Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood: a Danish nationwide cohort study

Abstract

Background: Paediatric seizures have been linked to psychiatric disorders in childhood, but there is a paucity of large-scale population-based studies of psychiatric comorbidity in later life. We aimed to examine the relation between childhood seizures and the risk of psychiatric disorders in adolescence and early adulthood.

Methods: We did a register-based cohort study of all individuals born in Denmark in 1978-2002. Using diagnostic information from the Danish National Patient Register, all cohort members were categorised according to occurrence of febrile seizures and epilepsy, before entering the follow-up period on their 10th birthday. Individuals were followed up until onset of mental illness, death, emigration, or the end of the study period on Dec 31, 2012. Cox regression analyses were used to estimate the risk of five predefined groups of psychiatric disorders (substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder), separately and combined. Models were adjusted for relevant confounders.

Findings: Between Jan 1, 1978, and Dec 31, 2002, 1 291 679 individuals were born in Denmark and followed up in our population cohort (approximately 15 million person-years). 43 148 individuals had a history of febrile seizures, 10 355 had epilepsy, and 1696 had both these disorders. 83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest. The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures (hazard ratio [HR] 1·12, 95% CI 1·08-1·17), epilepsy (1·34, 1·25-1·44), or both disorders (1·50, 1·28-1·75). Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders. Associations did not differ between males and females (p=0·30) but increased with a growing number of admissions for febrile seizures (p<0·0001) and with later onset of childhood epilepsy (p<0·0001).

Interpretation: Children with epilepsy and febrile seizures-with and without concomitant epilepsy-are at increased risk of developing a broad range of psychiatric disorders in later life. Clarification of the underlying mechanisms attributable to these associations is needed to identify potential options for prevention.

Funding: Novo Nordisk Foundation, Danish Epilepsy Association, Central Denmark Region, Lundbeck Foundation, and Stanley Medical Research Institute.

Figure 1:. Adjusted relative risks of psychiatric disorders associated with a history of febrile seizures and epilepsy in childhood among 1,291,769 children born in Denmark (1978–2002).

Footnote: All analyses are adjusted for sex, calendar year, birth weight, gestational age at delivery, Apgar score (5 minutes), maternal education, paternal income, parental age at birth, and parental psychiatric disease.

Figure 2:. Adjusted relative risks of subgroupings of psychiatric disorders associated with a history of febrile seizures and epilepsy in childhood, among 1,291,769 children born in Denmark (1978–2002).

Footnotes: The following classification of disorders were used: Mental and behavioral disorders due to alcohol use (ICD-10: F10, ICD-8: 291.x9, 303.x9, 303.20, 303.28, 303.90), Mental and behavioral disorders due to cannabis use (ICD-10: F12, ICD-8: 304.59), Schizophrenia (ICD-10: F20, ICD-8: 295.x9 (excluding 295.79)), Schizoaffective disorder (ICD-10: F25, ICD-8: 295.79, 296.89), Bipolar disorders (ICD-10: F30-F31, ICD-8: 296.19, 296.39, 298.19), Single and recurrent depressive disorder (ICD-10: F32-F33, ICD-8: 296.09, 296.29, 298.09, 300.49), Recurrent depressive disorder (ICD-10: F33, ICD-8: 296.09, 296.29, 298.09, 300.49b), Obsessive compulsive disorder (ICD-10: F42, ICD-8: 300.39), Borderline personality type (ICD-10: F60.31, ICD-8: 301.84) For recurrent depression, onset was defined as the second admission that occurred at least 8 weeks after the last discharge with these ICD-8 codes. All analyses are adjusted for sex, calendar year, birth weight, gestational age at delivery, Apgar score (5 minutes), maternal education, paternal income, parental age at birth, and parental psychiatric disease.

Figure 3:. Adjusted relative risks of psychiatric disorders according to number of admissions with febrile seizures, among 1,291,769 children born in Denmark (1978–2002).

Footnote: All analyses are adjusted for sex, calendar year, birth weight, gestational age at delivery, Apgar score (5 minutes), maternal education, paternal income, parental age at birth, and parental psychiatric disease.