Clinical Onset Of Multiple Sclerosis Research Articles

Altered EBV specific immune control in multiple sclerosis

Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.

Clinical Characteristics and Long-Term Outcomes of Late-Onset Multiple Sclerosis: A Swedish Nationwide Study.

Clinical onset of multiple sclerosis (MS) after the age of 50 years is uncommon and associated with a less favorable natural history. The differences in long-term outcomes in patients with late-onset MS (LOMS, onset 50 years or older) and adult-onset MS (AOMS, onset 18 years or older and younger than 50 years) during the disease-modifying therapy (DMT) era have been less studied. This study aimed to compare patient characteristics, DMT exposure, and disability progression in Swedish patients with LOMS and AOMS over 2 decades (2001-2022). The nationwide Swedish MS registry was searched for patients with an onset of MS between January 1, 2001, and December 31, 2018, with symptom onset at age 18 years or older and ≥2 recorded Expanded Disability Status Scale (EDSS) scores. Clinical and demographic parameters and exposure to DMT were compared between LOMS and AOMS. Time to disability milestones (EDSS 4 and 6) was assessed using Kaplan-Meier curves and Cox proportional hazards regression models adjusted for sex, disease course, calendar year at onset, and DMT exposure. Among 8739 patients with MS who met inclusion criteria, 1,028 (11.8%) were LOMS. Primary progressive MS was more frequently diagnosed in LOMS compared with that in AOMS (25.2% vs 4.5%; p < 0.001). Most of the patients had been prescribed DMT, but more rarely in LOMS compared with AOMS (74.7% vs 95.6%; p < 0.001). Less than half of patients with LOMS had been exposed to a high-efficacy DMT (45.8%) compared with 73.5% of AOMS (p < 0.001). The risk of reaching disability milestones was greater for LOMS compared with that for AOMS (EDSS 4; adjusted hazard ratio [aHR] 2.71; 95% CI 2.22-3.30; p < 0.001, and EDSS 6; aHR 2.67; 95% CI 2.12-3.36; p < 0.001). This study distinguishes LOMS as a particularly vulnerable group and clinically supports close vigilance of these patients. Further studies are needed to assess and clarify the benefit of DMT usage in older adults with MS.

Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis.

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

Serum metabolic profile in early multiple sclerosis as predictor of long-term disease progression in BENEFIT (P5-3.013)

Serum metabolic profile in early multiple sclerosis as predictor of long-term disease progression in BENEFIT (P5-3.013)

Altered Immune Response to the Epstein-Barr Virus as a Prerequisite for Multiple Sclerosis.

Strong epidemiologic evidence links Epstein–Barr virus (EBV) infection and its altered immune control to multiple sclerosis (MS) development. Clinical MS onset occurs years after primary EBV infection and the mechanisms linking them remain largely unclear. This review summarizes the epidemiological evidence for this association and how the EBV specific immune control is altered in MS patients. The two main possibilities of mechanisms for this association are further discussed. Firstly, immune responses that are induced during a symptomatic primary EBV infection, namely infectious mononucleosis, might be amplified during the following years to finally cause central nervous system (CNS) inflammation and demyelination. Secondly, genetic predisposition and environmental factors might not allow for an efficient immune control of the EBV-infected B cells that might drive autoimmune T cell stimulation or CNS inflammation. These two main hypotheses for explaining the association of the EBV with MS would implicate opposite therapeutic interventions, namely either dampening CNS inflammatory EBV-reactive immune responses or strengthening them to eliminate the autoimmunity stimulating EBV-infected B cell compartment. Nevertheless, recent findings suggest that EBV is an important puzzle piece in the pathogenesis of MS, and understanding its contribution could open new treatment possibilities for this autoimmune disease.

Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis.

Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case–control study, blood samples from 519 presymptomatic persons (age range 4–39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre‐MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0–5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5–10 years before onset. These results support that axonal injury occurs early in MS pathogenesis.

Newly Diagnosed Tumefactive Demyelinating Lesion and Multiple Sclerosis After COVID-19 Infection.

