Accounting for age of onset and family history improves power in genome-wide association studies.

Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age of onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here, we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), which jointly accounts for age of onset and sex as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields statistically significant power gains over LT-FH and large power gains over genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data and to mortality in the UK Biobank and found 20 genome-wide significant associations with LT-FH++, compared to ten for LT-FH and eight for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.

An algorithm for drug-resistant epilepsy in Danish national registers.

Patients with drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. Identification of persons with DRE in administrative data can allow for effective large-scale research, and we therefore aimed to construct an algorithm for identification of DRE in Danish nation-wide health registers. We used a previously generated sample of 525 persons with medical record-validated incident epilepsy between 2010-2019, of which 80 (15%) fulfilled International League Against Epilepsy (ILAE) criteria of DRE at the time of the latest contact - this cohort was considered the gold standard. We linked information in the validated cohort to Danish national health registers and constructed register-based algorithms for identification of DRE-cases. The accuracy of each algorithm was validated against the medical record-validated gold standard. We applied the best performing algorithm according to test accuracy (F1 score) to a large cohort with incident epilepsy identified in the Danish National Patient Registry between 1995 and 2013 and performed descriptive and logistic regression analyses to characterize the cohort with DRE as identified by the algorithm. The best performing algorithm in terms of F1 score was defined as 'fillings of prescriptions for ≥ 3 distinct antiseizure medications (ASMs) within 3 years or acute hospital visit with epilepsy/convulsions following fillings of prescriptions for two distinct ASMs' (sensitivity 0.59, specificity 0.93, positive predictive value 0.59, negative predictive value 0.92, area under the receiver operating characteristic curve 0.77, and F1 score 0.595). Applying the algorithm to a register-based cohort of 83,682 individuals with incident epilepsy yielded 8,650 cases (10.3 %) with DRE. In multivariable logistic regression analysis, early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse, were independently associated with risk of being classified with DRE. We developed an algorithm for the identification of DRE in Danish national registers, which can be applied for a variety of research questions. We identified early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse as risk factors for DRE.

Epilepsy in childhood and school performance: a nation-wide cohort study.

Childhood epilepsy has been linked to poor academic performance, but large-scale studies are lacking. In this nation-wide study of school-aged children, we examined the association between childhood epilepsy and school performance in standardized tests according to phenotypic and treatment-related characteristics. We performed a matched register-based cohort study of children born in Denmark (1997-2009) who participated in the Danish National School Test Programme between 2010 and 2019. We used population and health registers to identify children with epilepsy and a randomly sampled sex- and age-matched reference cohort without epilepsy (ratio 1:10). Norm-based test scores from language and mathematics reflecting performance as a percentile of the nation-wide distribution of scores (scale 1-100) were used to assess academic performance. Adjusted differences in mean standardized scores between children with and without epilepsy were estimated using linear regression models. Among 582 840 children participating in the School Test Programme, we identified 4659 (0.8%) children with epilepsy (52.8% males) and 46 590 matched reference children. Median age at epilepsy onset was 7.5 years (interquartile range: 4.0-10.6). Childhood epilepsy was associated with poorer school performance overall (mean score = 48.2 versus references = 56.7; adjusted difference = -6.7, 95% CI: -7.4 to -6.0), and worse performance was found in all epilepsy subgroups, including in 3534 children with uncomplicated epilepsy (i.e. no other pre-existing neurologic or intellectual disabilities and no identified possible cause for epilepsy; adjusted difference = -6.0, 95% CI: -6.8 to -5.2). No major variation by sex, age or subject was observed, but larger score differences were seen in children using antiseizure medication at time of testing (e.g. valproate monotherapy, adjusted difference = -9.3, 95% CI: -11.5 to -7.0 and lamotrigine monotherapy, adjusted difference = -13.1, 95% CI: -15.0 to -11.3) and in children with psychiatric comorbidity, especially epilepsy with comorbid intellectual disability (adjusted difference = -27.0, 95% CI: -30.0 to -23.9) and epilepsy with comorbid attention deficit/hyperactivity disorder (adjusted difference = -15.7, 95% CI: -19.0 to -12.4). Children with epilepsy scored significantly lower than their unaffected siblings (adjusted difference = -6.2, 95% CI: -7.1 to -5.4). In conclusion, childhood epilepsy was associated with impaired academic performance throughout schooling, which suggest that there is a widespread need for educational support of children with epilepsy, even when the child has no other comorbidities and when the epilepsy appears well-managed.

