Bio

Bio


Dr. Meador is a Professor of Neurology and Neurosciences at Stanford University, and Clinical Director, Stanford Comprehensive Epilepsy Center. Dr. Meador graduated from the Georgia Institute of Technology in Applied Biology (with high honor) and received his MD from the Medical College of Georgia. After an internship at the University of Virginia and service as an officer in the Public Health Corps, he completed a residency in Neurology at the Medical College of Georgia and a fellowship in Behavioral Neurology at the University of Florida. Dr. Meador joined the faculty at the Medical College of Georgia (1984-2002) where he became the Charbonnier Professor of Neurology. He was the Chair of Neurology at Georgetown University (2002-2004), the Melvin Greer Professor of Neurology and Neuroscience at the University of Florida (2004-2008) where he served as Director of Epilepsy Program and Director of the Clinical Alzheimer Research Program, and Professor of Neurology and Pediatrics at Emory University (2008-2013) where he served as Director of Epilepsy and of Clinical Neurocience Research. He joined the faculty of Stanford University in 2013. Dr. Meador has authored over 300 peer-reviewed publications. His research interests include: cognitive mechanisms (e.g., memory and attention); cerebral lateralization; pharmacology and physiology of cognition; mechanisms of perception, consciousness and memory; EEG; epilepsy; epilepsy and pregnancy; preoperative evaluation for epilepsy surgery; intracarotid amobarbital procedure (i.e., Wada test); functional imaging; therapeutic drug trials; neurodevelopmental effects of antiepileptic drugs; psychoimmunology; behavioral disorders (e.g., aphasia, neglect, dementia); and neuropsychiatric disorders. Dr. Meador has served as the PI for a long running NIH multicenter study of pregnancy outcomes in women with epilepsy and their children. Dr. Meador has served on the editorial boards for Clinical Neurophysiology, Epilepsy and Behavior, Epilepsy Currents, Journal of Clinical Neurophysiology, Neurology, Cognitive and Behavioral Neurology, and Epilepsy.com. His honors include Resident Teaching Award Medical College of Georgia, Outstanding Young Faculty Award in Clinical Sciences Medical College of Georgia, Distinguished Faculty Award for Clinical Research Medical College of Georgia Lawrence C. McHenry History Award American Academy of Neurology, Dreifuss Abstract Award American Epilepsy Society, Fellow of the American Neurological Association, Diplomat of American Neurologic Association, past Chair of the Section of Behavioral Neurology of American Academy of Neurology, past President of Society for Cognitive and Behavioral Neurology, past President of the Society for Behavioral & Cognitive Neurology, past President of the Southern EEG & Epilepsy Society, the American Epilepsy Society Clinical Research Award, and ranking in the top 10 experts in epilepsy worldwide by Expertscape.

Clinical Focus


  • Neurology

Academic Appointments


Professional Education


  • Fellowship:University of Florida (1984) FL
  • Residency:Medical College of Georgia (1983) GA
  • Internship:University of Virgina School of Medicine (1977) VA
  • Medical Education:Medical College of Georgia (1976) GA
  • Board Certification: Neurology, American Board of Psychiatry and Neurology (1985)

Publications

Journal Articles


  • Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA pediatrics Meador, K. J., Baker, G. A., Browning, N., Cohen, M. J., Bromley, R. L., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2014; 168 (8): 729-736

    Abstract

    Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities.To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years.Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery.Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures.In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P < .001 [adjusted IQ worse by 7-13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, -0.1; 95% CI, -0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2-10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0-8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0-7] points higher for breastfed children, P = .03).No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs.clinicaltrials.gov Identifier: NCT00021866.

    View details for DOI 10.1001/jamapediatrics.2014.118

    View details for PubMedID 24934501

  • Breastfeeding and Antiepileptic Drugs JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Meador, K. J. 2014; 311 (17): 1797-1798

    View details for DOI 10.1001/jamaneurol.2013.4290

    View details for Web of Science ID 000335382300025

    View details for PubMedID 24794373

  • Cortical cartography reveals political and physical maps. Epilepsia Loring, D. W., Gaillard, W. D., Bookheimer, S. Y., Meador, K. J., Ojemann, J. G. 2014; 55 (5): 633-637

    Abstract

    Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

    View details for DOI 10.1111/epi.12553

    View details for PubMedID 24815217

  • Patient and caregiver quality of life in psychogenic non-epileptic seizures compared to epileptic seizures SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Karakis, I., Montouris, G. D., Piperidou, C., San Luciano, M., Meador, K. J., Cole, A. J. 2014; 23 (1): 47-54

    Abstract

    Little is known about the effect of psychogenic non epileptic seizures (PNES) to caregiver quality of life (QOL), particularly as it compares to epileptic seizures (ES). We sought to characterize this effect and identify its determinants.The study population comprised of 126 ES and 33 PNES patients who underwent video EEG monitoring along with 48 and 18 caregivers respectively who accompanied them to their investigations. Patients completed questionnaires providing demographic, disease-related, cognitive, psychiatric, sleep and QOL information on admission, prior to their diagnosis being clarified. Their caregivers completed questionnaires providing demographic, disease burden and generic QOL information. Paraclinical data were also gathered. Regression analysis was used to identify patient and caregiver related determinants of patient and caregiver QOL.QOL scores were significantly worse for PNES than ES patients and were mainly linked to depression levels. PNES and ES caregivers had comparable demographic characteristics and QOL scores. ES caregiver QOL was better in employed caregivers with lower burden scores for the physical component summary (PCS) and worse in female caregivers of depressed patients with higher burden scores for the mental component summary (MCS). Caregiver burden score was the strongest correlate of PNES caregiver MCS QOL score.Caregiver QOL in PNES does not differ from caregiver QOL in ES, while patient QOL is worse in PNES. Caregiver burden emerges as a consistent correlate of caregiver QOL both in ES and PNES. These findings advocate for consideration of caregiver burden and QOL in PNES in clinical practice and for future research paradigms.

