Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence.

BACKGROUND: A history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy. METHODS: Information on the history of seizures was obtained by a questionnaire from twin pairs in the Mid-Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes. RESULTS: Histories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group. CONCLUSION: A twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities.

Importance of genetic factors in the occurrence of epilepsy syndrome type: a twin study.

Although there is strong evidence that genetic factors contribute to risk for epilepsy, their role in the determination of syndrome type is less clear. This study was undertaken to address this question. Information related to epilepsy was obtained from twins included in 455 monozygotic and 868 dizygotic pairs ascertained from population-based twin registries in Denmark, Norway and the United States. Syndrome type was determined based on medical record information and detailed clinical interviews and classified using the International Classification Systems for the Epilepsies and Epileptic Syndromes. Concordance rates were significantly increased in monozygotic versus dizygotic pairs for all major syndrome groups except localization-related cryptogenic epilepsy. Among generalized epilepsies, genetic factors were found to play an important role in the determination of childhood absence, juvenile absence, juvenile myoclonic, and idiopathic generalized epilepsy; and to a lesser degree for epilepsies with grand mal seizures on awakening. Among localization-related epilepsies, genetic factors contributed to risk for localization-related idiopathic and symptomatic syndromes overall, but did not appear to play an important role in determining risk for frontal, occipital or temporal lobe epilepsy. These results suggest that, while genetic factors contribute to risk for major syndrome types, determined when possible, their contribution to risk for localization-related syndrome sub-types, as defined by specific focality, may be modest.

The accuracy of self-reported history of seizures in Danish, Norwegian and U.S. twins.

Questionnaire surveys provide an efficient means of identifying potential seizure cases in large population-based cohorts. Concerns exist, however, with regard to the reliability of self-reported information both with respect to the validity of the results obtained and with regard to the usefulness of this approach in identifying true cases. Information on history of seizures obtained by questionnaire from members of 47,626 twin pairs included in the Mid-Atlantic (MATR), Danish (DTR) and Norwegian (NTR) Twin Registries was verified using medical records and detailed clinical and family interviews. The accuracy of these reports was assessed. Self-reported epilepsy was verified in 81.9% of twins overall (86.1% (DTR), 75.6% (NTR) and 80.7% (MATR)). However, when both pair members reported a history of epilepsy in the affected pair member, epilepsy was verified in >90% of cases. Among MATR twins with a verified history of epilepsy, 21.5% reported other seizures but not epilepsy and 18.5% of verified Norwegian epilepsy cases reported no history of epilepsy themselves and were identified only through their co-twin. The results of this study indicate that the accuracy of self-reported epilepsy and febrile seizures among those who provided information on health history was high across all populations. However, the relatively large percentage of twins with a verified diagnosis who did not acknowledge epilepsy suggests that the frequency of epilepsy may be under-estimated in self-reported samples.

Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration.

PURPOSE: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large sample of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. METHODS: Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. RESULTS: Eighteen twin pairs were identified (10 monozygous; eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total sample of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this sample was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. CONCLUSIONS: The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.

The feasibility of creating a population-based national twin registry in the United States.

Between 4 to 6 million twins exist in the US today who offer scientists a valuable potential resource for conducting behavioral and biomedical research. However, unlike many other countries, there is no national system in the US for identifying twins and eliciting their participation in these important research programs. Therefore, the National Institute of Environmental Health Sciences (NIEHS) is conducting a study to determine the feasibility of creating a national, population-based twin registry in the US. The major goal is to estimate the potential size and characteristics of a national twin registry based on the current twin population in the US, our ability to ascertain and enroll them, and their willingness to participate. Existing US twin cohorts are also being examined in this study as well as alternatives for improving US twin resources should a national twin registry be deemed infeasible. The various options will be compared in terms of possible source populations, generalizability and adequacy for statistically powering various types of etiological studies. Two expert advisory panels have been assembled to assist in the conduct of this study. The Scientific Advisory Panel is charged with providing expertise concerning study goals, design and methodology, and evaluating the study's conclusion. A separate Ethics Advisory Panel is charged with providing expertise on the ethical, legal, and social issues that might be encountered if a national twin registry is ultimately pursued. Having a national population-based twin registry in the US would be advantageous to US scientists and those worldwide. It would provide ample numbers of twin pairs to conduct various types of environmental genomic studies currently not possible with existing US twin resources. It would also allow US scientists to select for characteristics (race, ethnicity, environments, and so on) inherent in our own population. Finally and foremost, it would help to meet the worldwide demand for twin resources which is expected to increase over time, as new genomic and analytical tools become available and new hypotheses emerge concerning the complex interplay between genes, lifestyles and environment.

Genetic factors in seizures: a population-based study of 47,626 US, Norwegian and Danish twin pairs.

The purpose of the study was to describe a large sample of twins reporting a history of seizures, to characterize seizures in the three subpopulations, and to estimate the relative importance of genetic and environmental factors in seizure occurrence. Seizure history was determined by questionnaires completed by twins in population-based twin registries in the United States, Norway and Denmark. Concordance rates were calculated for all seizure categories within and across twin populations. Of 47,626 twin pairs evaluated, 6234 reported a history of seizures in one or both twins. Concordance rates were significantly higher for monozygotic (MZ) versus dizygotic (DZ)pairs for all seizure categories within and across populations. The results of this study involving the largest unselected, population-based sample of twins with seizures assembled to date confirm the importance of genetic factors in determining risk for epilepsy, febrile seizures, other seizures and staring spells. This sample is likely to provide an important resource for studying the genetics of epilepsy subtypes and febrile seizures.

