Irene Yee

Conjugal multiple sclerosis: Population-based prevalence and recurrence risks in offspring

From a population‐based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty‐three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%–0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease. Ann Neurol 2000;48:927–931

Maternal age and birth defects: a population study

Since more and more women in developed countries are delaying childbearing to an older age, it is important to find out whether birth defects, other than those resulting from chromosomal anomalies, are related to maternal age. We have studied all 26,859 children with birth defects of unknown aetiology identified among 576,815 consecutive livebirths in British Columbia. All these cases records were linked with provincial birth records to allow determination of maternal age at birth. We excluded children with chromosomal anomalies and those with other birth defects of known aetiology. Only 3 of the 43 birth defect categories studied showed significant maternal-age-specific trends: there were decreasing linear trends with maternal age for patent ductus arteriosus (chi 2 = 36.65, 1 df, p less than 0.01) and hypertrophic pyloric stenosis (chi 2 = 4.90, 1 df, p less than 0.05) and a bell-shaped curve (risk increasing to maternal age 30 then falling) for congenital dislocatable hip/hip click. The findings from this population-based analysis of no association between the incidence of birth defects of unknown aetiology and advancing maternal age should be reassuring to healthy women who opt to delay childbearing.

Multiple sclerosis in stepsiblings: recurrence risk and ascertainment

Reports implicating specific transmissible agents in multiple sclerosis (MS) susceptibility continue to appear. We therefore re-evaluated MS risk in 687 stepsiblings of 19 746 MS index cases. We found the risk of MS to be indistinguishable from that of the general population after diagnostic verification. These results are coherent with studies of adopted children, half siblings and conjugals, showing no risk attributable to the familial microenvironment. This family based genetic epidemiological approach found no trace of transmissibility other than genetic from one affected individual to another in the high prevalence area of Canada. This adds to existing data showing that the action of environment in influencing MS risk is operative at a population level.

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

BACKGROUNDnChronic 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.nnnMETHODSnWe 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.nnnFINDINGSnCatheter 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).nnnINTERPRETATIONnThis 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.nnnFUNDINGnMS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study

Background: The ratio of female to male (F:M) multiple sclerosis (MS) cases varies geographically, generally being greater in areas of high prevalence. In many regions, including Canada, rising MS incidence in women has been implied by the marked increase in F:M ratio. Methods: We examined the F:M ratio over time in MS patients in the Canadian Collaborative Study born outside Canada, with onset postmigration (nu200a=u200a2531). We compared the trends to native-born Canadians, by region of origin and age at migration. Results: Regression analysis showed that year of birth (YOB) was a significant predictor of sex ratio in immigrants (χ2u200a=u200a21.4, p<0.001 correlation ru200a=u200a0.61). The rate of change in sex ratio was increasing in all migrant subgroups (by a factor of 1.16 per 10-year period, p<0.001), with the steepest increase observed in those from Southern Europe (1.27/10 years, p<0.001). The overall immigrant F:M ratio was 2.17, but varied by country of origin. It was significantly lower in migrants from Southern Europe compared with Northern Europe or USA (1.89 vs 2.14 and 2.86, pu200a=u200a0.023 and pu200a=u200a0.0003, respectively). Increasing age at immigration was associated with decreasing sex ratio (pu200a=u200a0.041). The sex ratio of individuals migrating <21 was significantly higher than those migrating ⩾21 (2.79 vs 1.96, pu200a=u200a0.004). Conclusions: MS sex ratio in immigrants to Canada is increasing but variable by region of origin and influenced by age at migration. The findings highlight the importance of environmental effect(s) in MS risk, which are likely gender-specific.

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 22.9u2005years) and patients having children before MS onset were the quickest (mean 13.2u2005years). 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.

Reproductive decision making after the diagnosis of multiple sclerosis (MS)

Objective: This study aimed to determine reproductive practices and attitudes of North Americans diagnosed with multiple sclerosis (MS) and the reasons for their reproductive decision making. Methods: A self-administered questionnaire on reproductive practices was mailed to 13,312 registrants of the North American Research Committee on Multiple Sclerosis (NARCOMS) database who met inclusion criteria for the study. Completed questionnaires were then returned to the authors in an anonymous format for analysis. Results: Among 5949 participants, the majority of respondents (79.1%) did not become pregnant following diagnosis of MS. Of these, 34.5% cited MS-related reasons for this decision. The most common MS-related reasons were symptoms interfering with parenting (71.2%), followed by concerns of burdening partner (50.7%) and of children inheriting MS (34.7%). The most common reason unrelated to MS for not having children was that they already have a “completed family” (55.6%). Of the 20.9% of participants who decided to become pregnant (or father a pregnancy) following a diagnosis of MS, 49.5% had two or more pregnancies. Conclusion: This study indicates that an MS diagnosis does not completely deter the consideration of childbearing in MS patients of both genders.

Factors influencing sib risks for multiple sclerosis.

Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non‐genetic (environmental) factors. u2028The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1u2003083 MS index cases, 2u2003166 of their parents and 3u2003112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS. u2028These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.

Population-based study of long-term outcomes after amniocentesis

Amniocentesis is now commonly used in many countries; it is important to know whether there are any long-term adverse effects on children born after this procedure, in particular disabilities that may emerge during childhood or adolescence. We studied consecutive liveborn offspring of women who had had amniocentesis and compared them with matched controls whose mothers had not had amniocentesis. The controls were matched for age of mother, residence by geographic health unit, sex, and when the birth occurred. 1296 cases and 3704 controls were studied. With the exception of one disorder, the offspring of women who had had amniocentesis were no more likely than controls to have a registrable disability (such as hearing disabilities, learning difficulties, visual problems, and limb anomalies) during childhood and adolescence. The follow-up period was 7-18 years. Children of women who had amniocentesis had a significantly higher rate of haemolytic disease due to ABO isoimmunisation than matched controls. The results of this study should therefore be reassuring to women having amniocentesis, and be useful to women making decisions about having this procedure.

Disease onset in familial and sporadic primary progressive multiple sclerosis

The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration which is believed to start early in the disease process, even before the onset of clinical symptoms. Symptomatic onset then occurs when this process reaches a threshold after which the axonal loss can no longer be compensated. A preliminary study showed that patients with familial PPMS had an earlier clinical onset than patients with sporadic disease, suggesting a hereditary component to the disease process of PPMS. In this study, we combined data from two large, population-based, longitudinal MS databases to investigate disease onset in familial and sporadic PPMS. We examined 411 patients with PPMS. There were no differences in gender distribution or onset symptoms between familial and sporadic PPMS. Patients with familial PPMS were significantly younger at disease onset (n = 84, median age: 37.6 years) than patients with sporadic disease (n = 327, median age: 42.7, p = 0.007). This difference was due to a greater proportion of familial cases with a disease onset before the age of 30 and a smaller proportion with disease onset between 40 and 50 years of age (p = 0.002). Gender had no significant effect on the age at disease onset. Further analyses showed that these findings were unlikely to be due to ascertainment bias towards an earlier diagnosis in familial cases. Our findings suggest a hereditary component to the disease process of PPMS. It would be worthwhile to identify patients with familial PPMS for future research on disease modifying genes in MS.