    View details for DOI 10.1016/j.seizure.2013.09.011

    View details for Web of Science ID 000329960700010

    View details for PubMedID 24140136

  • Caregiver burden in epilepsy: determinants and impact. Epilepsy research and treatment Karakis, I., Cole, A. J., Montouris, G. D., San Luciano, M., Meador, K. J., Piperidou, C. 2014; 2014: 808421-?

    Abstract

    Aim. Caregiver burden (CB) in epilepsy constitutes an understudied area. Here we attempt to identify the magnitude of this burden, the factors associated with it, and its impact to caregiver quality of life (QOL). Methods. 48 persons with epilepsy (PWE) underwent video-EEG monitoring and their caregivers completed questionnaires providing demographic, disease-related, psychiatric, cognitive, sleep, QOL, and burden information. Results. On regression analysis, higher number of antiepileptic drugs, poorer patient neuropsychological performance, lower patient QOL score, and lower caregiver education level were associated with higher CB. Time allocated to patient care approximated but did not attain statistical significance. A moderate inverse correlation between CB and caregiver QOL physical component summary score and a stronger inverse correlation between CB and caregiver QOL mental component summary score were seen. Conclusion. In a selected cohort of PWE undergoing video-EEG monitoring, we identified modest degree of CB, comparable to that reported in the literature for other chronic neurological conditions. It is associated with specific patient and caregiver characteristics and has a negative effect on caregiver QOL.

    View details for DOI 10.1155/2014/808421

    View details for PubMedID 24808956

  • Do antiepileptic drugs cause suicidal behavior? NEUROLOGY Harden, C. L., Meador, K. J. 2013; 81 (22): 1889-1890

    View details for Web of Science ID 000330771500009

    View details for PubMedID 24174589

  • The effect of epilepsy surgery on caregiver quality of life. Epilepsy research Karakis, I., Montouris, G. D., Piperidou, C., Luciano, M. S., Meador, K. J., Cole, A. J. 2013; 107 (1-2): 181-189

    Abstract

    Epilepsy surgery has been shown to improve patient quality of life (QOL). Little is known about its effect on caregiver QOL.The study population comprised of 26 persons with epilepsy (PWE) who underwent long term video EEG monitoring at Massachusetts General Hospital for presurgical evaluation along with 16 caregivers. The PWE completed epilepsy directed QOL (QOLIE-31) and psychological (Beck depression-BDI and anxiety inventory-BAI) questionnaires before and after surgery. Their participating caregivers completed generic health related QOL (SF36v2) and disease burden (Zarit caregiver burden inventory-ZCBI) questionnaires before and after surgery. Demographic data for all participants and disease/surgery related data for the PWE were collected. Statistical analysis was performed to compare PWE and caregiver QOL before and after surgery.Mean patient age was 37 years. Most (77%) suffered from symptomatic partial epilepsy for approximately 18 years prior to surgery, averaging 4 seizures per month and 2.2 antiepileptic drugs (AEDs). 78% of them underwent an anterior temporal lobectomy and the rest extra-temporal resections. On follow up at approximately 9 months, 69% had a surgical outcome of Engel class I, 23% of class II and 8% class IV. Postoperatively, the PWE remained on average on 1.9 AEDs. There was a statistically significant improvement for both the aggregate QOLIE-31 score and all its subscales (except for medication effects) as well as the BAI scores. 96% of the PWE felt that the decision to go through surgery was worthwhile. Mean caregivers age was 47 years. Half of them were spouses to the PWE and the majority of the rest their parents. 50% of them stated that their overall time devoted to patient's care decreased after surgery and 50% that it remained unchanged. The mental component scale (SF36v2, MCS) of caregiver QOL showed statistically significant improvement. ZCBI score and the physical component scale of their QOL (SF36v2, PCS) did not significantly vary before and after surgery. 75% of caregivers deemed their QOL better post surgery vs 19% similar. 94% of the caregivers felt that the decision to go through surgery was worthwhile.Successful epilepsy surgery has a positive impact not only to patient QOL but also to their caregiver. To the best of our knowledge, this is the first pilot study to systematically address the impact of epilepsy surgery on caregivers providing additional support to epilepsy surgery as the optimal treatment modality in carefully selected patients. These findings call for further investigation on the caregiver quality of life in epilepsy and for its inclusion in the treatment plan and quality indicators for epilepsy surgery.

    View details for DOI 10.1016/j.eplepsyres.2013.08.006

    View details for PubMedID 24054427

  • Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years EPILEPSY & BEHAVIOR Cohen, M. J., Meador, K. J., Browning, N., May, R., Baker, G. A., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2013; 29 (2): 308-315

    Abstract

    The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.

