ARTICLE IN BRIEF
Researchers reported an association between one or two concussions in adolescents and the subsequent risk for multiple sclerosis (MS). But other independent experts noted that other risk factors for MS may be contributing factors, as well.
Having two or more concussions during adolescence more than doubles the subsequent risk of developing multiple sclerosis (MS), a large, prospective case-control study using Swedish national health registries found.
The study, in the September 4 online edition of Annals of Neurology, is one of the largest studies of traumatic head injury before age 20 and of a single concussion versus multiple concussions.
A single concussion that occurred between the ages of 11 and 20 produced an adjusted odds ratio of adolescents later being diagnosed with MS of 1.22 (95% CI: 1.05-1.42, p=0.008), while two or more concussions were associated with an odds ratio of 2.33 (1.35-4.04, p=0.002). No association with MS was observed for children aged 10 or younger who had concussions, or for adolescents who experienced the control diagnosis of broken limb bones.
The study also found that the number of days of hospitalization following concussion, a proxy for injury severity, was a significant predictor of subsequent risk of MS: the longer the stay, the higher the risk.
“The reason that a brain injury may increase MS risk,” the paper hypothesized, is “possibly due to initiation of an autoimmune process in the central nervous system. Although prior studies of MS and concussions reached conflicting conclusions, none focused specifically on concussion during adolescence.”
The implication of a dose response lends credence to the conclusion that the association may be causal, researchers who study MS epidemiology told Neurology Today.
“Whenever you see a dose-dependent relationship between an exposure and an outcome, that gives you reason to think that there's something there,” said Milena Gianfrancesco, PhD, MPH, an autoimmune disease epidemiologist and postdoctoral scholar at the University of Southern California San Francisco School of Medicine, who was not involved with the study.
Prior studies of MS and concussions have reached conflicting conclusions, she noted, but they failed to focus on adolescents.
By using a large, reliable set of prospectively collected data, and distinguishing between younger children and adolescents, the researchers hoped to bring some clarity to the subject.
Using the National Swedish Patient register, which comprises hospital diagnoses, and the Swedish Multiple Sclerosis register, they identified all MS diagnoses up to 2012 among people born since 1964. They then matched the 7,292 patients with MS with 72,920 non-MS subjects, controlling for sex, year of birth, age and vital status at MS diagnosis, and county of diagnosis. Diagnoses of concussion, and control diagnoses of broken limb bones, were identified from birth to age 10 years, and from ages 11 to 20.
The researchers found no association between MS and concussion for childhood, or for broken limb bones in either childhood or adolescence. By contrast, they observed significant associations between one or more concussions in adolescence and the subsequent risk of being diagnosed with MS.
Although no measure of concussion severity was available for the study, the authors did look at whether a longer stay at the hospital was associated with a higher risk of MS. Compared with no concussion, the odds ratio for MS following a single day at the hospital due to concussion was 1.15 (0.97-1.37, p=0.105), compared with 1.55 (1.12-2.14, p=0.008) for two days and 1.75 (1.16-2.64, p=0.007) for three days or more, the study found.
“In adolescents with more than one concussion, it's a doubling of the risk for MS,” said the first author of the paper, Scott Montgomery, PhD, an adjunct professor and director of clinical epidemiology and biostatistics at Örebro University and Örebro University Hospital in Sweden. “But the risk of developing MS is very low to begin with. That's why we want to know more about susceptibility. That's a study we're doing to do now, to look at genetic susceptibility. Then we might see a more precise estimate of risk for individuals. We know that smoking is modestly associated with an increased risk of developing MS, but for those who are genetically susceptible to developing MS, the increased risk associated with smoking is far higher.”
Asked whether his team had checked whether three or more concussions had an even greater effect on MS risk than did two, Dr. Montgomery said, “You run out of people if you look for more than two concussions. Very few have more than two.”
Distinguishing between adolescence and childhood makes sense, he said, because prior studies have shown that infection with Epstein-Barr-virus in adolescence, but not during childhood, significantly raises the risk of developing MS.
“It points to adolescence as a window of susceptibility when certain environmental exposures will increase the risk of MS,” Dr. Montgomery said.
Bianca Weinstock-Guttman, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Science at the University of Buffalo, and director of both its pediatric and adult MS centers, said she wondered why no association was seen between concussion in younger children and the subsequent risk of developing MS.
“Is it only because the injuries in adolescence might be more severe?” she asked. “Or it is that the immune system is more active in the adolescent years and, in the context of brain injury, will induce a stronger reaction?”
The study cited prior research showing that brain injury is associated with initiation of an autoimmune process in the central nervous system. But other mechanisms by which concussion is associated with MS could also be at play, said Lauren Krupp, MD, FAAN, professor of neurology and director of the Multiple Sclerosis Comprehensive Care Center at New York University's Langone Medical Center.
“Other risk factors have been associated with MS, including smoking and obesity, but I don't know that it's only the immune system mediating those effects,” Dr. Krupp said. “My take is that in somebody who is genetically vulnerable to the development of MS, if you insult the brain with stressors during adolescence, that may increase their risk of developing MS. I think of it as a stressor on the brain's development.”
Dr. Krupp pointed to a paper she coauthored earlier this year in the journal Frontiers in Neurology that found a relationship between adverse childhood experiences and the age of onset of MS. Higher scores on the Adverse Childhood Experiences measure were associated with an increased risk of MS, the study found [(onset (r) = -0.30, p=0.04)].
Dr. Gianfrancesco said she hoped that future studies of concussion and MS will control for these other risk factors, such as obesity, smoking, EBV, and vitamin D level.
“A subanalysis that controls for those risk factors and how they interact would be really interesting,” she said.
EXPERTS: ON CONCUSSION AND RISK FOR MS IN ADOLESCENTS
LINK UP FOR MORE INFORMATION:
•. Montgomery S, Hiyoshi A, Burkill S, et al Concussion in adolescence and risk of multiple sclerosis http://onlinelibrary.wiley.com/doi/10.1002/ana.25036/abstract. Ann Neurol
2017; Epub 2017 Sept 4.
•. Lunny CA, Fraser SN, Knopp-Sihota JA. Physical trauma and risk of multiple sclerosis: A systematic review and meta-analysis of observational studies http://http://www.jns-journal.com
/article/S0022-510X(13)02860-8/fulltext. J Neurol Sci
•. Pfleger CC, Koch-Henriksen N, Stenager E, et al Head injury is not a risk factor for multiple sclerosis: A prospective cohort study http://journals.sagepub.com/doi/10.1177/1352458508099475. Mult Scler
•. Belbasis L, Bellou V, Evangelou E, et al Environmental risk factors and multiple sclerosis: An umbrella review of systematic reviews and meta-analyses http://http://www.thelancet.com
/journals/laneur/article/PIIS1474-4422(14)70267-4/abstract. Lancet Neurol
•. Shaw MT, Pawlak NO, Frontario A, et al Adverse childhood experiences are linked to age of onset and reading recognition in multiple sclerosis https://http://www.frontiersin.org
/articles/10.3389/fneur.2017.00242/full. Front Neurol
•. Rhead B, Bäärnhielm M, Gianfrancesco M, et al Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk http://ng.neurology.org/content/2/5/e97.short. Neurol Genet