To describe the parainfectious or postinfectious effects of COVID-19 infection on the first demyelinating presentation of Multiple Sclerosis and tumefactive demyelinating lesion (TDL) developing with Longitudinally Extensive Transverse Myelitis (LETM). We present six patients who presented with a first CNS demyelination event or whose demyelinating lesions had aggravated after COVID-19 infection between May and December 2020. Nasopharyngeal swab SARS-CoV-2 PCR positivity was detected in five cases and cerebrospinal fluid (CSF) PCR was positive in one. The symptoms, neurological signs, radiological and CSF findings of the cases were examined. A 24-year-old woman presented with LETM aggravated by COVID-19, accompanied by a newly developed open-ring enhanced TDL. Four patients were diagnosed with the first presentation of MS, and one presented with clinically isolated syndrome according to the McDonald 2017 criteria. The interval between SARS-CoV-2 infection and the onset of clinical symptoms ranged from 4-93 days. All of the cases present with pyramidal or brain stem findings and have high brain and/or spinal MRI load. This suggests the moderate activity of CNS demyelinating disease after COVID-19 infection. Based on this case series, all these first demyelinating events suggested that COVID-19 infection might trigger or exacerbate CNS demyelinating disease. SARS-CoV-2 plays a role in the clinical onset of Multiple Sclerosis. Active delayed demyelination developed within the first three months. This can be explained by COVID-triggered neuroimmune response that had been latent, and the initiation of the active disease process began with triggering or aggravation of the lesions in MRI. Multiple Sclerosis should be maintained during the COVID-19 pandemic.

Neuroprotective associations of apolipoproteins A-I and A-II with neurofilament levels in early multiple sclerosis

The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known. The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis. sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.9±8.0years) during the first demyelinating event. CSF-NfL was available for 103 (77%) patients. CSF-NfL and sNfL were negatively associated with serum ApoA-II (P=.005, P<.001) and positively associated with albumin quotient (P<.001, P<.0001). In addition, higher CSF-NfL was associated with lower serum ApoA-I (P=.009) levels and higher sNfL was associated with lower high-density lipoprotein cholesterol (P=.010). In stepwise regression, age (P=.045), serum ApoA-II (P=.022), and albumin quotient (P<.001) were associated with CSF-NfL; albumin quotient (P=.002) and ApoA-II (P=.001) were associated with sNfL. Path analysis identified parallel pathways from ApoA-II (P=.009) and albumin quotient (P<.001) to the sNfL outcome that were mediated by CSF-NfL (P<.001). The associations of CSF-NfL with ApoA-I (P=.014) and ApoA-II (P=.015) and sNfL with ApoA-II (P<.001) remained significant after adjusting for number of contrast-enhancing lesions and T2 lesion volume. Lower serum ApoA-II and ApoA-I levels are associated with greater neuroaxonal injury as measured by CSF-NfL.

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.

Body mass index trajectories in pediatric multiple sclerosis.

To characterize growth trajectories of children who develop multiple sclerosis compared to typically developing, regional peers and Centers for Disease Control (CDC) normative values. This case-control study collected weight, height, and body mass index (BMI) in 40 consecutive pediatric patients with multiple sclerosis (28 females, 12 males), in addition to 120 typically developing peers (84 females, 36 males), identified and matched for year of birth, sex, ethnicity, and socio-economic status. BMI values were converted to z-scores based on CDC reference values and were compared with respect to age between our two cohorts and by years relative to multiple sclerosis onset for cases. Median age for the clinical onset of multiple sclerosis was 15years. BMI z-scores are significantly higher for patients with multiple sclerosis compared to typically developing, demographically-matched peers and CDC standards. These significant differences in BMI are noted from 4years of age and onward. Height trajectories were similar among case and control individuals and CDC normative values. BMI in pediatric multiple sclerosis is markedly higher, beginning in early childhood, years before the clinical-onset of the disease. Children with multiple sclerosis are significantly more overweight than typically developing peers at the time of diagnosis. Body mass index trajectories are significantly higher years before the clinical manifestation(s) of multiple sclerosis.

Neurofilament light chain serum levels correlate with 10-year MRI outcomes in multiple sclerosis.

