Major depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated whether this is due to specific symptoms of depression. We conducted a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) diagnosis. A history of major depression was 1.7-fold more common among cases than among controls (95% confidence interval, 1.1-2.7). A history of attempted suicide was 5.1-fold more common among cases than among controls (95% confidence interval, 2.2-11.5). Attempted suicide increased seizure risk even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression. Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important in the development of epilepsy.

Attention-deficit/hyperactivity disorder occurs more often than expected before unprovoked seizures, suggesting a common antecedent for both conditions.

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Summary: Mortality in people with epilepsy has been studied in many different populations. In population-based incidence cohorts of epilepsy with 7-29 years follow-up, there was up to a threefold increase in mortality, compared to the general population (standardized mortality ratios [SMR] ranged from 1.6 to 3.0). When studies include selected epilepsy populations where patients with frequent and severe seizures are more common, the mortality is even greater. Relative survivorship (RS) following the diagnosis of epilepsy was 91%, 85%, and 83% after 5, 10, and 15 years, respectively. In a population with childhood-onset epilepsy, RS was 94% and 88% after 10 and 20 years.The level of increased mortality is affected by several factors. In idiopathic epilepsy where the causes of seizures are unknown, the results are conflicting. There was no significant increase in mortality in studies from Iceland, France, and Sweden, a barely increased risk in a study from the United Kingdom, and a significantly increased risk in a study from the United States. In contrast, all studies report a significant increased mortality in remote symptomatic epilepsy (standardized mortality ratios [SMRs] ranging from 2.2 to 6.5). The highest mortality is found in patients with epilepsy and neurodeficits present since birth, including mental retardation or cerebral palsy (SMRs ranging from 7 to 50).Mortality is also affected by age, with the highest SMRs in children, the combined effect of low mortality in the reference population, and high mortality in children with neurodeficits and epilepsy. The highest excess mortality is found in the elderly, ≥75 years. A pronounced increase in mortality is found during the first year following the onset of seizures due to underlying severe diseases. The increased mortality remains in different studies 2-14 years following diagnosis.Most of the factors responsible for the increased mortality are related to the underlying disorder causing epilepsy with pneumonia, cerebrovascular disease, and neoplastic disorders (risk remains elevated when primary brain tumors are excluded), as the most frequently recorded causes. The most common direct seizure-related cause of death in adolescents and young adults is sudden unexpected death, which is 24 times more common than in the general population. Key Words: Epilepsy-SeizureMortality-Prognosis-Epidemiology.During the last decade, and especially during the last 5 years, several studies on mortality in epilepsy have been published and still others have been initiated with results expected over the coming years. These studies provide important information on an aspect of epilepsy that has largely been ignored in epileptology during the 1980s and early 1990s. During this period, population-based studies showed the prognosis of epilepsy to be much better than previous studies from tertiary referral centers and from epilepsy hospitals with an accumulation of patients with severe epilepsy. This new optimistic picture of epilepsy has been very important and has provided a ...

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

Summary: Purpose: We wished to determine the incidence of psychogenic nonepileptic (NES) seizures in a population-based study.Methods: Cases were identified through review of the results of all long-term video-EEG studies made in Iceland during the study period.Results: The incidence of NES was 1.4 in 100,000 personyears of observation. Age-specific incidence was highest in the youngest age group (age 15-24 years) and decreased thereafter. A strong female preponderance was observed.Conclusions: The incidence of NES is equal to almost 4% of that reported for epilepsy from Iceland for persons aged 2 15 years. For people aged 15-24 years, the incidence of NES is equal to -5% of the incidence of epilepsy. Half the patients also had epilepsy. Key Words: Epidemiology-Epilepsy-Psychogenic nonepileptic seizures (NES) constitute a clinical phenomenon that resembles epileptic seizures. The diagnosis is based on recognition of typical clinical symptoms and recording of normal EEG during the episodes. The clinical diagnosis can be very difficult, and NES are frequently misdiagnosed as epileptic seizures. Long-term video-EEG monitoring (LVEM) has revolutionized the diagnosis of NES and several groups of researchers (1-6) have described the various clinical manifestations of NES. Correct diagnosis is important because inappropriate treatment for suspected epilepsy or suspected status epilepticus (SE) may be dangerous or life-threatening to the patient (7-10).The incidence of NES in a defined population is unknown, but investigators (9-1 3) have described the relative frequency of NES in selected patient groups. In Iceland, we conducted a study in which we identified all adult patients in the country first diagnosed with NES in a 5-year period.

