A national registry-based study of ethnic differences in people with multiple sclerosis in Iran.

OBJECTIVE: The relationship between MS and ethnicity has been understudied in the Middle East compared to the United States and Europe. As Iran as the highest prevalence of MS in the Middle East, we decided to investigate the demographic and clinical differences in people with MS (pwMS) from major ethnicities Iran. METHODS: In a cross-sectional study using data from National Multiple Sclerosis Registry in Iran. PwMS from six provinces were chosen and interviewed for determining their ethnicity. Persians (Fars), Kurds, Lurs, Azeris and Arabs with a clear ethnic background were included. Recorded data from the registry was used to compare the demographic and clinical features. RESULTS: A total of 4015 pwMS (74.2% female) were included in the study with an average age of 36.76 ± 9.68 years. Persians and Kurds had the highest percentage of pwMS in youngest and oldest age groups, respectively, with 2.9% and 5.7% (p<0.01). The highest average age of onset was seen in Persians (29.47 ± 8.89) and the lowest observed in Mazandaranis (26.82 ± 7.68, p<0.01). Azeris and Kurds had the highest proportions of pwMS diagnosed <18 and >55, at rates of 12% and 1.6%, respectively (p<0.01). There were statistically significant differences in distribution of phenotypes (p<0.01) and time to progression to secondary progressive MS (p<0.01) such that Persians had the highest rate of clinically isolated syndrome (CIS) at 19.3% and Arabs had highest rates of relapsing-remitting MS (86.2%) and secondary progressive MS (16.4%). Lurs, Azeris and Mazandaranis had significantly more patients progressing to secondary-progressive MS <5 years from diagnosis (p<0.01). There was a significant difference in number of relapses between the ethnicities (p<0.01) with Lurs having the highest proportion of participants reporting >4 relapses with 23.0% and Azeris having the highest percentage of pwMS reporting no relapse (53.0%). Kurds had the highest Expanded Disability Status Scale (EDSS) average at 2.93 ± 1.99 and Lurs had the lowest with 1.28 ± 1.25 (p<0.01). The differences in prevalence of positive family history for the whole cohort between ethnicities were significant (P=0.02), ranging from 12.8% in Kurds to 19.6% in Persians. CONCLUSION: We found Persians to have higher rates of pediatric MS and higher rates of CIS. Kurds and Lurs had higher and lower EDSS scores, respectively. Lurs and Persian had higher annual relapse rates. We also found lower rates of SPMS among Arabs and earlier progression to SPMS in Lurs, Azeris and Mazandaranis. Such differences highlight the importance of the potential role of ethnicities in diagnosis and prognosis of MS, especially considering their observation within the geographical limits of a single country.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

A comparison of anxiety symptoms and correlates of anxiety in people with progressive and relapsing-remitting multiple sclerosis.

BACKGROUND: Anxiety appears to be more prevalent in people with multiple sclerosis (MS) than in the general population, though it is unclear if anxiety varies by MS disease course. There are experiences unique to each disease course that might increase the likelihood of anxiety. Additionally, the majority of research in MS has focused on people with relapsing-remitting MS (RRMS), while the experiences of people with progressive forms of MS are understudied. This study examined anxiety in people with progressive MS (PMS) and examined group differences in anxiety compared to people with RRMS, and assessed unique and common correlates of anxiety in people with PMS and RRMS. METHODS: Secondary analysis of data from the fourth survey in a longitudinal study of quality of life in people with physical disabilities. The current study included a subset of participants with MS. Anxiety level was measured by the 4-item Patient-Reported Outcomes Measurement Information System - Anxiety Short Form T-score. T-test and chi-square analyses were used to compare groups. Correlates of anxiety were tested by examining the interaction of MS subtype (PMS and RRMS) and each potential correlate in multiple regression models with bootstrapping. RESULTS: Participants were 464 adults with MS (PMS n = 183; RRMS n = 281) who were predominately female, non-Hispanic white, and not employed with a mean age of 56.9 ± 10.3 years and disease duration of 17.5 ± 9.3 years. On average, participants with PMS reported anxiety symptoms (50.6 ± 8.6) that were comparable to those in the United States general population and statistically lower than participants with RRMS (52.8 ± 9.5; p = .01). Across MS courses, common factors associated with greater anxiety symptoms were shorter disease duration, lower household income, greater speech and/or swallowing problems, and current smoking (tobacco), adjusted R2 = .19, F(4, 391) = 22.68, p < .001. There was no evidence of unique correlates of anxiety symptoms in participants with either MS course. CONCLUSIONS: In this community sample, people with MS, regardless of disease course, reported similar levels of anxiety to the United States general population. This is inconsistent with prior literature that largely involves clinical samples, suggesting a need for further research with community samples of individuals with MS. This discrepancy may also be due to measurement differences between studies (e.g., screen versus symptom measures). Participants with RRMS reported greater average anxiety compared to those with PMS. This statistically significant difference was small and not clinically significant, indicating the need for further examination and replication. Overall, the findings highlight the wide heterogeneity of anxiety presentation within people with MS and identify potential factors to improve conceptualization and treatment of anxiety in this population. Further research is needed with community and clinical samples to understand anxiety in MS as well as risk and protective factors to improve conceptualization and treatment of anxiety in this population.