Febrile seizures and childhood epilepsy and risk of internalizing and psychotic symptoms.

OBJECTIVE: To assess whether children with febrile seizures and/or epilepsy were at increased risk of experiencing internalizing symptoms or psychotic-like experiences at age 11 years. METHODS: This cohort study includes 44 819 children from the 11-year follow up of the Danish National Birth Cohort. Information on childhood seizures was retrieved from the Danish National Patient Registry, whereas child psychiatric symptoms were assessed in a web-based questionnaire using the Adolescent Psychotic-like Symptom Screener and the Strength and Difficulties Questionnaire. Adjusted odds ratios (aORs) with corresponding 95% confidence intervals (CIs) for the association between childhood seizures and internalizing symptoms (symptom score ≥8) and psychotic-like experiences (≥2 definite experiences) were obtained using logistic regression models. RESULTS: A total of 1620 children with febrile seizures (3.6%), and 311 children with epilepsy (0.7%) were identified. When adjusted for potential confounders, no association between febrile seizures and psychiatric symptoms was observed, and no association was observed between epilepsy and psychotic-like experiences. However, the OR for internalizing symptoms was 1.76 (95% CI: 1.20-2.58) in children with epilepsy compared to children without. This higher risk was evident mainly in boys (OR 2.30, 95% CI 1.37-3.85), children with ≥2 epilepsy-related hospital admissions (OR 2.79, 95% CI 1.81-4.32), and children whose age at first epilepsy-related hospital admission was 0-3 years (OR 2.47, 95% CI 1.45-4.19). SIGNIFICANCE: No association was found between febrile seizures and psychiatric symptoms or epilepsy and psychotic-like experiences at age 11. However, boys with epilepsy were at higher risk of experiencing internalizing symptoms.

Maternal Epilepsy and Long-term Offspring Mortality: A Nationwide Cohort Study.

OBJECTIVE: We examined how maternal epilepsy and use of antiseizure medications in pregnancy was associated with offspring mortality. METHODS: This population-based cohort study included all live- and stillborn singletons in Denmark between 1981 and 2016. We used nation-wide registers to retrieve information on pregnancy characteristics, epilepsy diagnoses, use of antiseizure medications, and mortality. Adjusted mortality rate ratios (MRR) were estimated using log-linear Poisson regression. RESULTS: The cohort consisted of 1,862,474 children. In total, 12,026 live-born children died during follow-up, of whom 170 (1.4%) were offspring of mothers with epilepsy. Overall mortality was increased in offspring of mothers with epilepsy compared to offspring of mothers without epilepsy (MRR = 1.46, 95% CI: 1.23-1.71), driven by an excess mortality only in the first year of life. Mortality was increased for natural deaths (MRR = 1.50, 95% CI: 1.25-1.78) but not from unnatural deaths (MRR = 1.38, 95% CI: 0.84-2.14), and only in offspring of women with epilepsy who used antiseizure medications during pregnancy (MRR = 1.51, 95% CI: 1.00-2.17), but not in offspring of women with epilepsy who did not use antiseizure medications while pregnant (MRR = 0.97, 95% CI: 0.69-1.31). When analyses were restricted to children born from 2000 and onwards, the excess mortality that was observed in the first year of life among children of mothers with epilepsy, was no longer evident. INTERPRETATION: During the 1981 to 1999 epoch, offspring of women with epilepsy were at increased risk of dying in the first year of life. However, this risk did not extend to children born after 2000. Future retrospective studies of the effects of maternal epilepsy on the health of the offspring should take this difference into account. ANN NEUROL 2022;91:455-465.