    View details for DOI 10.1016/j.yebeh.2013.08.001

    View details for Web of Science ID 000325422500010

    View details for PubMedID 24012508

  • Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy EPILEPSY & BEHAVIOR Reisinger, T. L., Newman, M., Loring, D. W., Pennell, P. B., Meador, K. J. 2013; 29 (1): 13-18

    Abstract

    The aims of the study were to characterize the magnitude of clearance changes during pregnancy for multiple antiepileptic drugs (AEDs) and to assess seizure frequency and factors increasing seizure risk in pregnant women with epilepsy. A retrospective analysis was performed for 115 pregnancies in 95 women with epilepsy followed at the Emory Epilepsy Center between 1999 and 2012. Antiepileptic drug blood levels (ABLs) obtained during routine clinical practice were used to calculate AED clearance at multiple points during pregnancy. Antiepileptic drug doses and seizure activity were also recorded. The data were analyzed for changes in clearance and dose across pregnancy and for an association between ABL and changes in seizure frequency. Significant changes in clearance during pregnancy were observed for lamotrigine (p<0.001) and levetiracetam (p<0.006). Average peak clearance increased by 191% for lamotrigine and 207% for levetiracetam from nonpregnant baseline. Marked variance was present across individual women and also across repeat pregnancies in individual women. Despite increased AED dose across most AEDs, seizures increased in 38.4% of patients during pregnancy. Seizure deterioration was significantly more likely in patients with seizures in the 12 months prior to conception (p<0.001) and those with localization-related epilepsy (p=0.005). When ABL fell >35% from preconception baseline, seizures worsened significantly during the second trimester when controlling for seizure occurrence in the year prior to conception. Substantial pharmacokinetic changes during pregnancy occur with multiple AEDs and may increase seizure risk. Monitoring of AED serum concentrations with dose adjustment is recommended in pregnant women with epilepsy. Further studies are needed for many AEDs.

    View details for DOI 10.1016/j.yebeh.2013.06.026

    View details for Web of Science ID 000324241300004

    View details for PubMedID 23911354

  • Comment: valproate dose effects differ across congenital malformations. Neurology Meador, K. J. 2013; 81 (11): 1002-?

    Abstract

    Fetal valproate exposure has been associated with the highest risk of congenital malformations among antiepileptic drugs.(1) Valproate's effect is dose-dependent(1) and has been associated with multiple specific malformations.(2,3) Vadja et al.(4) examined data from the Australian Pregnancy Registry (1999-2012 data), which included 1,705 pregnancies with 436 valproate exposures.(4) They found that the use and dosages of valproate have fallen over the last 5 years. The rates of spina bifida and hypospadius in those exposed dropped with reducing dosages of valproate, but the rates of other malformations did not. Mean dosages for malformations were higher for spina bifida (2,000 mg/d) and hypospadius (2,417 mg/d) than all other malformations (1,083 mg/d).

    View details for DOI 10.1212/WNL.0b013e3182a43eb7

    View details for PubMedID 23911754

  • Prenatal valproate exposure is associated with autism spectrum disorder and childhood autism JOURNAL OF PEDIATRICS Meador, K. J., Loring, D. W. 2013; 163 (3): 924-924

    View details for Web of Science ID 000323985300070

    View details for PubMedID 23973243

  • Managing common complex symptomatic epilepsies: tumors and trauma: american epilepsy society - 2012 annual course summary. Epilepsy currents Burneo, J. G., Sirven, J. I., Kiesel, L. W., Vecht, C. J., Jehi, L., Chung, S. S., Uhm, J., Politsky, J. M., Chang, E. F., Husain, A. M., Tatum, W. O., Meador, K. J., Noe, K., Hesdorffer, D. C., Herman, S. T., Wiebe, S., Engel, J., Schrader, S., Parko, K. L., Dichter, M. A., Kwan, P., Kossoff, E., Sperling, M. R. 2013; 13 (5): 232-235

    View details for DOI 10.5698/1535-7597-13.5.232

    View details for PubMedID 24348117

  • Epilepsy and neuropsychological comorbidities. Continuum (Minneapolis, Minn.) Rudzinski, L. A., Meador, K. J. 2013; 19 (3 Epilepsy): 682-696

    Abstract

    Epilepsy is a chronic disorder with several associated comorbidities requiring timely recognition and treatment. This article discusses aspects of cognitive impairment; psychiatric disorders including depression, anxiety, and psychosis; and health-related quality-of-life issues pertaining to patients with epilepsy.Cognitive problems in epilepsy may be present early in the disease course. Advances in imaging techniques are allowing correlation of structure and function as they relate to cognitive impairment in epilepsy. The relationship between epilepsy, depression, and anxiety is increasingly recognized, and these psychiatric comorbidities may affect suicide risk, patient-reported adverse antiepileptic drug effects, and quality of life. Psychiatric disorders are underrecognized and undertreated in patients with epilepsy.Physicians who treat patients with epilepsy should be aware of the major impact that cognitive impairment and psychiatric comorbidities have on these patients. Identifying and treating these comorbidities in epilepsy patients is just as important as seizure treatment.

    View details for DOI 10.1212/01.CON.0000431382.06438.cd

    View details for PubMedID 23739104

  • Famous face identification in temporal lobe epilepsy: Support for a multimodal integration model of semantic memory CORTEX Drane, D. L., Ojemann, J. G., Phatak, V., Loring, D. W., Gross, R. E., Hebb, A. O., Silbergeld, D. L., Miller, J. W., Voets, N. L., Saindane, A. M., Barsalou, L., Meador, K. J., Ojemann, G. A., Tranel, D. 2013; 49 (6): 1648-1667

    Abstract

    This study aims to demonstrate that the left and right anterior temporal lobes (ATLs) perform critical but unique roles in famous face identification, with damage to either leading to differing deficit patterns reflecting decreased access to lexical or semantic concepts but not their degradation. Famous face identification was studied in 22 presurgical and 14 postsurgical temporal lobe epilepsy (TLE) patients and 20 healthy comparison subjects using free recall and multiple choice (MC) paradigms. Right TLE patients exhibited presurgical deficits in famous face recognition, and postsurgical deficits in both famous face recognition and familiarity judgments. However, they did not exhibit any problems with naming before or after surgery. In contrast, left TLE patients demonstrated both pre- and postsurgical deficits in famous face naming but no significant deficits in recognition or familiarity. Double dissociations in performance between groups were alleviated by altering task demands. Postsurgical right TLE patients provided with MC options correctly identified greater than 70% of famous faces they initially rated as unfamiliar. Left TLE patients accurately chose the name for nearly all famous faces they recognized (based on their verbal description) but initially failed to name, although they tended to rapidly lose access to this name. We believe alterations in task demands activate alternative routes to semantic and lexical networks, demonstrating that unique pathways to such stored information exist, and suggesting a different role for each ATL in identifying visually presented famous faces. The right ATL appears to play a fundamental role in accessing semantic information from a visual route, with the left ATL serving to link semantic information to the language system to produce a specific name. These findings challenge several assumptions underlying amodal models of semantic memory, and provide support for the integrated multimodal theories of semantic memory and a distributed representation of concepts.

