TY - JOUR

T1 - Traumatic brain injury, stroke, and epilepsy

T2 - A mediation study in a Danish nationwide cohort

AU - Lolk, Kasper

AU - Lange, Theis

AU - Elwert, Felix

AU - Dreier, Julie W.

AU - Christensen, Jakob

N1 - Publisher Copyright: © 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

PY - 2023

Y1 - 2023

N2 - Objective: Traumatic brain injury (TBI) and stroke are well-known causes of acquired epilepsy. TBI is also a risk factor for stroke, and injury-induced stroke may indirectly convey a proportion of the epilepsy risk following TBI. We studied the extent to which the effect of TBI on epilepsy operated through intermediary stroke. Methods: We analyzed a nationwide, matched, register-based cohort of adults (Formula presented.) 40 years of age whose first TBI at Danish hospitals was recorded between 2004 and 2016. A matched reference population was sampled for comparison. During follow-up, we recorded all acute strokes. Cox proportional hazard models and the difference method were used to estimate the total and controlled direct effect hazard ratios (HRs) of TBI on epilepsy and the indirect effect HRs of TBI on epilepsy operating through stroke, and to calculate the proportion eliminated. Analyses were stratified by severity of, age at, and time since TBI. Results: We followed 57 900 persons with TBI (48.6% males) from median age 61 years (interquartile range = 51–75), and 561 977 age- and sex-matched references. The total effect of TBI on epilepsy was higher for persons aged 40–59 years (HR = 5.15, 95% confidence interval [CI] = 4.65–5.72) than for persons aged (Formula presented.) 60 years (HR = 4.55, 95% CI = 4.19–4.95). In contrast, the indirect effect of TBI mediated by stroke was lower for persons aged 40–59 years (HR = 1.02, 95% CI = 1.02–1.03) than for persons aged (Formula presented.) 60 years (HR = 1.05, 95% CI = 1.04–1.06). We estimated 2.3% and 5.6% of the risk of epilepsy after TBI to operate through stroke for these age groups, respectively. Significance: Less than 6% of the risk of epilepsy following TBI operated through intermediary stroke. However, this mechanism seems to play an increasing role with age and for late onset epilepsies. This warrants further investigation.

AB - Objective: Traumatic brain injury (TBI) and stroke are well-known causes of acquired epilepsy. TBI is also a risk factor for stroke, and injury-induced stroke may indirectly convey a proportion of the epilepsy risk following TBI. We studied the extent to which the effect of TBI on epilepsy operated through intermediary stroke. Methods: We analyzed a nationwide, matched, register-based cohort of adults (Formula presented.) 40 years of age whose first TBI at Danish hospitals was recorded between 2004 and 2016. A matched reference population was sampled for comparison. During follow-up, we recorded all acute strokes. Cox proportional hazard models and the difference method were used to estimate the total and controlled direct effect hazard ratios (HRs) of TBI on epilepsy and the indirect effect HRs of TBI on epilepsy operating through stroke, and to calculate the proportion eliminated. Analyses were stratified by severity of, age at, and time since TBI. Results: We followed 57 900 persons with TBI (48.6% males) from median age 61 years (interquartile range = 51–75), and 561 977 age- and sex-matched references. The total effect of TBI on epilepsy was higher for persons aged 40–59 years (HR = 5.15, 95% confidence interval [CI] = 4.65–5.72) than for persons aged (Formula presented.) 60 years (HR = 4.55, 95% CI = 4.19–4.95). In contrast, the indirect effect of TBI mediated by stroke was lower for persons aged 40–59 years (HR = 1.02, 95% CI = 1.02–1.03) than for persons aged (Formula presented.) 60 years (HR = 1.05, 95% CI = 1.04–1.06). We estimated 2.3% and 5.6% of the risk of epilepsy after TBI to operate through stroke for these age groups, respectively. Significance: Less than 6% of the risk of epilepsy following TBI operated through intermediary stroke. However, this mechanism seems to play an increasing role with age and for late onset epilepsies. This warrants further investigation.

KW - apoplexy

KW - brain injury

KW - cohort study

KW - intermediary factors

KW - posttraumatic epilepsy

U2 - 10.1111/epi.17497

DO - 10.1111/epi.17497

M3 - Journal article

C2 - 36537766

AN - SCOPUS:85145502857

VL - 64

SP - 718

EP - 727

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 3

ER -