Identification of drug resistance in a validated cohort of incident epilepsy patients in the Danish National Patient Register.

OBJECTIVE: The main purposes of this study were to validate the epilepsy diagnosis in incident epilepsy cases in the Danish National Patient Registry (DNPR), which contains information on nearly 9 000 000 individuals, and to identify persons in the validated cohort who fulfilled the International League Against Epilepsy (ILAE) criteria for drug-resistant epilepsy (DRE). METHODS: We reviewed a random sample of medical records from all individuals registered with a first diagnosis of epilepsy (International Classification of Diseases, 10th Revision [ICD-10]: G40) or seizures (ICD-10: G41, R56, or F445) in the Central Denmark Region from 2010 to 2019. In persons with a validated incident epilepsy diagnosis, we determined the proportion with DRE at the latest contact. We performed logistic regression analyses to identify clinical factors that correlated with risk of DRE. RESULTS: Of 20 723 persons with a first diagnosis of epilepsy (n = 11 812) or seizures (n = 8911), we reviewed the medical records of n = 1067 with incident epilepsy and n = 610 with incident seizures. Among those with a register diagnosis of epilepsy, the diagnosis was confirmed in 838 cases (45% females, mean age at onset = 42.4 years), providing a positive predictive value (PPV) of 79% (95% confidence interval [CI] = 76%-81%). The PPV of focal epilepsy was 86% (95% CI = 82%-89%), and the PPV of generalized epilepsy was 71% (95% CI = 61%-80%). Of 740 patients with confirmed incident epilepsy and ≥1 year of follow-up, 103 (14%) fulfilled the definition of DRE, 476 (64%) were drug responsive, and 161 (22%) had undefined responsiveness. In multivariable logistic regression analysis, early age at epilepsy onset, cognitive impairment, and a history of status epilepticus were associated with DRE. SIGNIFICANCE: In the DNPR, we found a PPV of the epilepsy diagnosis of 79%. Among persons with confirmed epilepsy, 14% fulfilled ILAE criteria for DRE. Early age at epilepsy onset, cognitive impairment, and a history of status epilepticus were independently associated with drug resistance.

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.

Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study.

BACKGROUND: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. METHODS AND FINDINGS: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. CONCLUSIONS: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.

Seasonal Variation and Risk of Febrile Seizures: A Danish Nationwide Cohort Study.

INTRODUCTION: Onset of febrile seizures varies with calendar season. However, it has not previously been assessed, how season of birth interacts with age and peak risk of febrile seizures, and whether season of birth correlates with the cumulative risk of febrile seizures at 5 years of age (i.e., when children are no longer of risk of febrile seizures). METHODS: We identified all singleton children born in Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). We used the Danish Civil Registration System to identify age and sex of the children and the Danish National Patient Register to identify children hospitalized with febrile seizures from 3 months to 5 years of age. Follow-up ended on December 31, 2016, when all children had reached 5 years of age. RESULTS: The relative risk of admission with a first febrile seizure varied with calendar month; in February (a winter month in Denmark), the risk was more than doubled (hazard ratio: 2.10 [95% confidence interval [CI]: 2.03-2.18]) compared with August (a summer month in Denmark). The age-specific incidence of a first febrile seizure by birth month identified the highest peak incidence of a first febrile seizure among children born in November (reaching a peak incidence of 350 first admissions with a febrile seizure per 100,000 person months at age 16 months) as compared to children born in July (reaching a peak incidence of 200 first admissions with a febrile seizure per 100,000 person months at age 16 months). However, the cumulative incidence of any admission with febrile seizures before 5 years was not correlated with season of birth (3.69% [95% CI: 3.64-3.74%] for winter births, 3.57% [95% CI: 3.52-3.62%] for spring births, 3.55% [95% CI: 3.50-3.59%] for summer births, and 3.64% [95% CI: 3.59-3.69%] for fall births). DISCUSSION/CONCLUSION: The study found a significant seasonal variation in onset of the first febrile seizure and in the age-specific peak incidence of febrile seizures. However, there was no correlation between season of birth and cumulative incidence of febrile seizures at 5 years of age suggesting that children who are predisposed to febrile seizures will eventually go on to experience a febrile seizure regardless of season of birth.

