Kimford J. Meador

Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

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. METHODS Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Childrens IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Development of the Quality of Life in Epilepsy Inventory

Summary: 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 (Cronbachs 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.

Development and Cross‐Cultural Translations of a 31‐Item Quality of Life in Epilepsy Inventory

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.

Rapid detection of major depression in epilepsy: a multicentre study

BACKGROUND Depression is a common comorbid disorder in epilepsy but is not routinely assessed in neurology clinics. We aimed to create a rapid yet accurate screening instrument for major depression in people with epilepsy. METHODS We developed a set of 46 items to identify symptoms of depression that do not overlap with common comorbid cognitive deficits or adverse effects of antiepileptic drugs. This preliminary instrument and several reliable and valid instruments for diagnosis of depression on the basis of criteria from the Diagnostic and Statistical Manual IV, depression symptom severity, health status, and toxic effects of medication were applied to 205 adult outpatients with epilepsy. We used discriminant function analysis to identify the most efficient set of items for classification of major depression, which we termed the neurological disorders depression inventory for epilepsy (NDDI-E). Baseline data for 229 demographically similar patients enrolled in two other clinical studies were used for verification of the original observations. FINDINGS The discriminant function model for the NDDI-E included six items. Internal consistency reliability of the NDDI-E was 0.85 and test-retest reliability was 0.78. An NDDI-E score of more than 15 had a specificity of 90%, sensitivity of 81%, and positive predictive value of 0.62 for a diagnosis of major depression. Logistic regression showed that the model of association of major depression and the NDDI-E was not affected by adverse effects of antiepileptic medication, whereas models for depression and generic screening instruments were. The severity of depression symptoms and toxic effects of drugs independently correlated with subjective health status, explaining 72% of variance. Results from a separate verification sample also showed optimum sensitivity, specificity, and predictive power at a cut score of more than 15. INTERPRETATION Major depression in people with epilepsy can be identified by a brief set of symptoms that can be differentiated from common adverse effects of antiepileptic drugs. The NDDI-E could enable rapid detection and improve management of depression in epilepsy in accordance with internationally recognised guidelines.

Functional MRI cerebral activation and deactivation during finger movement

Objective: To examine interhemispheric interactions of motor processes by using functional MRI (fMRI). Background: Despite evidence of interhemispheric inhibition from animal, clinical, and transcranial magnetic stimulation (TMS) studies, fMRI has not been used to explore activation and deactivation during unilateral motor tasks. fMRI changes associated with motor activity have traditionally been described by comparing cerebral activation during motor tasks relative to a “resting state.” In addition to this standard comparison, we examined fMRI changes in the resting state relative to a motor task. Methods: Thirteen healthy volunteers performed self-paced sequential finger/thumb tapping for each hand. During fMRI data acquisition, four epochs were obtained; each comprised of 30 seconds of rest, 30 seconds of right hand activity, and 30 seconds of left hand activity. Resultant echoplanar images were spatially normalized and spatially and temporally smoothed. Results: As expected, hand movements produced activation in the contralateral sensorimotor cortex and adjacent subcortical regions and, when present, the ipsilateral cerebellum. However, hand movement also produced a significant deactivation (i.e., decreased blood flow) in the ipsilateral sensorimotor cortex and subcortical regions, and when present, the contralateral cerebellum. Conjunction analysis demonstrated regions that are activated by one hand and deactivated by the contralateral hand. Conclusion: Unilateral hand movements are associated with contralateral cerebral activation and ipsilateral cerebral deactivation, which we hypothesize result from transcallosal inhibition.

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Methods: Systematic review of relevant articles published between January 1985 and June 2007. Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).

Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy ☆

Studies of causes of death among people with epilepsy suggest that the lifetime prevalence rate of suicide is elevated. Although not all of the studies have reported an increased risk for suicide, the collective data yield an average rate of approximately 12% among people with epilepsy, compared with 1.1-1.2% in the general population. The increased risk for suicide appears to affect children and adolescents as well as adults. Rates of suicide attempts have also been reported to be elevated among people with epilepsy. A suicide attempt is a significant risk factor for completed suicide. Certain psychiatric disorders, including primary mood disorders, also increase the risk for suicide. Among people with epilepsy, psychiatric comorbidity is common, and rates of mood disorders, particularly major depression, have consistently been reported to be elevated. Other potential risk factors are family issues, physical health, personality, life stress, previous suicidal behavior, and access to firearms. Assessing severity of risk helps to determine the appropriate level of intervention. The suicidality module of the Mini-International Neuropsychiatric Interview is a practical tool to help quantify current suicide risk.

Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts

PURPOSE To conduct a systematic review and meta-analysis to quantify the incidence of congenital malformations (CMs) and other pregnancy outcomes as a function of in utero anti-epileptic drug (AED) exposure. METHODS We performed a systematic literature review to identify all published registries and cohort studies of births from pregnant women with epilepsy (WWE) that reported incidence of CMs. Overall incidences were calculated using a random effects model. RESULTS The review included 59 studies that met inclusion/exclusion criteria, involving 65,533 pregnancies in WWE and 1,817,024 in healthy women. The calculated incidence of births with CM in WWE [7.08%; 95% CIs 5.62, 8.54] was higher than healthy women [2.28%; CIs 1.46, 3.10]. Incidence was highest for AED polytherapy [16.78%; CIs 0.51, 33.05]. The AED with the highest CM incidence was valproate, which was 10.73% [CIs 8.16, 13.29] for valproate monotherapy. CONCLUSIONS Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without epilepsy. The risk was significantly higher for children exposed to valproate monotherapy and to polytherapy of 2 or more drugs when the polytherapy combination included phenobarital, phenytoin, or valproate. Further research is needed to delineate the specific risk for each individual AED and to determine underlying mechanisms including genetic risk factors.

Unilateral cerebral inactivation produces differential left/right heart rate responses

We studied heart rate following unilateral hemispheric inactivation by intracarotid amobarbital in 25 patients undergoing preoperative evaluation for epilepsy surgery. Heart rate increased after left hemisphere inactivation, but decreased following right hemisphere inactivation. The results are consistent with differential left/right cerebral hemispheric effects on autonomic function, and appear related to functional and anatomic asymmetries in both the central and peripheral nervous systems.

Epilepsy and cognition

Patients with epilepsy are more prone to cognitive and behavioral deficits. Epilepsy per se may induce or exacerbate an underlying cognitive impairment, a variety of factors contribute to such deficits, i.e., underlying neuropathology, seizure type, age of onset, psychosocial problems, and treatment side effects. Epilepsy treatment may offset the cognitive and behavioral impairments by stopping or decreasing the seizures, but it may also induce untoward effects on cognition and behavior. The neurocognitive burden of epilepsy may even start through in utero exposure to medications. Epilepsy surgery can also induce certain cognitive deficits, although in most cases this can be minimized. Clinicians should consider cognitive side effect profiles of antiepileptic medications, particularly in extreme age groups. While no effective treatments are available for cognitive and behavioral impairments in epilepsy, comprehensive pretreatment evaluation and meticulous selection of antiepileptic drugs or surgical approach may minimize such untoward effects.