BACKGROUND-Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.

Summary: Purpose:We report the development of a questionnaire to assess health-related quality-of-life (HRQOL) in people with epilepsy and the process of cross-cultural translations of the questionnaire.Methods: A sample of 304 adults with epilepsy from 25 seizure clinics in the United States was used to derive an abbreviated questionnaire focusing on epilepsy-related issues from a longer, 89-item instrument (QOLIE-89). A rigorous forward-backward-forward system was used for cross-cultural translation.Results: A 3 1 -item questionnaire (QOLIE-3 1, version 1 .O) resulted, comprising seven subscales covering general and epilepsy-specific domains. Subscale and total scores can be calculated. The subscales were grouped into two factors: EmotionallPsychological Effects (seizure worry, overall QOL, emotional well-being, energy/fatigue subscales) and Medical/Social Effects (medication effects, work-driving-social limits, cognitive function subscales). Cross-cultural translations were made from US.-English into Danish, Dutch, German, Canadian French, French, Italian, Spanish, Swedish, and U.K. English The individual patient's perspective has become an integral aspect of health care assessment (1). In epilepsy, clinicians are careful to obtain a social history along with physical and neurological examinations and medical history. The chronic nature of epilepsy, like that of most neurological disorders, often results in long-term relationships among the neurologist, the patient, and the patient's family. However, with recent changes in medical care delivery, less time is available to learn about the impact of the disorder on the patient's life. At the same time, the concept of quality of life (QOL) assessment has led to development of generic and disease-specific questionnaires to evaluate areas of concern to patients (2).The purpose of addressing QOL include improving the quality of patient care, differentiating among treatment Accepted July 17, 1997. options, and evaluating the allocation of health care resources. The major domains of QOL are physical, psychological, and social issues (3). These areas go well beyond the traditional assessment of seizure frequency and severity, and adverse effects of medications, toward an understanding of the impact of epilepsy on daily life (1).A variety of approaches have been used to assess QOL issues for people with epilepsy (2). Unified questionnaires [e.g., QOLIE-89 (4), ESI-55 ( 5 ) ] and batteries of tests [e.g., Liverpool QOL Battery (6)] have been used for detailed research programs. However, to conduct multinational epilepsy studies that include assessments of QOL requires an instrument that has been rigorously translated and adapted to the culture of each country in which it will be used. Such instruments will allow researchers to compile and aggregate QOL data across sample populations from different countries. The process is complicated not only by the wide differences in the concept of what constitutes "health" among cultures, 81

We developed an instrument to measure health-related quality of life (HRQOL) in epilepsy. A 99-item inventory was constructed from the RAND 36-Item Health Survey (generic core), with 9 additional generic items, 48 epilepsy-targeted items, and 6 other items concerning attitudes toward epilepsy and self-esteem. We administered the 99-item inventory to 304 adults with epilepsy at 25 epilepsy centers. Patients and patient-designated proxies completed the inventory and were retested 1-91 days later. A multitrait scaling analysis of these data led to retention of 86 items distributed in 17 multiitem scales (Cronbach's alpha ranged from 0.78 to 0.92). Factor analysis of the 17 multiitem scales yielded four underlying dimensions of health: an epilepsy-targeted dimension, a cognitive factor, mental health, and physical health. Construct validity was supported by significant patient-proxy correlations for all scales and correlations between neuropsychologic tests and self-reported emotional and cognitive function (all p values < 0.05). There were significant negative correlations between the four factor scores derived from the HRQOL scales and neurotoxicity, systemic toxicity, and health care utilization (except for the correlation between mental health factor and health care utilization; all p values < 0.05). Patients who were seizure-free in the preceding year reported better HRQOL for the overall score, three of the four factor scores, and 8 of the 17 scale scores than did patients with a high frequency of seizures. Relative validity analysis showed that the epilepsy-targeted factor and three of its four component scales were more sensitive to categorization of patients by severity of seizure frequency and type than scales tapping physical health, mental health, or cognitive function. These cross-sectional data support the reliability and validity of this measure of HRQOL in epilepsy. The addition of an epilepsy-targeted supplement to the generic core improved the sensitivity to severity of epilepsy. The 86 items included in the field testing were supplemented by three additional items to form the Quality of Life in Epilepsy (QOLIE-89) inventory.

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.Methods: Children born to women with epilepsy (n 5 243) and women without epilepsy (n 5 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] 24.9 to 214.6; p , 0.001) for children exposed to high-dose (.800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p , 0.001). Valproate at doses ,800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (25.6, 95% CI 211.1 to 20.1; p 5 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p 5 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (24.2, 95% CI 20.6 to 27.8; p 5 0.02) and increased frequency of IQ ,85.Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. Antiepileptic drugs (AEDs) are associated with teratogenic risk to the development of the fetus, with the prevalence of major congenital malformations differing by treatment type and dose. Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, 2-4 retrospective studies, 5,6 and prospective studies. 7-15 Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.10 In a comparison across AED monotherapies, a significantly poorer IQ in school-aged children exposed in utero to