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.

Birth characteristics and risk of febrile seizures.

OBJECTIVE: Febrile seizure is a common childhood disorder that affects 2-5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development. METHODS: This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow-up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age. RESULTS: In total, 75,593 (3.59%, 95% CI: 3.57-3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5-24.0). The 5-year cumulative incidence of febrile seizures increased with decreasing birth weight (<1500 g; 5.42% (95% CI: 4.98-5.88% vs. 3,000-4,000 g; 3.53% (95% CI: 3.50-3.56%)) and with decreasing gestational age at birth (31-32 weeks; 5.90% (95% CI: 5.40-6.44%) vs. 39-40 weeks; 3.56% (95% CI: 3.53-3.60)). Lower gestational age at birth was associated with higher age at onset of a first febrile seizure; an association that essentially disappeared when correcting for age from conception. CONCLUSIONS: The risk of febrile seizures increased with decreasing birth weight and gestational age at birth. The association between low gestational age at birth and age at first febrile seizure suggests that onset of febrile seizures is associated with the stage of brain development.

Antiepileptic Drugs and Suicide: Role of Prior Suicidal Behavior and Parental Psychiatric Disorder.

OBJECTIVE: To examine whether prior suicidal behavior and familial predisposition to psychiatric disorders modify the association between antiepileptic drug use and completed suicide. METHODS: Using the Danish National Prescription Register, we identified all incident users of antiepileptic drugs aged 15 years or older in Denmark between July 1997 and December 2015. We carried out a nested case-control study and defined exposure to antiepileptic drugs at the index date (ie, time of suicide). Conditional logistic regressions were used to estimate mortality rate ratios (MRRs) of suicide in current versus previous users of antiepileptic drugs. We also analyzed suicide risk associated with the 9 most commonly used antiepileptic drugs. RESULTS: We identified 1,759 individuals completing suicide. Current versus previous use of any antiepileptic drug was associated with an increased risk of suicide (MRR = 1.26, 95% confidence interval [CI] = 1.13-1.40). This excess risk was observed in individuals with a history of suicidal behavior (MRR = 1.28, 95% CI = 1.07-1.54) and in those without (MRR = 1.26, 95% CI = 1.11-1.43), and in individuals with a familial predisposition to psychiatric disorders (MRR = 1.48, 95% CI = 1.18-1.87) and in those without (MRR = 1.21, 95% CI = 1.07-1.35). INTERPRETATION: Use of antiepileptic drugs was associated with an increased risk of suicide. The findings do not support that the risk of suicide following treatment with antiepileptic drugs identified in randomized trials is explained by prior suicidality or familial predisposition to psychiatric disorders. The additional risk of suicide associated with use of antiepileptic drugs was generally low and should be balanced against benefits of treatment. ANN NEUROL 2019;86:951-961.

Accidental deaths in young people with epilepsy and psychiatric comorbidity-A Danish nationwide cohort study.