Atherosclerosis and multiple sclerosis: An overview on the prevalence of risk factors.

BACKGROUND: Atherosclerosis is the leading cause of ischemic heart disease and coronary artery disease. The process of atherosclerosis develops over a period of years and is mainly immune-mediated. Data regarding the prevalence of vascular disease and atherosclerosis among people with multiple sclerosis (pwMS) is inconsistent, therefore, we aimed to provide an overview of the prevalence of atherosclerotic risk factors in pwMS. METHODS: This is a cross-sectional study over a period of one year among pwMS visiting the Isfahan MS center. Study data have been extracted using participants' files and a checklist that was completed by the observers. Only people with relapsing-remitting (RRMS) and secondary progressive (SPMS) forms of MS were included in the study. Participants with primary progressive (PPMS) disease are only described and have been excluded from analyses. RESULTS: Of the 396 pwMS (343 with RRMS and 53 with SPMS), in descending order, the reported risk factors were tobacco smoking (18.4%), dyslipidemia (10%), hypertension (8.8%), and diabetes mellitus (4.5%). In people with RRMS, 17.4% were smokers, 9.9% had dyslipidemia, 8.1% had hypertension, and 4.3% had diabetes mellitus. In SPMS patients 24.5% reported a history of smoking, 13.2% had hypertension, 9.4% had dyslipidemia, and 3.7% had diabetes mellitus. Smoking was insignificantly associated with higher expanded disability status scale (Z: 1.70, p-value = 0.090). Male sex (RR [95%CI]: 1.628 [1.172, 2.261], p-value = 0.004) and increasing age (RR [95%CI]: 1.024 [1.008, 1.040], p-value = 0.003) were associated with a higher number of risk factors. CONCLUSION: The highest observed atherosclerosis risk factor among pwMS was smoking. Diabetes mellitus was the least reported risk factor in our population as a whole. Overall, and in participants with RRMS, dyslipidemia and hypertension were the second and third most commonly reported risk factors, however, hypertension exceeded dyslipidemia in participants with SPMS. Male sex and increasing age were associated with a higher number of atherosclerosis risk factors.

Early predictors of conversion to secondary progressive multiple sclerosis.

BACKGROUND: We conducted this study to estimated the time of conversion from relapsing-remitting MS (RRMS) to SPMS and its early predictor factors. METHODS: In this retrospective study, demographic, clinical, and imaging data from MS patients at diagnosis were extracted. Cox proportional hazards model was used to assess the association between various baseline characteristics and conversion to SPMS. We also assessed the association brtween escalation and early intensive therapy approaches with transition to progressive phase. RESULTS: Out of 1903 patients with RRMS at baseline, 293 (15.4%) patients progressed to SPMS during follow-up. The estimated number of patients converted to SPMS was 10% at 10-years, 50% at 20-years, and 93% at 30-years. On multivariate Cox regression analysis older age at onset (HR: 1.067, 95%CI: 1.048-1.085, p < 0.001), smoking (HR: 2.120, 95%CI: 1.203-3.736, p = 0.009), higher EDSS at onset (HR: 1.199, 95%CI: 1.109-1.295, p < 0.001), motor dysfunction (HR: 2.470, 95%CI: 1.605-3.800, p < 0.001), cerebellar dysfunction (HR: 3.096, 95%CI: 1.840-5.211, p < 0.001), and presence of lesions in spinal cord (HR: 0.573, 95%CI: 0.297-0.989, p = 0.042) increased the risk of conversion from RRMS to SPMS. No significant difference between escalation and EIT groups in the risk of transition to progressive phase (weighted HR = 1.438; 95% CI: 0.963, 2.147; p = 0.076) was found. CONCLUSION: Our data support previous observations that smoking is a modifiable risk factor for secondary progressive MS and confirms that spinal cord involvement, age, and more severe disease at onset are prognostic factors for converting to secondary progressive MS.