    View details for DOI 10.1016/j.cortex.2012.08.009

    View details for Web of Science ID 000321169200016

    View details for PubMedID 23040175

  • Risks of In Utero Exposure to Valproate JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Meador, K. J., Loring, D. W. 2013; 309 (16): 1730-1731

    View details for DOI 10.1001/jama.2013.4001

    View details for Web of Science ID 000317906700030

    View details for PubMedID 23613078

  • Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study LANCET NEUROLOGY Meador, K. J., Baker, G. A., Browning, N., Cohen, M. J., Bromley, R. L., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2013; 12 (3): 244-252

    Abstract

    Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age.In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866.We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine (105, 102-108; p=0·0015), lamotrigine (108, 105-110; p=0·0003), or phenytoin (108, 104-112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001), verbal ability (r=-0·40, p=0·0045), non-verbal ability (r=-0·42, p=0·0028), memory (r=-0·30, p=0·0434), and executive function (r=-0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106-111) than they were in unexposed children (101, 98-104; p=0·0009).Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies.

    View details for DOI 10.1016/S1474-4422(12)70323-X

    View details for Web of Science ID 000318531300010

    View details for PubMedID 23352199

  • Acute lorazepam effects on neurocognitive performance EPILEPSY & BEHAVIOR Loring, D. W., Marino, S. E., Parfitt, D., Finney, G. R., Meador, K. J. 2012; 25 (3): 329-333

    Abstract

    A double-blind, placebo-controlled, crossover design was employed to determine whether acute lorazepam (2 mg orally) cognitive side effects would emerge in a differential age-dependent fashion in 15 young (mean age=22 years) and 12 older (mean age=64 years) subjects. Acute use of lorazepam is frequently the initial treatment choice for convulsive status epilepticus or repetitive seizure clusters. Cognitive assessment was performed during drug and placebo conditions using a computerized battery of cognitive tests. With the exception of performance on the reasoning composite score, significant drug effects were present on all primary cognitive domain measures. However, the only significant drug-by-age interaction effect was seen for dual-task performance. The relationship between test performance and plasma lorazepam concentrations was generally modest and non-significant, suggesting that individual differences in pharmacokinetics are not a major factor contributing to the emergence of cognitive side effects. Despite robust lorazepam effects on multiple measures of neurocognitive function, differential age effects are largely restricted to dual-task performance. These results indicate that with the exception of dual-task performance, older individuals in the age range of this study do not appear to be at increased risk for the emergence of cognitive side effects following a single 2-mg dose of lorazepam.

    View details for DOI 10.1016/j.yebeh.2012.08.019

    View details for Web of Science ID 000310917000006

    View details for PubMedID 23103305

  • Differential effects of antiepileptic drugs on neonatal outcomes EPILEPSY & BEHAVIOR Pennell, P. B., Klein, A. M., Browning, N., Baker, G. A., Clayton-Smith, J., Kalayjian, L. A., Liporace, J. D., Privitera, M., Crawford, T., Loring, D. W., Meador, K. J. 2012; 24 (4): 449-456

    Abstract

    Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

    View details for DOI 10.1016/j.yebeh.2012.05.010

    View details for Web of Science ID 000306900300012

    View details for PubMedID 22749607

  • EPILEPSY Maximizing cognitive outcomes in epilepsy NATURE REVIEWS NEUROLOGY Loring, D. W., Meador, K. J. 2012; 8 (8): 416-417

    View details for DOI 10.1038/nrneurol.2012.143

    View details for Web of Science ID 000307417400002

    View details for PubMedID 22777245

  • Depressive and anxiety disorders in epilepsy: Do they differ in their potential to worsen common antiepileptic drug-related adverse events? EPILEPSIA Kanner, A. M., Barry, J. J., Gilliam, F., Hermann, B., Meador, K. J. 2012; 53 (6): 1104-1108

    Abstract

    To compare the effect of anxiety disorders, major depressive episodes (MDEs), and subsyndromic depressive episodes (SSDEs) on antiepileptic drug (AED)-related adverse events (AEs) in persons with epilepsy (PWE).The study included 188 consecutive PWE from five U.S. outpatient epilepsy clinics, all of whom underwent structured interviews (SCID) to identify current and past mood disorders and other current Axis I psychiatric diagnoses according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. A diagnosis of SSDE was made in patients with total Beck Depression Inventory-II (BDI-II) scores >12 or the Centers of Epidemiologic Studies-Depression (CES-D) > 16 (in the absence of any DSM diagnosis of mood disorder. The presence and severity of AEs was measured with the Adverse Event Profile (AEP).Compared to asymptomatic patients (n = 103), the AEP scores of patients with SSDE (n = 26), MDE only (n = 10), anxiety disorders only (n = 21), or mixed MDE/anxiety disorders (n = 28) were significantly higher, suggesting more severe AED-related AEs. Univariate analyses revealed that having persistent seizures in the last 6 months and taking antidepressants was associated with more severe AEs. Post hoc analyses, however, showed that these differences were accounted for by the presence of a depressive and/or anxiety disorders.Depressive and anxiety disorders worsen AED-related AEs even when presenting as a subsyndromic type. These data suggest that the presence of psychiatric comorbidities must be considered in their interpretation, both in clinical practice and AED drug trials.