ObjectiveTo assess the value of annual serum neurofilament light (NfL) measures in predicting 10‐year clinical and MRI outcomes in multiple sclerosis (MS).MethodsWe identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high‐resolution 3T MRI scans. Correlations between averaged annual NfL and 10‐year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models.ResultsAveraged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1–5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1–5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15–20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort.InterpretationSerum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10‐year MRI brain lesion load and atrophy.

Does pregnancy affect women with multiple sclerosis? A prospective study in Western China

Objectives: Pregnancy is considered to be protective for multiple sclerosis (MS) but little is known about Asian MS women. Our study aimed to investigate whether pregnancy affects the course of MS and whether MS affects pregnancy in a Chinese cohort.Methods: We established a database (2009–2016) of 94 females with MS in the Department of Neurology at West China Hospital. From this database, we enrolled females who had been pregnant before or after the clinical onset of MS and consecutively followed up the patients and their offspring for at least one year after delivery. We registered their demographic, clinical and pregnancy-related information, as well as the annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score.Results: We enrolled 55 females with MS and 126 pregnancies. Among them, 14 females had 15 deliveries after MS onset. In these 15 full-term pregnancies after MS onset, the average ARR decreased from 0.46 ± 0.52 in the year before pregnancy to 0.07 ± 0.26 (P = .034) during pregnancy and no drug exposure were observed during pregnancy. The average EDSS score at one year after delivery (1.50 ± 1.72) was higher than that at conception (0.77 ± 1.35; P = .045).Conclusions: The natural history of MS during pregnancy suggests that full-term pregnancy protects MS females from relapse. However, the disability of MS females may develop after delivery.

Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers.

BackgroundNeurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization.ObjectiveThis study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course.MethodsThis cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction.ResultsExcept for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400–2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration.ConclusionsIn clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality.

To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration. We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 [1.44-2.80]; <0.0005), cardiovascular comorbidity (4.04 [2.78-5.87]; <0.0005), lung comorbidity (1.93 [1.42-2.62]; <0.0005), diabetes comorbidity (1.78 [1.04-3.06]; 0.035), and cancer comorbidity (2.10 [1.20-3.67]; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 [1.67-3.01]; <0.0005), cerebrovascular comorbidity (2.47 [2.05-2.79]; <0.0005), cardiovascular comorbidity (1.68 [1.39-2.03]; <0.0005), lung comorbidity (1.23 [1.01-1.50]; 0.036), diabetes comorbidity (1.39 [1.05-1.85]; 0.021), cancer comorbidity (3.51 [2.94-4.19]; <0.0005), and Parkinson disease comorbidity (2.85 [1.34-6.06]; 0.007). An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.

Chronic comorbidity in multiple sclerosis is associated with lower incomes and dissolved intimate relationships.

The social and economic consequences of comorbidity in multiple sclerosis (MS) are largely unexplored. Differences were investigated in income and in the rate of broken relationships between cases of MS with and without chronic comorbidity. We conducted a nationwide cohort study including all incident cases of MS in Denmark with clinical MS onset between 1980 and 2005. The difference in income was investigated at MS onset and 5 and 10 years after MS onset. The difference in the rate of broken relationships was investigated in subjects who were in a relationship at MS onset or who entered a relationship after MS onset. We used logistic, multiple linear and Poisson regression analyses. Cases of MS with somatic comorbidity had increased odds of low incomes both 5 years {odds ratio (OR), 1.41 [95% confidence interval (CI), 1.19-1.67; P < 0.0005]} and 10 years [OR, 1.37 (95% CI, 1.17-1.60); P < 0.0005] after MS onset. The odds of a low income with psychiatric comorbidity was increased 10 years after MS onset [OR, 3.06 (95% CI, 1.47-6.37); P = 0.003]. The rate of broken relationships was increased in cases of MS with any somatic comorbidity [incidence rate ratio, 1.46 (95% CI, 1.32-1.61); P < 0.0005]. Our results underscore the burden of comorbidity in MS on patients, their partners and society.

Vascular comorbidities in multiple sclerosis: a nationwide study from Denmark.