Potential risk of disease modifying therapies on neoplasm development and coadjutant factors in multiple sclerosis outpatients.

Neoplasm development in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) has been widely discussed. The aim of this work is to determine neoplasm frequency, relationship with the prescription pattern of DMTs, and influence of the patients' baseline characteristics. Data from 250 MS outpatients were collected during the period 1981-2019 from the medical records of the Neurology Service of the HUPM (Hospital Universitario Puerta del Mar)-in Southern Spain-and analysed using Cox models. Neoplasm prevalence was 24%, mainly located on the skin, with cancer prevalence as expected for MS (6.8%). Latency period from MS onset to neoplasm diagnosis was 10.4 ± 6.9 years (median 9.30 [0.9-30.5]). During the observation period ß-IFN (70.4% of patients), glatiramer acetate (30.4%), natalizumab (16.8%), fingolimod (24.8%), dimethyl fumarate (24.0%), alemtuzumab (6.0%), and teriflunomide (4.8%) were administered as monotherapy. Change of pattern in step therapy was significantly different in cancer patients vs unaffected individuals (p = 0.011) (29.4% did not receive DMTs [p = 0.000]). Extended Cox model: Smoking (HR = 3.938, CI 95% 1.392-11.140, p = 0.010), being female (HR = 2.006, 1.070-3.760, p = 0.030), and age at MS diagnosis (AGE-DG) (HR = 1.036, 1.012-1.061, p = 0.004) were risk factors for neoplasm development. Secondary progressive MS (SPMS) phenotype (HR = 0.179, 0.042-0.764, p = 0.020) and treatment-time with IFN (HR = 0.923, 0.873-0.977, p = 0.006) or DMF (HR = 0.725, 0.507-1.036, p = 0.077) were protective factors. Tobacco and IFN lost their negative/positive influence as survival time increased. Cox PH model: Tobacco/AGE-DG interaction was a risk factor for cancer (HR = 1.099, 1.001-1.208, p = 0.049), followed by FLM treatment-time (HR = 1.219, 0.979-1.517). In conclusion, smoking, female sex, and AGE-DG were risk factors, and SPMS and IFN treatment-time were protective factors for neoplasm development; smoking/AGE-DG interaction was the main cancer risk factor.

Aspectos clínicos y demográficos de los pacientes con esclerosis múltiple secundaria progresiva en Argentina / Clinical and demographic aspects of secondary progressive multiple sclerosis in Argentina

Resumen El objetivo del estudio fue evaluar los aspectos clínicos y demográficos de los pacientes con esclerosis múltiple (EM) secundaria progresiva (EMSP) en los pacientes incluidos en el Registro Argentino de EM (RelevarEM, número de registro de Clinical Trials 03375177). RelevarEM es un registro longitudinal, estrictamente observacional, de pacientes con EM y trastornos del espectro de neuromielitis óptica. Los aspectos clínicos y demográficos fueron descriptos en pacientes con EMSP respecto a aquellos con EM recaída en remisión (EMRR). Se incluyeron 1723 pacientes con EM (1605, 93.2% EMRR y 118, 6.8%, EMSP). En el grupo con EMSP la mediana de edad fue de 53 (intervalo inter-cuartil [IIQ] 47-62) años, 67% eran mujeres, mediana de tiempo de evolución de enfermedad 19.5 (IIQ 14-26) años, EDSS (expanded disability status scale), 6.5 y 48.3% estaban en tratamiento para su EM. Solo el 23.7% con EMSP estaban trabajando activamente y el 86% tenía certificado de discapacidad. Un 35.6% con EMSP presentaron nuevas lesiones en resonancia magnética y 5% tuvo recaídas clínicas en los 12 meses previos al análisis, mostrando una actividad de la enfermedad significativamente menor respecto a la forma EMRR (p < 0.01).