    View details for DOI 10.1111/j.1528-1167.2012.03488.x

    View details for Web of Science ID 000304715900023

    View details for PubMedID 22554067

  • Antiepileptic drugs in women with epilepsy during pregnancy. Therapeutic advances in drug safety Gedzelman, E., Meador, K. J. 2012; 3 (2): 71-87

    Abstract

    Prescribing antiepileptic drugs (AEDs) in pregnancy is a challenge to the clinician. A multitude of questions arise that must be addressed even prior to conception. In women with proven epilepsy, it may be dangerous to stop or even change the AED regimen during pregnancy. Changes could lead to injury or death in both the mother and the fetus. In the rare cases when discontinuing an AED is plausible, it should be done methodically in consultation with the physician prior to conception. Most women with epilepsy are consigned to continue their AEDs before, during and after pregnancy. The metabolism of AEDs may change drastically during pregnancy. These changes must be addressed by the clinician. Drug levels should be monitored consistently during pregnancy. The risks to the fetus must be delineated in terms of side effects from specific drugs as well as risks from the seizure disorder itself. Many AEDs have well known teratogenic effects, and these must be elucidated to the mother. There are risks (theoretical and evidence based) for obstetrical complications, poor neonatal outcomes, congenital malformations and even cognitive effects on the child later in life. These risks are addressed in this article with respect to individual AEDs. Recommendations include but are not limited to preconception counseling, taking folate pre and post conception, prescribing the most effective AED while minimizing risks, and avoiding polytherapy and valproate if possible.

    View details for DOI 10.1177/2042098611433192

    View details for PubMedID 25083227

  • Effects of fetal antiepileptic drug exposure Outcomes at age 4.5 years NEUROLOGY Meador, K. J., Baker, G. A., Browning, N., Cohen, M. J., Bromley, R. L., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2012; 78 (16): 1207-1214

    Abstract

    To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5).Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills.Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

    View details for DOI 10.1212/WNL.0b013e318250d824

    View details for Web of Science ID 000302933200006

    View details for PubMedID 22491865

  • Different structural correlates for verbal memory impairment in temporal lobe epilepsy with and without mesial temporal lobe sclerosis HUMAN BRAIN MAPPING Mueller, S. G., Laxer, K. D., Scanlon, C., Garcia, P., McMullen, W. J., Loring, D. W., Meador, K. J., Weiner, M. W. 2012; 33 (2): 489-499

    Abstract

    Memory impairment is one of the most prominent cognitive deficits in temporal lobe epilepsy (TLE). The overall goal of this study was to explore the contribution of cortical and hippocampal (subfield) damage to impairment of auditory immediate recall (AIMrecall), auditory delayed recall (ADMrecall), and auditory delayed recognition (ADMrecog) of the Wechsler Memory Scale III (WMS-III) in TLE with (TLE-MTS) and without hippocampal sclerosis (TLE-no). It was hypothesized that volume loss in different subfields determines memory impairment in TLE-MTS and temporal neocortical thinning in TLE-no.T1 whole brain and T2-weighted hippocampal magnetic resonance imaging and WMS-III were acquired in 22 controls, 18 TLE-MTS, and 25 TLE-no. Hippocampal subfields were determined on the T2 image. Free surfer was used to obtain cortical thickness averages of temporal, frontal, and parietal cortical regions of interest (ROI). MANOVA and stepwise regression analysis were used to identify hippocampal subfields and cortical ROI significantly contributing to AIMrecall, ADMrecall, and ADMrecog.In TLE-MTS, AIMrecall was associated with cornu ammonis 3 (CA3) and dentate (CA3&DG) and pars opercularis, ADMrecall with CA1 and pars triangularis, and ADMrecog with CA1. In TLE-no, AIMrecall was associated with CA3&DG and fusiform gyrus (FUSI), and ADMrecall and ADMrecog were associated with FUSI.The study provided the evidence for different structural correlates of the verbal memory impairment in TLE-MTS and TLE-no. In TLE-MTS, the memory impairment was mainly associated by subfield-specific hippocampal and inferior frontal cortical damage. In TLE-no, the impairment was associated by mesial-temporal cortical and to a lesser degree hippocampal damage.

    View details for DOI 10.1002/hbm.21226

    View details for Web of Science ID 000299071200018

    View details for PubMedID 21438080

  • Neurological and psychiatric sequelae of developmental exposure to antiepileptic drugs. Frontiers in neurology Gedzelman, E. R., Meador, K. J. 2012; 3: 182-?

    Abstract

    The neurons in the developing mammalian brain are susceptible to antiepileptic drug (AED) effects. It is known that later in life deficits in cognitive performance as well as psychiatric deficits can manifest after early AED exposure. The extent of these deficits will be addressed. This review will attempt to draw parallels between the existent animal models and human studies. Through analysis of these studies, important future research will be elucidated and possible new and emerging therapies will be discussed.

    View details for DOI 10.3389/fneur.2012.00182

    View details for PubMedID 23293628

  • Mapping and mining interictal pathological gamma (30-100 Hz) oscillations with clinical intracranial EEG in patients with epilepsy. Expert systems with applications Smart, O., Maus, D., Marsh, E., Dlugos, D., Litt, B., Meador, K. 2012; 39 (8): 7355-7370

    Abstract

    Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30-100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG (<100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure-areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) post-surgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain.

