Traumatic brain injury, stroke, and epilepsy: A mediation study in a Danish nationwide cohort.

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 ≥ 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 ≥ 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 ≥ 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.

Perinatal adversities and risk of epilepsy after traumatic brain injury: A Danish nationwide cohort study.

OBJECTIVES: Traumatic brain injury (TBI) and perinatal adversities such as low gestational age at birth, low birth weight, low Apgar, and being born small for gestational age are well-established risk factors for epilepsy. We examined whether perinatal adversities modified the risk of epilepsy after TBI in a nationwide cohort study of Danish singletons born from 1982 to 2011. MATERIALS AND METHODS: We categorized perinatal adversities as a composite measure of preterm delivery, low birth weight, low Apgar score, or being born small for gestational age. Cox regression and competing risk regression were used to estimate the risk of epilepsy after TBI according to such perinatal adversities. The study included 1,715,095 singletons (51.1% males). The mean age at end of follow-up was 19.3 years (Interquartile range [IQR] = 12.1-26.3). During follow-up, 85,636 persons (58.2% males) sustained a TBI and 18,064 developed epilepsy (50.7% males), of whom 1329 persons had a preceding TBI. RESULTS: The hazard ratio (HR) of epilepsy in persons with perinatal adversities was 1.19 (95% confidence interval [CI] 1.15-1.24), compared to persons without. The HR of epilepsy in persons with TBI was 2.31 (95% CI 2.18-2.45) compared to persons without TBI, but this risk was not modified by perinatal adversities (p = 0.2460). CONCLUSIONS: Perinatal adversities and TBI both increased the risk of epilepsy, but the risk of epilepsy after TBI was not modified by these perinatal adversities.

Repeated traumatic brain injury and risk of epilepsy: a Danish nationwide cohort study.

Traumatic brain injury is associated with increased risk of epilepsy, but the importance of repeated traumatic brain injuries has not yet been established. We performed a nationwide population-based cohort study of 2 476 905 individuals born in Denmark between 1977 and 2016. We estimated hazard ratios (HRs) and the cumulative incidence of epilepsy following traumatic brain injury using Cox and competing risk regression, respectively. To estimate the cumulative incidence of epilepsy in the population without traumatic brain injury, we matched 10 controls for each subject with traumatic brain injury on year of birth, sex, and date of brain insult in the index person. In the cohort, traumatic brain injury was sustained by 167 051 subjects (71 162 females and 95 889 males), and 37 200 individuals developed epilepsy (17 905 females and 19 295 males). Compared with subjects without traumatic brain injury, the relative risk of epilepsy increased after a first traumatic brain injury [HR 2.04, 95% confidence interval (CI) 1.96-2.13] and even more after a second traumatic brain injury (HR 4.45, 95% CI 4.09-4.84). The risk increased with the severity of the first and the second traumatic brain injury, most notably after severe traumatic brain injuries. Females were more likely than males to develop epilepsy after mild traumatic brain injury (HR 2.13, 95% CI 2.00-2.28 versus HR 1.77, 95% CI 1.66-1.88; P < 0.0001); in contrast, males were more likely than females to develop epilepsy after severe traumatic brain injury (HR 5.00, 95% CI 4.31-5.80 versus 3.21, 95% CI 2.56-4.03; P = 0.0012). The risk remained increased for decades after the traumatic brain injury. This knowledge may inform efforts to prevent the development of post-traumatic epilepsy.

Duration and timing of depression and risk of family dissolution: A register-based cohort study of newly-formed Danish families.

BACKGROUND: Depression is detrimental to partnership stability. However, it remains unclear if and how the duration and timing of depression affect the risk of family dissolution. METHODS: We conducted a Danish register-based cohort study of newly-formed cohabiting and married couples in 2008 and 2009, who were followed from the second year after family formation. Depressive episodes were defined by individual-level prescription patterns of antidepressant drugs (ATC codes N06A) in either partner. Family dissolution was characterized by the discontinuation of a shared residential address. Using Longitudinal Targeted Minimum Loss-based Estimation, we estimated the risk of family dissolution after 5 years of follow-up under various lengths and timings of depressive episodes. RESULTS: There were 102,335 families included. The covariate-adjusted risk of family dissolution in families without depressive episodes was 30.0 % (95 % CI 29.6-30.4 %) and 35.5 % (95 % CI 29.5-41.5 %) in families with at least one depressive episode during follow-up. The risk of family dissolution increased with the duration of depressive episodes to 42.2 % (95 % CI 40.8-43.6 %) for five coherent years of depression. Depression shortly after family formation carried higher risk of family dissolution; this risk was 42.3 % (95 % CI 38.4-46.3 %) for depression experienced in the first year of family formation versus 32.9 % (95 % CI 31.8-34.0 %) in the fifth year of family formation. LIMITATIONS: Proxy measures of depression by antidepressant prescriptions fails to identify milder depression. Annual measures of family dissolution precluded more fine-grained analyses of time-intervals. CONCLUSIONS: Depression is disruptive to family stability, particularly with longer duration and early onset after family formation.

Directionality of the Association Between Epilepsy and Depression: A Nationwide Register-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Epilepsy and depression share a bidirectional relationship; however, its magnitude and long-term temporal association remain to be elucidated. This study investigates the magnitude and long-term association between epilepsy and depression, comparing with the risks of the 2 disorders after another chronic medical illness (asthma). METHODS: In a nationwide register-based matched cohort study, we identified all individuals who received a first diagnosis of epilepsy, depression, and asthma from January 1, 1980, to December 31, 2016. We used a Cox regression model to estimate the risk of epilepsy after depression and vice versa and the risk of epilepsy or depression after asthma, compared with healthy references matched on age and sex, adjusting for medical comorbidity, substance abuse, and calendar time. Results were stratified by epilepsy subtype. We furthermore investigated the risk of admission with acute seizures for persons with epilepsy who became depressed. RESULTS: In a population of 8,741,955 individuals, we identified 139,014 persons with epilepsy (54% males, median age at diagnosis 43 years [inter quartile range (IQR) 17-65 years]), 219,990 persons with depression (37% males, median age at diagnosis 43 years [IQR 29-60 years]), and 358,821 persons with asthma (49% males, median age at diagnosis 29 years [IQR 6-56 years]). The adjusted hazard ratio (aHR) of depression after epilepsy was 1.88 (95% CI 1.82-1.95), and the aHR of epilepsy after depression was 2.35 (95% CI 2.25-2.44). The aHR of depression after asthma was 1.63 (95% CI 1.59-1.67) and that of epilepsy after asthma, 1.48 (95% CI 1.44-1.53). The risk of depression was highest in the few years preceding and after an epilepsy diagnosis, and vice versa, but remained elevated during the entire follow-up period for both directions of the association. There was no evidence of a stronger association with depression for any epilepsy subtype. Receiving a diagnosis of depression subsequent to an epilepsy diagnosis was associated with a 1.20-fold (95% CI 1.07-1.36) increased HR of acute hospital admission with seizures. DISCUSSION: We identified a long-term bidirectional relationship between depression and epilepsy in a large-scale cohort study. Risk estimates were higher than those of epilepsy or depression after asthma.