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.

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.

Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study.

BACKGROUND: Stroke is associated with a risk of epilepsy, but associations with age, sex, stroke type and severity, time trends, and mortality are uncertain. We studied the risk of epilepsy after stroke while accounting for sex, age, stroke types and severity, calendar time, and death. METHODS: This was a prospective nationwide register-based, matched cohort study of patients admitted with a validated first stroke in Denmark from April 1, 2004, to December 16, 2018, excluding those with prior epilepsy. Patients with stroke were matched 10:1 on age, sex, and calendar time with reference people without prior epilepsy or stroke. We estimated the cumulative incidence of an epilepsy diagnosis in the Danish National Patient Registry (International Classification of Diseases Tenth Revision: G40) with death as a competing risk using competing risk regression and estimated adjusted hazard ratios by Cox regression models. RESULTS: We identified 101 034 patients with stroke (46.5% female; mean age, 70.4 years) who survived 14 days after stroke along with 1 010 333 matched reference people. Two years after the stroke, the cumulative incidence of epilepsy was 3.0% (95% CI, 2.9-3.2) after ischemic stroke and 8.6% (95% CI, 8.0-9.2) after intracerebral hemorrhage versus 0.7% (95% CI, 0.7-0.7) in the matched references. Compared with the reference population, the 2-year hazard ratio of epilepsy was 21.7 (95% CI, 20.3-23.2) after ischemic stroke and 61.3 (95% CI, 51.1-73.4) after intracerebral hemorrhage. The risk of epilepsy increased with stroke severity; the 2-year cumulative incidence of epilepsy was 10.5% (95% CI, 9.5-11.4) for very severe ischemic stroke and 13.1% (95% CI, 11.1-15.1) after very severe intracerebral hemorrhage. CONCLUSIONS: In this population-based study of patients with validated stroke, the absolute and relative risk estimates of poststroke epilepsy were lower compared with previous studies. Reasons for the lower risk estimates include accounting for the high mortality associated with stroke, which had a significant impact on risk especially for severe stroke.

Socioeconomic differences in use of antiseizure medication in pregnancies with maternal epilepsy: A population-based study from Nordic universal health care systems.

OBJECTIVE: Research points to disparities in disease burden and access to medical care in epilepsy. We studied the association between socioeconomic status (SES) and antiseizure medication (ASM) use in pregnancies with maternal epilepsy. METHODS: We conducted a cross-sectional study consisting of 21 130 pregnancies with maternal epilepsy identified from Nordic registers during 2006-2017. SES indicators included cohabitation status, migrant background, educational attainment, and household income. Main outcomes were the proportion and patterns of ASM use from 90 days before pregnancy to birth. We applied multiple imputation to handle SES variables with 2%-4% missingness. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) using modified Poisson regression with the highest SES category as reference. RESULTS: Mothers with the highest education and the highest income quintile used ASMs least frequently (56% and 53%, respectively). We observed increased risks of ASM discontinuation prior to or during the first trimester for low SES. The risk estimates varied depending on the SES indicator from aRR = 1.27 for low income (95% CI: 1.03-1.57) to aRR = 1.66 for low education (95% CI: 1.30-2.13). Migrant background was associated with ASM initiation after the first trimester (aRR 2.17; 95% CI 1.88-2.52). Low education was associated with the use of valproate during pregnancy in monotherapy (aRR 1.70; 95% CI 1.29-2.24) and in polytherapy (aRR 2.65; 95% CI 1.66-4.21). Low education was also associated with a 37% to 39% increased risk of switching from one ASM to another depending on the ASM used. For the other SES indicators, aRRs of switching varied from 1.16 (foreign origin; 95% CI 1.08-1.26) to 1.26 (not married or cohabiting; 95% CI 1.17-1.36). SIGNIFICANCE: Low SES was associated with riskier patterns of ASM use: discontinuation, late initiation, and switching during pregnancy. These findings may reflect unplanned pregnancies, disparities in access to preconception counseling, and suboptimal care.

Prescribing patterns for higher dose folic acid in pregnant women with epilepsy treated with antiseizure medication.

OBJECTIVE: This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). METHODS: In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country-specific time trends. RESULTS: Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM-treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. SIGNIFICANCE: Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM-treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real-world applicability.