OBJECTIVE: The objective of this study was to investigate the accident-related mortality among people younger than 55 years of age with epilepsy compared with the general population and to study how psychiatric comorbidity influences this risk. METHODS: This is a population-based cohort study of individuals born in Denmark between 1960 and 2015 (n = 3, 665 616). Persons diagnosed with epilepsy and psychiatric disorders were identified in the Danish National Patient Register and the Danish Central Psychiatric Central Register. We estimated the hazard ratio (HR) with 95% confidence intervals (CIs) of accidental death in people with epilepsy compared with persons without epilepsy. RESULTS: We identified 61 330 persons (1.7%) diagnosed with epilepsy. Median age at end of follow-up was 27.8 years. In people with epilepsy, 5253 died during follow-up, 480 (9%) of whom died from accidents. Among people without epilepsy, 52 588 died during follow-up, of whom 1280 (2.4%) died from accidents. People with epilepsy had a 3.7-fold (95% CI 3.4-4.1) increased risk of accidental death compared with persons without epilepsy. When we adjusted for psychiatric disorders, the risk remained significantly elevated in people with epilepsy compared to people without epilepsy (adjusted HR [aHR] 2.44, 95% CI 2.22-2.69). When stratifying the analyses on epilepsy and psychiatric disorders, people with epilepsy and psychiatric disorders had an aHR of 4.95 (95% CI 3.82-6.41) when compared with persons without epilepsy and psychiatric disorders. SIGNIFICANCE: The risk of accidental death was increased in people with epilepsy and was particularly high among people with epilepsy with psychiatric comorbidity. The findings highlight the need for awareness and prevention strategies in people with epilepsy, especially in people with comorbid psychiatric disorders.

Infections and risk of epilepsy in children and young adults: A nationwide study.

OBJECTIVE: The development of epilepsy has been linked to infections of the central nervous system, but recently also to infections and inflammation outside of the central nervous system. Thus we investigated the association between infections and the risk of subsequent epilepsy. METHODS: This was a Danish nationwide population-based cohort study comprising a total of 1 938 555 individuals born between 1982 and 2012. Individuals were followed from birth until December 31, 2012, death, disappearance, emigration, or epilepsy diagnosis, whichever came first (28 512 666 person-years of follow-up). The exposure was hospital contacts for infection and the outcome was a diagnosis of epilepsy as recorded in the Danish National Hospital Register. Hazard ratios were calculated using Cox proportional hazards models adjusted for age, sex, calendar period, Apgar score, gestational age, birth weight, and parental history of epilepsy. RESULTS: A total of 25 825 individuals received an epilepsy diagnosis during the study period, among whom 8235 (32%) had a previous hospital contact for infection. A hospital contact for infection was associated with a 78% increase in the risk of subsequently receiving an epilepsy diagnosis (hazard ratio 1.78, 95% confidence interval [CI] 1.73-1.83) compared with those without infection. The highest risk was observed after central nervous system infections (hazard ratio 4.97, 95% CI 4.42-5.59), but increased risks were identified across all infected organ systems and types of pathogens. The risk of receiving an epilepsy diagnosis was correlated with the temporal proximity of the infection (P < 0.001) and increased with the number of hospital contacts for infection (P < 0.001) and with the severity of infection (P < 0.001). SIGNIFICANCE: The risk of receiving an epilepsy diagnosis was increased after a wide range of infections, suggesting that systemic inflammatory processes may be involved in the development of epilepsy.

Parental age and risk of epilepsy: A nationwide register-based study.

OBJECTIVE: This study aims to examine the association between maternal age, paternal age, and parental age difference at the time of birth and the risk of epilepsy in the offspring. METHODS: We carried out a prospective population-based register study of all singletons born in Denmark between 1981 and 2012. Cox regression was used to estimate hazard ratios (HRs) of epilepsy and their corresponding 95% confidence intervals (CIs), adjusted for relevant confounders. RESULTS: We followed 1 587 897 individuals for a total of ~25 million person-years and identified 21 797 persons with epilepsy during the study period. An excess risk of epilepsy was found in individuals born to mothers younger than 20 years (HR = 1.17, 95% CI = 1.07-1.29) and born to parental couples where paternal age exceeded maternal age by at least 5 years. The risk of epilepsy increased with increasing parental age gap and was highest when the father was ≥15 years older than the mother (adjusted HR = 1.28, 95% CI = 1.16-1.41). In contrast to maternal age, we found that paternal age did not independently contribute to offspring epilepsy risk, once we accounted for the parental age difference (P = .1418). The observed associations with maternal age and parental age gap were invariant to epilepsy subtypes, but were modified by age of epilepsy onset, with the effect being most pronounced in the first 10 years of the child's life. SIGNIFICANCE: Maternal age and parental age gap, but not paternal age, were associated with the offspring's risk of epilepsy. Our results do not support the hypothesis that de novo mutations associated with advanced paternal age increase the risk of epilepsy in the offspring.

