Dessa Sadovnick

Early onset multiple sclerosis: a longitudinal study.

Objective To evaluate the clinical course of MS in individuals with onset of MS before age 16. Methods Patients with onset of MS before age 16 (n = 116) with complete clinical information on the clinical course from the MS Clinic at The University of British Columbia (UBC) Site Hospital computerized database (MS-COSTAR) were included in this study. The data were compared to those from the Canadian natural history study for MS clinic attendees, regardless of age at onset. Results The mean duration of observation was 19.76 ± 0.90 years; the mean age at MS onset was 12.73 ± 0.25 years. Only three cases (2.6%) had a primary progressive (PP) MS course. To date, 60 (53.1%) of 113 subjects have developed secondary progressive (SP) MS. The 50% probability for SPMS was reached 23 years after onset. For patients with relapsing remitting (RR) or SPMS the mean disease duration from onset to the time of confirmed Expanded Disability Status Scale (EDSS) 3.0 was 16.03 ± 1.17 years (at mean age 28.47 ± 1.14); mean duration from onset to the time of EDSS 6.0 was 19.39 ± 1.43 years (at mean age 32.32 ± 1.44). Annual relapse rate was 0.54 ± 0.05 per year. The correlation between the number of relapses during the first year of disease and the course of the disease was also significant. Conclusions The prevalence of early onset MS (3.6%) in our study confirms the previous findings on early onset MS. A RR course was seen in the majority of cases of early onset MS. A high frequency of relapses, early age at permanent disability, and the presence of malignant cases raise the question of possible early use of disease-modifying therapy in patients with early onset MS.

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

BACKGROUND 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. METHODS 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. FINDINGS 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%. INTERPRETATION 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. FUNDING Canadian Multiple Sclerosis Scientific Research Foundation.

Incidence of acquired demyelination of the CNS in Canadian children

Background: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS). Objective: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS. Methods: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children. Results: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66–18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3. Conclusion: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review

Objective: To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). Methods: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Results: Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Conclusion: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Neonatal and Delivery Outcomes in Women with Multiple Sclerosis

To determine (1) whether the risk of adverse neonatal and delivery outcomes differs between mothers with and without multiple sclerosis (MS) and (2) whether risk is differentially associated with clinical factors of MS.

Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study

BACKGROUND Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers. METHODS We did an assessor-blinded, case-control, multicentre study of people with multiple sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised 177 adults: 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues. Catheter venography data were available for 149 participants and ultrasound data for 171 participants. FINDINGS Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0·41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled in 35 of 79 (44%) participants with multiple sclerosis, 17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple sclerosis) and 17 of 38 (45%) unrelated controls (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing on catheter venography was 0·406 (95% CI 0·311-0·508), and specificity was 0·643 (0·480-0·780). INTERPRETATION This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown. FUNDING MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

A Role for VAV1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

VAV1 plays a role in regulating proinflammatory cytokines, which underlie the susceptibility for developing experimental autoimmune encephalomyelitis and multiple sclerosis. Rat Genetics Moving Up Multiple sclerosis (MS) is a common autoimmune disease with a complex etiology that attacks the brain and spinal cord and emerges as a result from both genetic and environmental factors. At present, there is no predictive biomarker for MS and no cure for adults who present with the disease, and only a few genes have been unambiguously linked to its development. The hunt has been to address these challenges, but also to uncover new targets that are associated with a high susceptibility for MS to augment disease-modifying treatments that are in clinical use. Using experimental autoimmune encephalomyelitis, an animal model of MS, Jagodic et al. have focused on a region of the rat genome on chromosome 9 that encodes the gene Vav1. Although this gene was initially identified as an oncogene, it later was found to be an important signal transducer with a pivotal role in immune cells, the very first hint being its specific activation after T cell receptor stimulation. The authors show that a specific mutation identified in rat Vav1 altered Vav1 protein abundances, immune cell activation, and neuroinflammation induction. Taking this observation a step further, among 12,735 individuals of European descent, Jagodic et al. reveal an association between a set of common variants within the first intron of VAV1 and susceptibility for MS. Like what they observed in the rat, common VAV1 variants altered VAV1 expression and immune activation in the peripheral blood and in the cerebrospinal fluid cells of MS patients. This study displays the power of using rat genetics to encourage the discovery of human genetic targets in common diseases such as MS. Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-γ expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.

Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study.

Objective Pregnancy has a well documented effect on relapse risk in multiple sclerosis (MS). Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months postpartum. However, it is unclear as to whether there are any long term effects on disability. Methods Data were collated from clinical records and family histories systematically collected from the University of British Columbia MS Clinic. Results Clinical and term pregnancy data were available from 2105 female MS patients. MS patients having children after MS onset took the longest time to reach an Expanded Disability Status Scale (EDSS) score of 6 (mean 22.9 years) and patients having children before MS onset were the quickest (mean 13.2 years). However, these effects were not related to term pregnancy and were fully accounted for by age of MS onset. Conclusions Pregnancy had no effect on the time to reach an EDSS score 6. As MS predominantly affects women of childbearing age, women with MS can be reassured that term pregnancies do not appear to have any long term effects on disability.

Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice.

Background: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS. Objective: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity. Methods: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident ‘acquired demyelinating syndromes’ (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004–2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status. Results: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice. Conclusion: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.

Genome Wide Linkage Analysis of 972 Bipolar Pedigrees Using Single Nucleotide Polymorphisms

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ∼1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.