Cause-specific mortality and life years lost in people with epilepsy: a Danish cohort study.

Mortality rates are two to three times higher in people with epilepsy than in the general population. This study aimed to quantify how this increased mortality translates into reduced life expectancy and to identify the underlying causes of deaths, thereby offering suggestions for how to reduce mortality associated with epilepsy. In this population-based cohort study, we included all individuals aged 0-94 years who were living in Denmark between 2000 and 2015. Using the nationwide registers, we identified people diagnosed with epilepsy and estimated the excess of life years lost due to 13 overall and nine specific causes of death. Among 6 022 160 people, we identified 129 598 with epilepsy (52.6% males), with a mean age of epilepsy onset of 36.5 years (standard deviation = 26.3 years). During the 16 years of follow-up, 851 087 individuals died, and of these 36 923 had been diagnosed with epilepsy. The average reduction in life expectancy in people with epilepsy was 11.84 years in males (95% confidence interval: 11.66-12.00) and 10.91 years in females (95% confidence interval: 10.70-11.11) compared to the general population. Life expectancy was reduced irrespective of epilepsy aetiology (symptomatic ∼14 years; idiopathic ∼8-10 years), and in particular in people with epilepsy and psychiatric comorbidity (∼13-16 years). Excess mortality was evident across all causes of death including cardiovascular disorders, accidents, and suicide. People with epilepsy experience a substantial reduction in lifespan that can only partly be explained by underlying conditions. Prevention of epilepsy-related deaths should focus on the consequences of psychiatric comorbidity and on modifiable risk factors associated with preventable causes of death such as accidents and neurological and cardiovascular disorders.

Correlation of drug dose estimated from national prescription registers with mean blood level of antiseizure medication in pregnancy.

PURPOSE: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy. METHODS: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values. RESULTS: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate. CONCLUSIONS: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.

Neonatal phototherapy and risk of epilepsy-A Danish population based study.

To evaluate the risk of epilepsy in children who received neonatal phototherapy. A cohort of live singletons born at a Danish hospital (2002-2016) with a gestational age ≥ 35 weeks. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy in children treated with neonatal phototherapy compared to children not treated with neonatal phototherapy in the general population, and in a subpopulation of children who had serum bilirubin measurement. Adjusted HRs (aHR) were computed using multivariable and propensity score matching models to take maternal and neonatal factors into consideration. Children were followed from day 29 after birth to diagnosis of epilepsy, death, emigration, or December 31, 2016. Among 65,365 children, 958 (1.5%) received neonatal phototherapy. Seven children (incidence rates (IRs): 10.8 /10,000 person-years) who received neonatal phototherapy and 354 children (IR: 7.7) who did not receive neonatal phototherapy were diagnosed with epilepsy. Neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 0.95, 95% CI: 0.43-2.09) and propensity score matched (aHR 0.94, 95% CI: 0.39-2.28) models. In the subpopulation of 9,378 children with bilirubin measurement, 928 (9.9%) received neonatal phototherapy. In the analysis of the subpopulation in which bilirubin level and age at the time of bilirubin measurement were further taking into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 1.26, 95% CI: 0.54-2.97) and propensity score matched (aHR 1.24, 95% CI: 0.47-3.25) models,Conclusions: Neonatal phototherapy was not associated with an increased risk of epilepsy after taking maternal and neonatal factors into consideration. What is known: • A few studies have suggested that neonatal phototherapy for hyperbilirubinemia may increase the risk of childhood epilepsy. • Whether the observed associations contribute to hyperbilirubinemia, phototherapy, or underlying factors requires further investigation. What is new: • This study revealed no increased risk of epilepsy in children treated with neonatal phototherapy compared to children not treated with phototherapy after taking maternal and neonatal factors into consideration. • After further taking bilirubin level and age at the time of bilirubin measurement into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy.

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.

Automated detection of focal seizures using subcutaneously implanted electrocardiographic device: A proof-of-concept study.

Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof-of-concept (phase 1) study, we recruited six patients admitted to long-term video-electroencephalographic monitoring. Fifteen-minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1-8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home-monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%-99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%-100%), and 38 of the 41 seizures in the out-of-hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%-100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long-term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes.

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.