Abstract The objective of the study was to describe the clinical and demographic aspects of patients with secondary progressive multiple sclerosis (SPMS) included in the Argentine MS Registry (RelevarEM, Clinical Trials registry number 03375177). RelevarEM is a longitudinal, strictly observational registry of patients with MS and neuromyelitis optica spectrum disorders. Clinical and demographic aspects were described in patients with SPMS and compared with relapsing remitting MS patients (RRMS). A total of 1723 patients with MS were included (1605, 93.2% RRMS and 118, 6.8%, SPMS). In SPMS, the median age was 53 (inter quartile range [IQR] 47-62) years, 67% were women, median disease duration of 19.5 (IQR 14-26) years, median EDSS (expanded disability status scale) 6.5 and 48.3% were under treatment for their MS. Only 23.7% of patients with SPMS were actively working and 86% had a disability certificate; 35.6% of patients with SPMS presented new lesions in MRI and 5% had clinical relapses during the past 12 months of the registry entry showing a significantly lower disease activity compared with RRMS (p < 0.01).

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis.

Multiple sclerosis (MS), an autoimmune disease of the central nervous system, generally starts as the relapsing remitting form (RRMS), but often shifts into secondary progressive MS (SPMS). SPMS represents a more advanced stage of MS, characterized by accumulating disabilities and refractoriness to medications. The aim of this study was to clarify the microbial and functional differences in gut microbiomes of the different stages of MS. Here, we compared gut microbiomes of patients with RRMS, SPMS, and two closely related disorders with healthy controls (HCs) by 16S rRNA gene and whole metagenomic sequencing data from fecal samples and by fecal metabolites. Each patient group had a number of species having significant changes in abundance in comparison with HCs, including short-chain fatty acid (SCFA)-producing bacteria reduced in MS. Changes in some species had close association with clinical severity of the patients. A marked reduction in butyrate and propionate biosynthesis and corresponding metabolic changes were confirmed in RRMS compared with HCs. Although bacterial composition analysis showed limited differences between the patient groups, metagenomic functional data disclosed an increase in microbial genes involved in DNA mismatch repair in SPMS as compared to RRMS. Together with an increased ratio of cysteine persulfide to cysteine in SPMS revealed by sulfur metabolomics, we postulate that excessive DNA oxidation could take place in the gut of SPMS. Thus, gut ecological and functional microenvironments were significantly altered in the different stages of MS. In particular, reduced SCFA biosynthesis in RRMS and elevated oxidative level in SPMS were characteristic.

Diabetes and anxiety adversely affect cognition in multiple sclerosis.

OBJECTIVE: To determine whether comorbid diabetes and hypertension are associated with cognition in multiple sclerosis (MS) after accounting for psychiatric comorbidities. METHODS: Participants completed a structured psychiatric interview, the Hospital Anxiety and Depression Scale (HADS), a comorbidity questionnaire, and cognitive testing including the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and verbal fluency. Test scores were converted to age-, sex- and education-adjusted z-scores. We evaluated associations between diabetes and hypertension and the four cognitive z-scores using a multivariate linear model, adjusting for comorbid depression and anxiety disorders, psychotropic medications, disease-modifying therapies, smoking status and body mass index. RESULTS: Of 111 participants, most were women (82.9%) with relapsing remitting MS (83.5%), of mean (SD) age 49.6 (12.7) years. Comorbidity was common; 22.7% participants had hypertension, 10.8% had diabetes, 9.9% had current major depression, and 9.9% had current anxiety disorders. Mean (SD) z-scores were: SDMT -0.66 (1.15), CVLT-II -0.43 (1.32), BVMT-R -0.49 (1.07) and fluency -0.59 (0.86). Diabetes (p = 0.02) and anxiety disorder (p = 0.02) were associated with cognitive function overall. Diabetes was associated with lower BVMT-R (ß = -1.18, p = 0.0015) and fluency (ß = -0.63, p = 0.037) z-scores. Anxiety was associated with lower SDMT (ß = -1.07, p = 0.0074) z-scores. Elevated anxiety symptoms (HADS-A ≥ 11) were associated with lower z-scores on the SDMT and CVLT-II. CONCLUSION: Comorbidities, including diabetes and anxiety, are associated with cognitive dysfunction in MS. Their presence may contribute to the heterogeneous pattern of impairments seen across individuals and they may represent targets for improved management of cognitive symptoms.

Clinical deterioration due to co-occurrence of multiple sclerosis and glioblastoma: report of two cases.

