS. Concerning mortality, in a large French cohort of 27,603 patients, there was no difference between MS patients and controls in the first 20 years of the disease, although life expectancy was reduced by 6–7 years in MS patients. In 2004, the prevalence of MS in France was 94.7/100,000 population, according to data from the French National Health Insurance Agency for Salaried Workers (Caisse nationale d’assurance maladie des travailleurs Salariés [CNAM-TS]), which insures 87% of the French population. This prevalence was higher in the North and East of France. In several countries, including France, the gender ratio for MS incidence (women/men) went from 2/1 to 3/1 from the 1950s to the 2000s, but only for the relapsing–remitting form. As for risk factors of MS, the most pertinent environmental factors are infection with Epstein-Barr virus (EBV), especially if it arises after childhood and is symptomatic. The role of smoking in MS risk has been confirmed, but is modest. In contrast, vaccines, stress, traumatic events and allergies have not been identified as risk factors, while the involvement of vitamin D has yet to be confirmed. From a genetic point of view, the association between HLA-DRB1*15:01 and a high risk of MS has been known for decades. More recently, immunogenetic markers have been identified (IL2RA, IL7RA) and, in particular thanks to studies of genome-wide associations, more than 100 genetic variants have been reported. Most of these are involved in the immune response and often associated with other autoimmune diseases. Studies of the natural history of MS suggest it is a two-phase disease: in the first phase, inflammation is focal with flares; and in the second phase, disability progresses independently of focal inflammation. This has clear implications for therapy. Age may also be a key factor in the phenotype of the disease. In conclusion, France is a high-risk country for MS, but it only slightly reduces life expectancy. MS is a multifactorial disease and the implications of immunogenetics are major. Preventative approaches might be derived from knowledge of the risk factors and natural history of the disease (smoking, vitamin D).

Polymorphisms in CD28, CTLA-4, CD80 and CD86 genes may influence the risk of multiple sclerosis and its age of onset

CD28/CTLA-4–CD80/CD86 molecules play an important role in the regulation of T cells activation. Defects in proteins involved in this pathway may lead to the development of autoimmune diseases in which T cells are involved.In this case–control study (336 multiple sclerosis (MS) patients and 322 controls) we investigated the possible association of eleven polymorphisms in CD28, CTLA-4, CD80 and CD86 genes with susceptibility to MS and/or its progression. We also took into account HLA-DRB1*15:01 status. Moreover, this study aimed to determine the possible gene-gene interactions between examined SNPs associated with the susceptibility to MS and its outcome.Our investigation revealed that in HLA-DRB1*15:01 negative individuals, G allele in rs231775A>G of CTLA-4 gene was associated with higher risk of multiple sclerosis. Additionally, the association of rs2715267T>G of CD86 gene with MS susceptibility was detected. In details, carriers of G allele at this polymorphic site possessed higher risk of MS in comparison to TT homozygotes. On the other hand, the lower risk of MS was observed in individuals carrying A allele at the rs1599795T>A polymorphic site of CD80. Furthermore, the analysis revealed an interaction between three polymorphisms: rs3116496T>C (CD28), rs6641T>G (CD80) and rs17281995G>C (CD86), associated with the age of MS onset.

Multiple Sclerosis Epidemiology in Middle East and North Africa: A Systematic Review and Meta-Analysis

Background: Multiple sclerosis (MS) is one of the most common neurological disorders and a leading cause of nontraumatic disability in young adults in many countries. Recent reports from the Middle East and North Africa have suggested a moderate to high risk of MS in these countries. Methods: A literature search was performed in August 2014 in MEDLINE, EMBASE, and IMEMR to retrieve original population-based studies on MS epidemiology in the Middle East and North African countries published between 1st January 1985 and 1st August 2014. We designed search strategies using the key words: MS, prevalence, incidence, and epidemiology. According to the inclusion criteria, 52 studies were included in this systematic review. Results: McDonald's criteria were the most widely used diagnostic criteria in the studies. Most studies were conducted in single hospital-based centers with a defined catchment area. The female/male ratio ranged from 0.8 in Oman to 4.3 in Saudi Arabia. MS prevalence ranged from 14.77/100,000 population in Kuwait (2000) to 101.4/100,000 in Turkey (2006). The overall MS prevalence in the region was 51.52/100,000. The mean age at disease onset ranged from 25.2 years in Kuwait to 32.5 years in Northeastern Iran, with an overall estimate of 28.54 years. Conclusions: Recent advances in MS registries will allow nation-wide studies and temporal comparisons between countries, provided that age- and sex-standardized estimates are available.