Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS: A Nationwide Population-Based Case-Control Study.

Background and objectives: Previous studies have suggested that traumatic head injury (THI) may be a risk factor of amyotrophic lateral sclerosis (ALS) development, yet the association remains unclear. We aimed to determine whether hospital-diagnosed THI is an important ALS risk factor, and we investigated the magnitude and duration of associated ALS risk.

Methods: In this population-based case-control study, we used individual-level data linkage across nationwide health registers from 1980 to 2021 to identify patients with hospital-diagnosed ALS. Each patient was matched 1:10 with individuals from the general population by age, sex, and diagnostic index date. We used conditional logistic regression to examine the relative risk of ALS associated with having previous hospital-diagnosed THI. To avoid the effect of reverse causation, we investigated ALS risk within several time windows and repeated all analyses after restricting THI exposures to more than 3 years before the date of ALS diagnosis.

Results: THI was observed in 4.7% of 5,943 ALS cases vs 3.7% of 59,426 controls, with a matched odds ratio (OR) of 1.3 (95% CI 1.1-1.4). However, the risk of ALS declined considerably with increasing time since head injury, with a high OR of 4.5 (95% CI 2.8-7.3) observed within the 6 months before ALS diagnosis. If head injury was suffered 6-12 months before ALS diagnosis, the OR was 2.4 (95% CI 1.4-4.0). Restricting the analysis to THI suffered more than 3 years before ALS diagnosis, we found no association with an OR of 1.1 (95% CI 1.0-1.3).

Discussion: Although a strong association of ALS with THI experienced ≤1 year before ALS diagnosis was evident, our results suggest that this is due to reverse causation. When restricting the analysis to a period deemed relevant for causative events leading to ALS development, no association was observed. Consequently, we do not consider THI an important ALS risk factor. This study was limited by the inability to consider minor THIs not receiving hospital attendance. Future research should explore alternative models to unfold this possible ALS risk factor.