Clinical worsening during the course of multiple sclerosis (MS) might be secondary to not only an incomplete recovery after relapses, to progressive accumulation of deficits, but also to other etiologies, different from MS. This report discusses the cases of two MS patients showing a gradual and progressive deterioration of locomotor and cognitive functions which were due to the co-occurrence of MS and glioblastoma. Additional investigations (especially magnetic resonance imaging) are strongly recommended to exclude concomitant pathologies in MS patients suffering from new neurological symptoms over weeks to months, without remission, or an unexpected rapid and progressive accumulation of disability.

The Framingham cardiovascular risk score in multiple sclerosis.

BACKGROUND AND PURPOSE: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10-year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes. METHODS: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. RESULTS: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001). CONCLUSION: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course.

Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review.

Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10-15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS.

Risk factors for multiple sclerosis and associations with anti-EBV antibody titers.

Multiple sclerosis (MS) is an inflammatory demyelination of the central nervous system. We investigated the prevalence of EBV seropositivity and other known risk factors for MS (age, smoking, low vitamin D) and their effect on anti-EBV antibody titers. We retrospectively studied 249 MS patients receiving care at the American University of Beirut Medical Center and 230 controls, during 2010-2014. EBV seropositivity was higher in MS patients compared to controls for both anti-VCA (99.5%; 97.2%) and anti-EBNA-1 (96.3%; 89.4%), and the titers were significantly higher in MS patients. MS patients had a significantly lower vitamin D level (15.5 ± 8.3 ng/ml) compared to controls (20.4 ± 11.3 ng/ml). The proportion of heavy smokers and overweight individuals was significantly higher in MS patients. Lebanese MS patients have risk factors similar to those in western countries. Older age and female gender were associated with a higher anti-VCA titer and male gender with a higher anti-EBNA-1.

Smoking as a risk factor for development of Secondary Progressive Multiple Sclerosis: A study in IRAN, Guilan.

BACKGROUND: Cigarette smoking seems to contribute to susceptibility and progression of multiple sclerosis (MS).Although the incidence of MS in Iranian population has increased during recent years, the effects of smoking on progression of MS have not been studied. The aim of this study was to investigate the association between cigarette smoking and development of secondary progressive MS (SPMS) in Iranian patients with MS. METHODS: This study was carried out on patients registered in the MS Society (Guilan, Iran) database. Using a structured questionnaire, information on smoking status of 400 of patients could be obtained. The association between cigarettes smoking and SPMS was analyzed by Cox regression model. RESULTS: The relationship between smoking and development of SPMS was still evident after adjusting for age at disease onset, gender and number of relapses per year (P =0.004). Smoking more than 10 cigarettes per day increased risk of development of SPMS (HR: 2.43; 95% CI: 1.28 to 4.6; P =0.007). CONCLUSIONS: Our results indicated that smokers have an increased risk for progression of relapsing-remitting MS (RRMS) to SPMS compared with non-smokers. We also showed that the disease progression may be influenced by increase of cigarette smoking.

Evaluation of apoptosis-related genes: Fas (CD94), FasL (CD178) and TRAIL polymorphisms in Iranian multiple sclerosis patients.

Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease characterized by a relapsing-remitting course leading to progressive disability. Given the critical role of apoptosis-related genes in the maintenance of homeostasis in the immune privilege sites, mutations in these genes have a profound effect on occurring autoimmune diseases such as multiple sclerosis. In the current study, polymorphisms in the apoptosis-related genes: Fas _-670 A>G, FasL _-844C>T, FasLIVS2nt _124 A>G and TRAIL_1595C>T were analyzed in 107 Iranian patients suffering from MS and 112 unrelated healthy controls using PCR-RFLP method. Our results demonstrated that among Iranian patients with MS and controls being homozygous in Fas_670A/A, G/G and FasL_-844C/C, TT in the promoter region and homozygocity in the minor allele for FasLIVS2nt_124G/G and TRAIL_1595C/C, polymorphisms were not associated with the MS risk in Iranian patients when compared with normal controls. However, the Fas _-670G/G genotype had a borderline significantly increased frequency with secondary progressive MS type (X(2)=5.8, P=0.05). In conclusion, no statistical association was found between the Fas, FasL and TRAIL polymorphisms and the risk of MS in Iranian patients.

Cigarette smoking and the risk of multiple sclerosis: a sibling case-control study in Isfahan, Iran.