    View details for DOI 10.1016/j.eswa.2012.01.071

    View details for PubMedID 23105174

  • Fetal antiepileptic drug exposure: Motor, adaptive, and emotional/behavioral functioning at age 3 years EPILEPSY & BEHAVIOR Cohen, M. J., Meador, K. J., Browning, N., Baker, G. A., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2011; 22 (2): 240-246

    Abstract

    The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain.

    View details for DOI 10.1016/j.yebeh.2011.06.014

    View details for Web of Science ID 000295706800015

    View details for PubMedID 21783425

  • Variation of seizure frequency with ovulatory status of menstrual cycles EPILEPSIA Herzog, A. G., Fowler, K. M., Sperling, M. R., Liporace, J. D., Kalayjian, L. A., Heck, C. N., Krauss, G. L., Dworetzky, B. A., Pennell, P. B. 2011; 52 (10): 1843-1848

    Abstract

    To determine if seizure frequency differs between anovulatory and ovulatory cycles.The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis.ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only.Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.

    View details for DOI 10.1111/j.1528-1167.2011.03194.x

    View details for Web of Science ID 000296067000019

    View details for PubMedID 21756250

  • Cognitive effects of carisbamate in randomized, placebo-controlled, healthy-volunteer, multidose studies EPILEPSY & BEHAVIOR Meador, K. J., Brashear, H. R., Wiegand, F., Zannikos, P., Novak, G. 2011; 22 (2): 324-330

    Abstract

    Adverse cognitive effects are an important concern for drugs that influence the central nervous system. Carisbamate is a novel drug in development for treatment of seizures and neuropathic pain. Information on its cognitive effects is limited. Three controlled, multiple-dose, crossover studies with treatment durations of 5-9 days were designed to examine the cognitive effects of carisbamate on healthy volunteers. In one study, apparent dose-dependent effects on response, vigilance, and recognition speed were observed (1000 mg and 1500 mg/day). Carisbamate did not differ from placebo for most variables in the other two studies, but increased reaction time and reduced Sternberg memory were seen at higher dosages. Carisbamate did not produce clinically significant adverse effects on cognitive performance at doses <1000 mg/day. Effects were mild to modest at the higher doses tested.

    View details for DOI 10.1016/j.yebeh.2011.07.006

    View details for Web of Science ID 000295706800028

    View details for PubMedID 21849260

  • Networks, cognition, and epilepsy NEUROLOGY Meador, K. J. 2011; 77 (10): 930-931

    View details for DOI 10.1212/WNL.0b013e31822cfcd6

    View details for Web of Science ID 000294538100006

    View details for PubMedID 21832233

  • Cognitive and neurodevelopmental effects of antiepileptic drugs EPILEPSY & BEHAVIOR Bromley, R. L., Leeman, B. A., Baker, G. A., Meador, K. J. 2011; 22 (1): 9-16

    Abstract

    This article primarily represents the contributions of two young investigators to the understanding of the neuropsychological consequences of epilepsy and its treatment. The authors have reviewed two key areas of importance: the complex relationship between cognitive dysfunction and epilepsy and the risks of cognitive dysfunction in children as a consequence of in utero exposure to antiepileptic drug treatment. The work of two young investigators is presented and future research needs are outlined.

    View details for DOI 10.1016/j.yebeh.2011.04.009

    View details for Web of Science ID 000294984000003

    View details for PubMedID 21684214

  • Disparities in NIH funding for epilepsy research NEUROLOGY Meador, K. J., French, J., Loring, D. W., Pennell, P. B. 2011; 77 (13): 1305-1307

    Abstract

    Using data from NIH Research Portfolio Online Reporting Tools (RePORT) and recently assembled prevalence estimates of 6 major neurologic diseases, we compared the relative prevalences and the annual NIH support levels for 6 major neurologic disorders: Alzheimer disease, amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis, Parkinson disease, and stroke. Compared to these other major neurologic disorders, epilepsy research is funded at a persistently lower rate based on relative disease prevalences. Relative NIH funding for these other disorders in 2010 adjusted for prevalence ranged from 1.7x (stroke) to 61.1x (ALS) greater than epilepsy. The disparity cannot be explained by differences in the overall impact of these diseases on US citizens. Greater transparency in the review and funding process is needed to disclose the reason for this disparity.

    View details for DOI 10.1212/WNL.0b013e318230a18f

    View details for Web of Science ID 000295253800020

    View details for PubMedID 21947534

  • Antiepileptic Drugs and Neurodevelopment: An Update CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Palac, S., Meador, K. J. 2011; 11 (4): 423-427

    Abstract

    In utero exposure to some antiepileptic drugs (AEDs) is associated with an increased risk of impaired cognitive development. Specifically, valproate and polytherapy exposure are each associated with an increased risk of cognitive impairment in children compared with other antiepileptic medications. The data regarding the risk to neurocognitive development imposed by maternal use of other AEDs are conflicting or insufficient at this time to draw definitive conclusions. Behavioral dysfunction including autistic spectrum disorder is also associated with maternal use of AEDs during pregnancy. Whether treatment with AEDs during childhood permanently affects cognitive neurodevelopment is yet to be determined.

    View details for DOI 10.1007/s11910-011-0194-y

    View details for Web of Science ID 000292462900010

    View details for PubMedID 21465150

  • Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure EPILEPSY & BEHAVIOR Meador, K. J., Baker, G. A., Browning, N., Clayton-Smith, J., Cohen, M. J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2011; 21 (2): 147-152

    Abstract

    Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs. Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child's cognitive outcome.

