Risk of Autism Elevated Following Pediatric Ischemic Stroke, Study Suggests

Heléne E.K. Sundelin, MD, PhD

In a cohort study that spanned almost 50 years, investigators found a 3-fold increased risk of autism after pediatric stroke, an even greater risk observed in individuals with comorbid epilepsy. These findings could not be explained by being born preterm, being small for gestational age, or having a first-degree relative with autism.

Lead author Helene Sundelin, MD, PhD, postdoctoral researcher, Department of Women’s and Children’s Health, Karolinska Institutet, and colleagues concluded that these data emphasize the need for readily screening for autism among children who have had an ischemic stroke if the disorder is suspected.“Although autism cannot be acquired later in life and the main cause of autism is considered genetic, stroke might be an additional for reaching the turning point as autism has multiple and complex causes. Although there are some differences in etiology and risk factors between perinatal and childhood stroke, in our study it seems that the developmental stage of the brain at the insult was not critical for the risk of developing autism after stroke," Sundelin et al wrote.

Using Swedish registries, Sundelin and colleagues identified 1322 indexed individuals with ischemic stroke who were younger than 18 years, alive 1 week after stroke, and were without prior autism. Each child with ischemic stroke was compared with 10 controls matched for sex, year of birth, and country of residence. Controls and first-degree relatives of children with ischemic stroke and their controls were identified using the Total Population and Multi-Generation Registers.

Follow-up started at the date of ischemic stroke or corresponding date in matched controls that ended with diagnosis of autism, death, or December 31, 2016, whichever occurred first. Cox regression analyses, conditioned on a matching set, were used to calculate hazard ratios (HRs) to estimate the risk of future autism amongst these individuals.

After excluding children who died within the first week after stroke or diagnosed with autism before their stroke, 1322 index individuals and 13,193 controls remained. Of index individuals with ischemic stroke, 46 (3.5%) were diagnosed with autism compared with 161 (1.2%) controls, corresponding to an adjusted HR (aHR) of 3.02 (95% CI, 2.15-4.25).

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To Sundelin et al’s knowledge, there was only one other study that has investigated the association between stroke and autism in a mixed cohort of hemorrhage and ischemic perinatal stroke. At the conclusion of the analysis, aHRs for the risk of autism after perinatal ischemic stroke and childhood stroke were 2.69 (95% CI, 1.44-5.03) and 3.18 (95% CI, 2.12-4.78), respectively. Notably, there was no significant difference in the risk increase between females and males or regarding age at stroke.

After the exclusion of children born preterm and small for gestational age (SGA), the increased risk of autism remained for both perinatal (aHR, 4.02; 95% CI, 2.01-8.02) and childhood stroke (aHR, 3.66; 95% CI, 2.27-5.91). Children with stroke and comorbid epilepsy saw an even greater increased risk of autism, demonstrated by aHR of 7.05 (95% CI, 3.74-13.30). When stratifying this group according to age at stroke, the risk of autism was represented by aHRs of 5.52 (95% CI, 1.88-16.19) in perinatal stroke and by aHRs of 8.05 (95% CI, 3.63-17.85) in childhood stroke.

For individuals with ischemic stroke who had adverse motor outcomes, the aHR for the risk of autism was 4.28 (95% CI, 2.44-7.51). According to age at stroke, investigators recorded aHRs of 5.77 (95% CI, 2.09-15.87) for perinatal and 3.85 (95% CI, 1.95-7.59) for childhood stroke.

Relative to controls, an exploratory analysis indicated an increased risk for autism among first-degree relatives to children with ischemic stroke (HR, 1.59; 95% CI, 1.20-2.11), largely due to the increased risk in siblings (HR, 1.73; 95% CI, 1.25-2.41). Notably, this was only significant in relatives to individuals with childhood stroke (stroke onset >28 days)(HR, 1.64; 95% CI, 1.20-2.25) but not with perinatal stroke (HR, 1.40; 95% CI, 0.73-2.66). The increased risk remained even in siblings to index individuals without autism.

REFERENCE
1. Sundelin H, Soderling J, Bang P, Bolk J. Risk of autism after pediatric ischemic stroke: a nationwide cohort study. Neurology. Published online March 21, 2022. doi:10.1212/WNL.00000000000200253