AIMS: We aimed to study the smoking habits of multiple sclerosis (MS) patients and their healthy siblings in Isfahan province in Iran. METHODS: MS patients registered with the Isfahan MS society database were compared to their healthy siblings who served as controls. Data regarding the smoking habits of patients and their siblings were collected using a specially designed questionnaire. Conditional logistic regression was adopted to analyze the association of smoking with the risk of MS, adjusting for age and sex. RESULTS: There were 1,606 participants with 516 cases and 1,090 controls. After adjustments for age and sex, subjects who were ever-smokers had a significant risk of developing MS [odds ratio (OR) 2.67; 95% confidence interval (CI) 1.70-4.21; p <0.001]. Past smokers (OR 8.83; 95% CI 3.98-19.60; p < 0.001) and current smokers (OR 1.84; 95% CI 1.10-3.10; p = 0.021) had a significant risk for developing MS. Disease progression (current expanded disability status scale/disease duration) was not different between smokers and nonsmokers (0.54 ± 0.42 vs. 0.49 ± 0.48; p = 0.61). CONCLUSION: Using a sibling pair method our data confirm the association between smoking and MS. A degree of confounding due to overmatching between siblings was unavoidable, but any bias would be conservative and should have lessened the effect of smoking.

Demographic and clinical characteristics of malignant multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) that causes patients to require assistance for ambulation (Expanded Disability Status Scale [EDSS] ≥6) within 5 years from symptom onset is generally termed malignant. Malignant status can be transient (TM) or sustained until year 5 (SM). We studied the incidence, predictors, and demographic and clinical characteristics of malignant MS. METHODS: Patients with symptom onset in 2002-2005 and 5-year follow-up were selected from the Partners Multiple Sclerosis Center database. Patients with TM were further grouped into TM and SM. The mechanism of reaching EDSS 6 (relapse- vs progression-related) was determined. RESULTS: A total of 487 patients were included (17 TM, 42 SM). The incidence proportion of ever malignant (EM=SM+TM) was estimated as 12.11% and SM as 8.62%. Patients with older age at onset, male gender, and positive smoking history were more likely to become SM. Compared to nonmalignant patients, the proportion of progressive-onset MS in the SM group was significantly higher, but not different in TM. Within relapsing-onset patients, most of TM, and a smaller proportion of the SM group had a relapse-related as opposed to progression-related mechanism. The final model predictors for EM vs nonmalignant were older age at onset, motor symptoms at onset, and progressive disease onset. Within the malignant patients, predictors of TM vs SM were younger age and brainstem symptoms at onset. CONCLUSIONS: Over 10% of patients with MS experience a malignant course as defined above. Some demographic and clinical factors are found to predict a malignant outcome. MS in patients who reach a high EDSS based on disease progression is more likely to remain malignant.

Temporal relationship between environmental influenza A and Epstein-Barr viral infections and high multiple sclerosis relapse occurrence.

BACKGROUND: Multiple sclerosis (MS) relapses have been associated with viral and bacterial infection epidemics in MS patients who have not used interferon. OBJECTIVES: We studied whether environmental viral infections in the general population can be associated with increased MS relapse occurrence using retrospective data from 1986 to 1995 when interferons were not yet available. METHODS: Logistic regression modelling was used to compare retrospectively the monthly relapse occurrence from 407 MS patients in Turku University hospital archives and data on ten different specifically diagnosed viral infection epidemics in the general population of Southwestern Finland from 1986 to 1995. The outcome was the odds ratio (OR) of very high relapse occurrence versus low relapse occurrence, or moderate versus low relapse occurrence. RESULTS: After a peak in diagnosed influenza A cases in the general population, the MS relapse occurrence was 6.5 times more likely to be very high (95% CI 1.8-24.0) and 7.1 times more likely to be moderately high (95% CI 1.5-33.2). An increase in MS relapse counts also followed Epstein-Barr virus (EBV) infections (OR 4.4, 95% CI 1.3-15.1), but we found no significant association with adenovirus infections and MS relapses. The MS relapse occurrence was lowest in the summer months July-August (Chi-square test, p<0.01). CONCLUSIONS: Our findings suggest that influenza A and EBV viral infections in the general population are associated with a higher occurrence of exacerbations in MS patients, and thus environmental infection data should be included in epidemiological models on MS relapses.

Seasonal prevalence of MS disease activity.

OBJECTIVE: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. METHODS: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. RESULTS: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. CONCLUSION: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.