To investigate the occurrence of vascular comorbidities before and after the clinical onset of multiple sclerosis. In this combined case-control and cohort study, all Danish born citizens with onset of multiple sclerosis 1980-2005 were identified from the Danish Multiple Sclerosis Registry and randomly matched with controls regarding year of birth, gender, and municipality on January 1st in the year of multiple sclerosis (MS) onset (index date). Individual-level information on comorbidities was obtained from several independent nationwide registries and linked to the study population by unique personal identification numbers. To assess the presence of vascular comorbidities before and after MS onset, cases and controls were followed from January 1977 to the index date, and from the index date through December 2012. We used logistic regression to calculate odds ratios (ORs) and Cox regression to calculate hazard ratios (HRs). Before the index date, MS cases had a decreased probability for cerebrovascular comorbidity [OR 0.69 (95% CI 0.48-0.99, p=0.043)], and a numerically but not statistically significant decreased probability for cardiovascular comorbidity [OR 0.87 (95% CI 0.71-1.07, p=0.188)]. After the index date, MS cases had an increased risk for cerebrovascular comorbidity [HR 1.84 (95% CI 1.69-2.00, p<0.0005)], and for cardiovascular comorbidity [HR 1.08 (95% CI 1.02-1.15, p=0.013)]. The lower occurrence of cerebrovascular comorbidities in cases prior to MS onset could be due to protective immune mechanisms, while the higher occurrence of vascular comorbidities in cases after MS onset could be because of converging causal pathways of the coexisting diseases. These findings deserve to be studied closer in a broader spectrum of comorbidities in MS.

Self-rated health in women prior to clinical onset of multiple sclerosis: A study within the Danish National Birth Cohort

Background: It has been suggested that onset of multiple sclerosis (MS) is preceded by a clinically silent period of up to 10 years. Objectives: Examine whether such a period should be associated with poor self-rated health (SRH). Methods: Information on SRH before pregnancy was ascertained among 80,848 women participating in the Danish National Birth Cohort (DNBC) 1996–2002. Women were followed for MS from enrolment in DNBC in the 16th week of pregnancy until 31 December 2011. Associations between SRH and MS were evaluated by means of hazard ratios (HR) with 95% confidence intervals (CIs) using Cox proportional hazard models. Results: During on average 11.7 years of follow-up, 239 women were diagnosed with MS. Overall, neither women with fair (HR = 1.09 (95% CI = 0.83–1.41), n = 113) nor poor pre-pregnancy SRH (HR = 0.94 (95% CI = 0.47–1.87), n = 9) were at an increased risk of MS compared with women reporting very good pre-pregnancy SRH. Supplementary analyses showed no significant differences in MS risk in consecutive periods of follow-up. Conclusion: In this first prospective cohort study assessing MS risk as a function of SRH, we found no indication of a long period of poor SRH prior to MS. Our findings based on pregnant women may not necessarily apply to all women.

P048 - Seizures and epilepsy in multiple sclerosis patients: A Tunisian study of 9 cases