High-dose folic acid and cancer risk; unjustified concerns by von Wrede and colleagues regarding our paper.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

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.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required. OBJECTIVES: To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child. SEARCH METHODS: For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy. DATA COLLECTION AND ANALYSIS: Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases. AUTHORS' CONCLUSIONS: Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.

ANTECEDENTES: La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC. OBJETIVOS: Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa. RESULTADOS PRINCIPALES: De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médicos fueron limitados. En cuanto a la exposición a la fenitoína, la prevalencia de MCG fue elevada en los datos de los estudios de cohortes (5,4%; IC del 95%: 3,6 a 8,1) y en los datos rutinarios de los historiales médicos (6,8%; IC del 95%: 0,1 a 701,2). La prevalencia de MCG fue mayor en los niños expuestos a la fenitoína en comparación con los hijos de mujeres sin epilepsia (RR 3,81; IC del 95%: 1,91 a 7,57) y los hijos de mujeres con epilepsia que no reciben tratamiento (RR 2,01; IC del 95%: 1,29 a 3,12); no hubo datos procedentes de estudios con datos rutinarios de los historiales médicos. Los datos agrupados de los estudios de cohortes indicaron un riesgo significativamente mayor de MCG en los niños expuestos a lamotrigina en comparación con los niños nacidos de mujeres sin epilepsia (RR 1,99; IC del 95%: 1,16 a 3,39); con una diferencia de riesgos (DR) que indica un riesgo 1% mayor de MCG (DR 0,01. IC del 95%: 0,00 a 0,03). Esto no se repitió en la comparación con los hijos de las mujeres con epilepsia que no reciben tratamiento (RR 1,04; IC del 95%: 0,66 a 1,63), que contenía el mayor grupo de niños expuestos a la lamotrigina (> 2700). Además, también se encontró una diferencia no significativa tanto en comparación con los hijos de mujeres sin epilepsia (RR 1,19; IC del 95%: 0,86 a 1,64) como con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,00; IC del 95%: 0,79 a 1,28) a partir de los estudios con datos rutinarios. Para la exposición al levetiracetam, los datos agrupados proporcionaron razones de riesgos similares a las de las mujeres sin epilepsia en los estudios de cohortes (RR 2,20; IC del 95%: 0,98 a 4,93) y en los estudios con datos rutinarios de los historiales médicos (RR 0,67; IC del 95%: 0,17 a 2,66). Los resultados agrupados de los estudios de cohortes (RR: 0,71; IC del 95%: 0,39 a 1,28) y de los estudios con datos rutinarios de los historiales médicos (RR: 0,82; IC del 95%: 0,39 a 1,71) respaldan esta afirmación cuando se comparan con los hijos de las mujeres con epilepsia que no reciben tratamiento. En el caso del topiramato, la prevalencia de MCG fue del 3,9% (IC del 95%: 2,3 a 6,5) a partir de los datos de los estudios de cohortes y del 4,1% (0,0 a 27.050,1) a partir de los estudios con datos rutinarios de los historiales médicos. Las razones de riesgos fueron significativamente más altas para los niños expuestos al topiramato en comparación con los hijos de mujeres sin epilepsia en estudios de cohortes (RR 4,07; IC del 95%: 1,64 a 10,14), pero no en una comparación más pequeña con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,37; IC del 95%: 0,57 a 3,27); actualmente se dispone de pocos datos a partir de estudios con datos rutinarios de los historiales médicos. La exposición en el útero al topiramato también se asoció con RR significativamente mayores en comparación con otros FAC para las hendiduras orofaciales. Los datos de todos las demás FAC fueron extremadamente limitados. Debido a los diseños observacionales, todos los estudios presentaron un alto riesgo de ciertos sesgos, pero los sesgos observados en los estudios de obtención de datos primarios y el uso secundario de historiales médicos rutinarios fueron diferentes y, en parte, complementarios. Los sesgos estaban equilibrados entre los FAC investigados, y es poco probable que los resultados diferenciales observados entre los FAC se expliquen únicamente por estos sesgos. CONCLUSIONES DE LOS AUTORES: La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

The clinical use of electroencephalography in a general psychiatric setting.