    View details for DOI 10.1016/j.yebeh.2011.03.020

    View details for Web of Science ID 000292019000008

    View details for PubMedID 21546316

  • ABNORMAL INTERICTAL GAMMA ACTIVITY MAY MANIFEST A SEIZURE ONSET ZONE IN TEMPORAL LOBE EPILEPSY INTERNATIONAL JOURNAL OF NEURAL SYSTEMS Medvedev, A. V., Murro, A. M., Meador, K. J. 2011; 21 (2): 103-114

    Abstract

    Even though recent studies have suggested that seizures do not occur suddenly and that before a seizure there is a period with an increased probability of seizure occurrence, neurophysiological mechanisms of interictal and pre-seizure states are unknown. The ability of mathematical methods to provide much more sensitive tools for the detection of subtle changes in the electrical activity of the brain gives promise that electrophysiological markers of enhanced seizure susceptibility can be found even during interictal periods when EEG of epilepsy patients often looks 'normal'. Previously, we demonstrated in animals that hippocampal and neocortical gamma-band rhythms (30-100 Hz) intensify long before seizures caused by systemic infusion of kainic acid. Other studies in recent years have also drawn attention to the fast activity (>30 Hz) as a possible marker of epileptogenic tissue. The current study quantified gamma-band activity during interictal periods and seizures in intracranial EEG (iEEG) in 5 patients implanted with subdural grids/intracranial electrodes during their pre-surgical evaluation. In all our patients, we found distinctive (abnormal) bursts of gamma activity with a 3 to 100 fold increase in power at gamma frequencies with respect to selected by clinicians, quiescent, artifact-free, 7-20 min "normal" background (interictal) iEEG epochs 1 to 14 hours prior to seizures. Increases in gamma activity were largest in those channels which later displayed the most intensive electrographic seizure discharges. Moreover, location of gamma-band bursts correlated (with high specificity, 96.4% and sensitivity, 83.8%) with seizure onset zone (SOZ) determined by clinicians. Spatial localization of interictal gamma rhythms within SOZ suggests that the persistent presence of abnormally intensified gamma rhythms in the EEG may be an important tool for focus localization and possibly a determinant of epileptogenesis.

    View details for DOI 10.1142/S0129065711002699

    View details for Web of Science ID 000288805100002

    View details for PubMedID 21442774

  • Epilepsy Five New Things NEUROLOGY Rudzinski, L. A., Meador, K. J. 2011; 76 (7): S20-S24

    View details for Web of Science ID 000287362300004

    View details for PubMedID 21321347

  • Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age BRAIN Meador, K. J., Baker, G. A., Browning, N., Cohen, M. J., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2011; 134: 396-404

    Abstract

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled pregnant females with epilepsy on monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used drugs (carbamazepine, lamotrigine, phenytoin and valproate). This report compares verbal versus non-verbal cognitive outcomes in 216 children who completed testing at the age of three years. Verbal and non-verbal index scores were calculated from the Differential Ability Scales, Preschool Language Scale, Peabody Picture Vocabulary Test and Developmental Test of Visual-Motor Integration. Verbal abilities were lower than non-verbal in children exposed in utero to each drug. Preconceptional folate use was associated with higher verbal outcomes. Valproate was associated with poorer cognitive outcomes. Performance was negatively associated with valproate dose for both verbal and non-verbal domains and negatively associated with carbamazepine dose for verbal performance. No dose effects were seen for lamotrigine and phenytoin. Since foetal antiepileptic drug exposure is associated with lower verbal than non-verbal abilities, language may be particularly susceptible to foetal exposure. We hypothesize that foetal drug exposure may alter normal cerebral lateralization. Further, a dose-dependent relationship is present for both lower verbal and non-verbal abilities with valproate and for lower verbal abilities with carbamazepine. Preconceptional folate may improve cognitive outcomes. Additional research is needed to confirm these findings, extend the study to other drugs, define the risks associated with drug treatment for seizures in the neonates, and understand the underlying mechanisms.

    View details for DOI 10.1093/brain/awq352

    View details for Web of Science ID 000286990800009

    View details for PubMedID 21224309

  • Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam EPILEPSIA Meador, K. J., Gevins, A., Leese, P. T., Otoul, C., Loring, D. W. 2011; 52 (2): 264-272

    Abstract

    Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain.A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs).Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions.The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.

    View details for DOI 10.1111/j.1528-1167.2010.02746.x

    View details for Web of Science ID 000287239800008

    View details for PubMedID 20887370

  • Topiramate dose effects on cognition A randomized double-blind study NEUROLOGY Loring, D. W., Williamson, D. J., Meador, K. J., Wiegand, F., Hulihan, J. 2011; 76 (2): 131-137

    Abstract

    Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers.To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week).Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis.Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks.Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

    View details for Web of Science ID 000286098400009

    View details for PubMedID 21148119

  • A Method to Combine Cognitive and Neurophysiological Assessments of the Elderly DEMENTIA AND GERIATRIC COGNITIVE DISORDERS Gevins, A., Ilan, A. B., Jiang, A., Chan, C. S., Gelinas, D., Smith, M. E., McEvoy, L. K., Schwager, E., Padilla, M., Davis, Z., Meador, K. J., Patterson, J., O'Hara, R. 2011; 31 (1): 7-19

    Abstract

    The development of better treatments for brain diseases of the elderly will necessitate more sensitive and efficient means of repeatedly assessing an individual's neurocognitive status.To illustrate the development of an assessment combining episodic memory and working memory tasks with simultaneous electroencephalography and evoked potential (EP) brain function measures.Data from matched groups of elderly subjects with mildly impaired episodic verbal memory on neuropsychological tests and those with no objective signs of impairment were used for scale development. An exploratory multivariate divergence analysis selected task performance and neurophysiological variables that best recognized impairment. Discriminant validity was then initially assessed on separate impaired and unimpaired groups.Decreased response accuracy and parietal late positive component EP amplitude in the episodic memory task best characterized impaired subjects. Sensitivity in recognizing impairment in the validation analysis was 89% with 79% specificity (area under the curve = 0.94). Retest reliability was 0.89 for the unimpaired and 0.74 for the impaired validation groups.These promising initial results suggest that with further refinement and testing, an assessment combining cognitive task performance with simultaneous neurofunctional measures could eventually provide an important benefit for clinicians and researchers.