Summary:Purpose: Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered to have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection.Methods: We performed a historical population-based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19-year period in Iceland.Results: In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7-fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy.Conclusions: Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring. Key Words: Epidemiology-Epilepsy-Pregnancy-Congenital malformations-Iceland.Women with epilepsy who become pregnant are frequently considered to have a high risk of an adverse outcome (1,2). Numerous studies also indicate an increased risk of malformations (3,4) in offspring of mothers with epilepsy. Few population studies have determined the proportion of all pregnancies that occur in women with active epilepsy. We performed a population-based survey in Iceland to identify all women with epilepsy who gave birth during the 19-year period from 1972 through 1990. We wished to determine the proportion of pregnancies in women with active epilepsy among all pregnancies and to compare the proportion with complications of pregnancy, delivery, and outcome in those with and without epilepsy. PATIENTS AND METHODSIndex cases were all women with epilepsy treated with antiepileptic drugs (AEDs) during pregnancy or during a 5-year period preceding the pregnancy. All the women were residents of Iceland and gave birth in Iceland during the study period. Only live births, products of pregnancies progressing at least through week 28 of gestation were included. The study period was from January 1, 1972 to December 31, 1990.Index cases were identified from records of all the hospitals in the country where children are born. Supplemental inform...

Summary:Purpose: Few population-based studies of longterm survival in people with seizures or epilepsy have been made.Methods: Between January 1, 1960 and December 31, 1964, we identified 224 incidence cases of unprovoked seizures in Iceland and determined survivorship status and date of death for the cases as of January 1, 1996. We compared survivorship with that expected based on data from age-/sex-specific life tables from the country for 196 1-1 990 and calculated the standardized mortality ratio (SMR).Results: By 30 years after diagnosis, there were 45 deaths among patients with unprovoked seizures as compared with an expected 28 deaths [standardized mortality ratio (SMR) 1.6; 95% confidence interval (CI) 1.2-2.21. Patients with unprovoked seizures of unknown etiology did not have a significant increase in mortality overall (SMR 1.3, 95% CI 0.8-1.9) or in any time interval. For patients with remote symptomatic unprovoked seizures, mortality was increased (SMR 2.3, 95% CI 1.4-3.5). This increase was attributable to excess mortality for the first 15 years after diagnosis (SMR 4.1, 95% CI 2.4-6.6), and SMR was not different after that time.Conclusions: Survivorship was decreased for the population of patients with unprovoked seizures. The increased mortality was primarily due to excess mortality in patients with remote symptomatic seizures, occurring in the first 15 years after diagnosis. Overall mortality for idiopathic unprovoked seizures was not significantly increased. Key Words: EpidemiologyEpilepsy-Seizures-Mortality-Iceland-Long-term survival.Epilepsy can often influence the life expectancy of the persons affected and several medical conditions associated with seizures are also associated with increased mortality. Decreased long-term survival of selected populations (clinical series, holders of life insurance policies) with epilepsy has been reported in several studies and increased mortality has been reported in most of them. Only one population-based study (1) of mortality and long-term survival is available. We wished to determine long-term survival in a population-based incidence cohort of patients with unprovoked seizures. MATERIALS AND METHODSIndex cases were the 224 inhabitants of Iceland first diagnosed with unprovoked seizures (single, 15; recurrent, 209) during the 5-year period from 1960 through ~~