Introduction The prevalence of seizures and epilepsy in patients with multiple sclerosis (MS) is higher than in general population. We investigated the clinical, electrical and radiological findings for Tunisian patients with MS who had experienced seizures. Methods We retrospectively reviewed the medical records of patients who had epileptic seizures and MS, over a 22-year period, from February 1992 to May 2014, at the department of neurology in Hbib Bourguiba hospital. The diagnosis of MS was made according to McDonald revised criteria. The diagnosis of epilepsy was based on the criteria proposed by the International League against Epilepsy (ILAE) 1993 and seizures were classi?ed according to the classification of ILAE, 1981. All patients with seizures or epilepsy were submitted to EEG recording and MRI imaging. Results We identified 9 patients (8 female). The mean age at the onset of MS was 47 years old. None had the history of seizure or epilepsy before clinical MS onset.7 patients had relapsing remitting MS that became secondary progressive in 3cases.The mean age at the onset of seizures was 40.6 years old. Epileptic seizures were recurrent in 3cases and 2 patients had epilepsy. The seizures occurred essentially during the course of the disease (7cases) and the delay between the onset of MS and seizures was 7.1 years. Seizures are related to a new relapse in 7 cases. The mean concomitant EDSS score was 2.9. 4 patients had partial seizures with secondary generalization in 1case. Cognitive impairment was observed in 3 cases. Interictal EEG was normal in 4 patients, focal or generalized epileptic discharges were seen in 3 patients and generalized slowing was noted in 1 patient. All patients had lesions in juxtacortical areas and in the brain stem. Gadolinium-enhancing were visible in 3 cases and cortical atrophy in 4 cases. Anti-epileptic drugs were administered in all patients and six were on monotherapy. The Carbamazepine is the most prescribed. Seizures were controlled in 5 cases, but 1 patient presented a status epilepticus. Conclusion Seizures and epilepsy are more frequent in the MS patients. The causal link between MS and epileptic seizures is unclear. The presence of cortical and juxtacortical lesions and progressive brain atrophy can probably be the pathophysiological mechanism underlying this association. The higher frequency of partial seizures and the better response to antiepileptic drugs are noted. The prevalence of seizures and epilepsy in patients with multiple sclerosis (MS) is higher than in general population. We investigated the clinical, electrical and radiological findings for Tunisian patients with MS who had experienced seizures. We retrospectively reviewed the medical records of patients who had epileptic seizures and MS, over a 22-year period, from February 1992 to May 2014, at the department of neurology in Hbib Bourguiba hospital. The diagnosis of MS was made according to McDonald revised criteria. The diagnosis of epilepsy was based on the criteria proposed by the International League against Epilepsy (ILAE) 1993 and seizures were classi?ed according to the classification of ILAE, 1981. All patients with seizures or epilepsy were submitted to EEG recording and MRI imaging. We identified 9 patients (8 female). The mean age at the onset of MS was 47 years old. None had the history of seizure or epilepsy before clinical MS onset.7 patients had relapsing remitting MS that became secondary progressive in 3cases.The mean age at the onset of seizures was 40.6 years old. Epileptic seizures were recurrent in 3cases and 2 patients had epilepsy. The seizures occurred essentially during the course of the disease (7cases) and the delay between the onset of MS and seizures was 7.1 years. Seizures are related to a new relapse in 7 cases. The mean concomitant EDSS score was 2.9. 4 patients had partial seizures with secondary generalization in 1case. Cognitive impairment was observed in 3 cases. Interictal EEG was normal in 4 patients, focal or generalized epileptic discharges were seen in 3 patients and generalized slowing was noted in 1 patient. All patients had lesions in juxtacortical areas and in the brain stem. Gadolinium-enhancing were visible in 3 cases and cortical atrophy in 4 cases. Anti-epileptic drugs were administered in all patients and six were on monotherapy. The Carbamazepine is the most prescribed. Seizures were controlled in 5 cases, but 1 patient presented a status epilepticus. Seizures and epilepsy are more frequent in the MS patients. The causal link between MS and epileptic seizures is unclear. The presence of cortical and juxtacortical lesions and progressive brain atrophy can probably be the pathophysiological mechanism underlying this association. The higher frequency of partial seizures and the better response to antiepileptic drugs are noted.

Gender and autoimmune comorbidity in multiple sclerosis

Background: The female preponderance in incidence of multiple sclerosis (MS) calls for investigations into sex differences in comorbidity with other autoimmune diseases (ADs). Objectives: To determine whether male and female patients with MS have a higher frequency of autoimmune comorbidity than controls, and to describe the type and frequency of ADs that are associated with MS. Methods: Our database was established by linkage of the Danish MS Registry to The Danish National Patient Register and consisted of 1403 patients of both sexes with clinical onset of MS between 2000 and 2004, and 25 matched controls for every case. Results: None of the ADs occurred more frequently in female cases than in controls. Male cases were more likely to have Type I diabetes mellitus (odds ratio (OR) = 3.34; 95% CI 1.40 – 7.02; p < 0.008), Crohn’s disease (OR = 5.03; 95% CI 1.18 – 16.10; p = 0.03) and systemic lupus erythematosus (OR = 12.55; 95% CI 1.62 – 69.95; p = 0.02) than male controls. Conclusions: Autoimmune disorders are rare, but some of them tend to occur together with MS at a higher rate than in controls. Although women are generally more prone to ADs than men, significantly increased occurrence of other ADs were only found in male MS patients.

Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study

HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61-4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99-222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26-273·85) or CSF oligoclonal bands (6·33, 3·35-11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Canadian Multiple Sclerosis Scientific Research Foundation.