Which seizure-precipitating factors do patients with epilepsy most frequently report?

When treating patients with epilepsy, dealing with seizure-precipitating factors is a partly neglected and underestimated supplement to more traditional therapies. The aim of this study was to investigate the incidence of seizure precipitants in a large epilepsy population and to determine which precipitants patients most often reported. Study participants included twins and their family members ascertained from the Norwegian Twin Panel (NTP), the Danish Twin Registry (DTR), and the Mid-Atlantic Twin Registry (MATR). One thousand six hundred seventy-seven patients with epilepsy were identified and were asked about seizure precipitants using a closed-ended questionnaire. Fifty-three percent reported at least one seizure-precipitating factor, while 30% claimed to have experienced two or more such factors. Emotional stress, sleep deprivation, and tiredness were the three most frequently reported precipitants. Patients with generalized seizures seemed to be more sensitive to sleep deprivation and flickering light than those with partial seizures, while women with partial seizures appeared to be more prone to seizures during menstruation than women with generalized seizures. Knowledge of seizure precipitants has practical implications, not only in patient treatment and counseling, but also for diagnosis, in that it may be helpful in facilitating the appearance of interictal epileptiform discharges in EEG and ictal EEG recordings.

Status epilepticus in a population-based Virginia twin sample.

PURPOSE: To characterize status epilepticus (SE) and estimate its frequency of first occurrence, as well as to assess the contribution of genetic factors to risk of SE occurrence in a sample of Virginia-born twins ascertained from the population-based Mid-Atlantic Twin Registry. METHODS: The occurrence of SE was determined in 13,506 unselected Virginia-born twin pairs ascertained from birth records. Twins included in the study were between ages 2 and 75 years when surveyed. History of seizures and SE was validated through medical records and by detailed personal or parental interviews. RESULTS: Among 381 twins included in 332 pairs with a verified history of seizures, 70 (18.4%) were validated to have had at least one episode of SE. The frequency of first SE in this sample was 309 per 100,000 twins. First SE occurred in conjunction with 21 of 158 febrile and 49 of 223 afebrile seizure cases, respectively. Mean length of SE episode was 76.2 +/- 14.9 min. Age at first SE occurrence ranged from 2 months to 59 years. All concordant twin pairs in the sample were monozygotic (MZ), with a proband-wise concordance rate estimated for SE in this population of 0.31 [95% confidence interval (CI), 0.14-0.52) overall, and 0.67 (95% CI, 0.35-0.90) in pairs concordant for epilepsy. CONCLUSIONS: These results provide a direct estimate of the frequency of SE in a defined population of twins and afford further evidence for a genetic contribution to risk for SE.

The role of the children of twins design in elucidating causal relations between parent characteristics and child outcomes.

BACKGROUND: Determination of causal connections between parental measures and child outcomes using typical samples is limited by the inability to account for all confounds, both environmental and genetic. This paper discusses the strength of the Children of Twins (COT) design to highlight the role of specific environments. METHODS: A new analytical model is presented which helps differentiate and quantify the environmental and genetic processes underlying associations between family-level risk factors and child adjustment. In order to illustrate the COT design, the relation between smoking during pregnancy and child birth weight (BW) is examined in a sample of female twins and their children from Norway and the United States. RESULTS: The results illustrate that smoking during pregnancy is influenced by genetic factors. However, the Children of Twins model supports the claim that smoking during pregnancy has a direct environmental influence on BW and that genetic and shared environmental confounds cannot account for the association. CONCLUSIONS: An assessment of the strengths and limitations of the Children of Twins design and a comparison with other research strategies suggest that the design plays a unique role in the study of developmental psychology and psychopathology. Finally, the authors describe how methodological advances and future applications of the design will provide additional insight into the causal processes underlying children's adjustment to environmental stimuli.

Epileptic seizures and syndromes in twins: the importance of genetic factors.

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.

The Mid-Atlantic Twin Registry.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of twin pairs ascertained from birth records and school system records of Virginia, North Carolina, and South Carolina. The MATR was formed in 1997 with the merging of the Virginia and North Carolina Twin Registries, and it expanded to include South Carolina when access to twin birth records in that state was granted in 1998. Registered twins ("participants") number more than 51,000, with approximately 46,000 of these individuals representing complete pairs. Roughly two-thirds of MATR participants are over age 18, with a mean age of approximately 35 years. These participants have primarily been drawn from the more than 170,000 identical and fraternal twin pairs born in the three states between 1913 and 2000. Twins and their family members have participated in numerous research projects, ranging from general health surveys to studies on specific health topics such as cardiovascular disease; depression and anxiety; seizures; behavioral development; pregnancy complications; conduct disorder; drug use, abuse, and dependence; cleft lip/palate; obesity; and chronic fatigue syndrome. The MATR has established a privacy policy and strict standard operating procedures to protect the confidentiality of participant data. The MATR considers a limited number of qualified requests per year from investigators interested in recruiting MATR participants into their research studies.