OBJECTIVE: Electroencephalography (EEG) is used in psychiatric services, however, clinical guidelines do not clearly state when EEG is indicated, and its diagnostic value in psychiatric settings is unclear. We aimed to characterize the clinical use and diagnostic consequences of EEG in a general psychiatric setting to evaluate and optimize its use. METHODS: We performed a quality development project at the psychiatric services of the Central Denmark Region. We identified patients referred for EEG examination from psychiatric services between 1 September 2017 and 1 September 2022. We extracted data from electronic health records on patient characteristics, indications, EEG results, and treatment consequences and analyzed risk factors for abnormal EEGs. RESULTS: Among 57,031 persons seen in the psychiatric services in the study period, 219 (0.4%) were referred for EEG examination. Psychosis (n = 70, 32%) was the most common symptom and suspicion of epilepsy (n = 129, 59%) was the most common clinical suspicion leading to referral. Of the 219 patients, 53 (24%) had an abnormal EEG result including 17 (7.8%) with epileptiform changes. Abnormal EEGs led to treatment alterations in six patients (3%). Age, prior epilepsy, use of antiseizure medication, use of clozapine, and convulsions were associated with epileptiform changes in the EEG. CONCLUSION: EEG is rarely used in psychiatric settings and seldom has treatment consequences. However, in specific clinical settings, the EEG result leads to an alteration of clinical management and the findings, therefore, call for refinement of clinical guidelines to optimize the use of EEG.

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.

Cardiac morbidity and mortality associated with the use of lamotrigine.

OBJECTIVE: The US Food and Drug Administration recently issued a warning against the use of the antiseizure medication lamotrigine in people at risk of cardiac rhythm and conduction abnormalities. This study assessed the risk of cardiac morbidity and mortality in new users of lamotrigine. METHODS: In a Danish population-based cohort study, we followed cohort members aged ≥15 years for the first 2 years after they initiated lamotrigine therapy. The main outcomes were cardiac conduction disorders in people without pre-existing cardiac morbidity and all-cause mortality in people with pre-existing cardiac morbidity. Cox proportional hazards models provided hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for comparison of the risk in current versus past users of lamotrigine. RESULTS: There were 91 949 (36 618 males [39.8%]) new users of lamotrigine (median age = 45.7 years, interquartile range = 32.0-60.2 years). Among users without pre-existing cardiac disease (n = 86 769), 194 (.23%) developed a cardiac conduction disorder. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR of new onset cardiac conduction disorder of 1.03 (95% CI = .76-1.40). Among users with pre-existing cardiac disease (n = 5180), 1150 (22.2%) died. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR for all cause-mortality of 1.05 (95% CI = .93-1.19). SIGNIFICANCE: In this large population-based study, lamotrigine use was associated neither with a risk of cardiac conduction disorders in people without pre-existing cardiac morbidity nor with all-cause mortality in people with pre-existing cardiac morbidity.

Care in Europe after presenting to the emergency department with a seizure; position paper and insights from the European Audit of Seizure Management in Hospitals.

BACKGROUND AND PURPOSE: This position paper makes recommendations following an audit of care provided to people presenting with a seizure to emergency departments (EDs) in Europe. METHODS: Participating countries were asked to include five hospitals agreeing to identify 50 consecutive seizure patients presenting to their ED between 1 August 2016 and 31 August 2017. Anonymous data were collected to a web database. Where quoted, percentages are mean site values and ranges are the 10th-90th centile. RESULTS: Data were collected on 2204 ED visits (47 sites, up to six per country, across 15 countries): 1270 (58%) known epilepsy, 299 (14%) previous blackouts but no epilepsy diagnosis, 634 (29%) with a first seizure. Wide variability was identified for most variables. Of those with known epilepsy, 41.2% (range 26.2%-59.6%) attended the ED in the previous 12 months, but only 64.7% (range 37.2%-79.8%) had seen an epilepsy specialist in the previous 12 months. 67.7% (range 34.0%-100%) were admitted, 53.1% to a neurology ward (range 0.0%-88.9%). Only 37.5% first seizure patients (range 0.0%-71.4%) were given advice about driving. CONCLUSIONS AND RECOMMENDATIONS: It is recommended that in Europe guidance is agreed on the management and onward referral of those presenting to the ED with a seizure; a referral process is created that can be easily implemented; it is ensured that the seizure services receive referrals and see the patients within a short time period; and a simple system is developed and implemented to allow continuous monitoring of key indices of epilepsy care.

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.