Utility of data from the Danish National School Test Program for health research purposes: Content and associations with sociodemographic factors and higher education.

The Danish National School Test Program is a set of nationwide tests performed annually since 2010 in all public schools in Denmark. To assess the utility of this data resource for health research purposes, we examined the association of school test performance with demographic and socioeconomic characteristics as well as correlations with ninth-grade exams and higher educational attainment. This nationwide descriptive register-based study includes children born between 1994 and 2010 who lived in Denmark at the age of six years. Norm-based test scores (range 1-100, higher scores indicate better performance) in reading (Danish) and mathematics from the Danish National School Test Program were obtained for children aged 6-16 attending public schools in Denmark from 2010 to 2019. Population registers were used to identify relevant demographic and socioeconomic variables. Mean test scores by demographic and socioeconomic variables were estimated using linear regression models. Among the full Danish population of 1,137,290 children (51.3% male), 960,450 (84.5%) children attended public schools. There were 885,360 children who completed one or more tests in reading or mathematics (test participation was 77.8% for the entire population, and 92.1% for children in public schools). Mean test scores varied by demographic and socioeconomic characteristics, most notably with education and labour market affiliation of parents. For every 1-point decrease in the test scores, there was a 0.95% (95% CI: 0.93%; 0.97%) lower probability of scoring B or higher in the ninth-grade exam and a 1.03% (95% CI: 1.00%; 1.05%) lower probability of completing high school within five years after graduating from lower secondary school. In this study of schoolchildren in Denmark, demographic and socioeconomic characteristics were associated with test scores from the Danish National School Test Program. Performance in school tests correlated closely with later educational attainment, suggesting that these early measures of school performance are good markers of subsequent academic potential.

Epilepsy risk in offspring of affected parents; a cohort study of the "maternal effect" in epilepsy.

OBJECTIVE: To assess whether the risk of epilepsy is higher in offspring of mothers with epilepsy than in offspring of fathers with epilepsy. METHODS: In a prospective population-based register study, we considered all singletons born in Denmark between 1981 and 2016 (N = 1,754,742). From the Danish National Patient Register since 1977, we identified epilepsy diagnoses in all study participants and their family members. Cox regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CI), adjusted for relevant confounders. RESULTS: We included 1,754,742 individuals contributing > 30 million person-years of follow-up. The incidence rate of epilepsy in offspring of unaffected parents was 78.8 (95% CI: 77.8-79.8) per 100,000 person-years, while the corresponding rate in offspring with an affected father was 172 per 100,000 person-years (95% CI: 156-187) and in offspring with an affected mother was 260 per 100,000 person-years (95% CI: 243-277). Having an affected mother was associated with a 1.45-fold (95% CI: 1.30-1.63) higher risk of epilepsy in the offspring, compared to having an affected father. This maternal effect was found both in male (HR = 1.39, 95% CI: 1.19-1.62) and female offspring (HR = 1.53, 95% CI: 1.30-1.80), and across various ages at onset in the offspring. The maternal effect was also found in familial epilepsies (i.e. where the affected parent had an affected sibling; HR = 1.50, 95% CI: 1.04-2.16). INTERPRETATION: We found a clear maternal effect on offspring risk of epilepsy in this nationwide cohort study.

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

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.