    View details for DOI 10.1159/000322108

    View details for Web of Science ID 000286425500002

    View details for PubMedID 21109739

  • Lorazepam Effects on Word Memory Test Performance: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial CLINICAL NEUROPSYCHOLOGIST Loring, D. W., Marino, S. E., Drane, D. L., Parfitt, D., Finney, G. R., Meador, K. J. 2011; 25 (5): 799-811

    Abstract

    The Word Memory Test (WMT) is a common measure of symptom validity. To investigate the effects of acute benzodiazepines on WMT scores, oral lorazepam 2 mg (LOR) and placebo were administered 1 week apart in a randomized, double-blind, placebo-controlled, crossover study. A total of 28 participants completed the study and were administered the WMT during each drug condition. Within-participant comparisons of LOR vs placebo revealed significant LOR effects for Immediate Recognition (p = .007) and Consistency (p = .019), but not Delayed Recognition (p = .085). Significant LOR effects were present for Reaction Time Measures (Immediate Recognition RT, p = .013; Delayed Recognition RT, p = .001; Multiple Choice RT, p = .011) and Delayed Memory scores (Multiple Choice, p = .007; Paired Associates, p = .029; Free Recall, p = .001). A pattern similar to crossover results was detected for LOR vs placebo between-group differences for initial test assessment scores. When examined using publisher recommended cut scores for the principal WMT measures, there were six participants failing the WMT during initial LOR testing; all six subsequently performed in the normal range upon retesting with placebo. One participant failed WMT during placebo and obtained passing scores during LOR. These data indicate that multiple WMT measures may be affected by acute LOR dosing, and provide additional evidence that potential latent variables and their effects on both SVT performance and cognitive function should be part of the clinical decision-making process.

    View details for DOI 10.1080/13854046.2011.583279

    View details for Web of Science ID 000299559000007

    View details for PubMedID 21756210

  • Effects of breastfeeding in children of women taking antiepileptic drugs NEUROLOGY Meador, K. J., Baker, G. A., Browning, N., Clayton-Smith, J., Combs-Cantrell, D. T., Cohen, M., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2010; 75 (22): 1954-1960

    Abstract

    Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children.The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children.A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96-103) and nonbreastfed = 98 (95-101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups.This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.

    View details for Web of Science ID 000284685800007

    View details for PubMedID 21106960

  • Is antiepileptic drug use related to depression and suicidal ideation among patients with epilepsy? EPILEPSY & BEHAVIOR Wen, X., Meador, K. J., Loring, D. W., Eisenschenk, S., Segal, R., Hartzema, A. G. 2010; 19 (3): 494-500

    Abstract

    Depression and suicide are increased in patients with epilepsy. The U.S. Food and Drug Administration warns that antiepileptic drugs (AEDs) are associated with increased risk of suicidality. This study examines the relationship among depression, suicidal ideation, and AEDs in a prospective cohort of 163 patients with epilepsy from a registry at the University of Florida (January 2006 to August 2008). The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to measure mood and suicidal ideation across two time points (median = 154 days). Groups included: (1) No AED Change, (2) New AED Added, (3) AED Dose Increased, (4) AED Reduced/Stopped, (5) Multiple AED Changes, and (6) Combined Any AED Change (groups 2-5 combined). No group had worsening mood or suicidal ideation. Significant improvements in proportions of depression and suicidal ideation were seen only for the No AED Change group, which differed only with the AED Dose Increased group with respect to suicidal ideation.

    View details for DOI 10.1016/j.yebeh.2010.08.030

    View details for Web of Science ID 000285451600051

    View details for PubMedID 20880757

  • How localized is localization-related epilepsy? NEUROLOGY Meador, K. J., Hermann, B. 2010; 75 (5): 386-387

    View details for Web of Science ID 000280565600001

    View details for PubMedID 20679631

  • Anxiety disorders, subsyndromic depressive episodes, and major depressive episodes: Do they differ on their impact on the quality of life of patients with epilepsy? EPILEPSIA Kanner, A. M., Barry, J. J., Gilliam, F., Hermann, B., Meador, K. J. 2010; 51 (7): 1152-1158

    Abstract

    To compare the impact of anxiety disorders, major depressive episodes (MDEs), and subsyndromic depressive episodes (SSDEs) on the quality of life of patients with epilepsy (PWEs), and to identify the variables predictive of poor quality of life.A psychiatric diagnosis according to DSM-IV-TR criteria was established in 188 consecutive PWEs with the MINI International Neuropsychiatric Interview. Patients also completed the Beck Depression Inventory-II (BDI-II), the Centers for Epidemiologic Studies-Depression (CES-D), and the Quality of Life in Epilepsy-89 (QOLIE-89). A diagnosis of SSDE was made in any patient with total scores of the BDI-II >12 or CES-D >16 in the absence of any DSM-IV diagnosis of mood disorder according to the MINI.Patients with SSDEs (n = 26) had a worse quality of life than asymptomatic patients (n = 103). This finding was also observed among patients with MDEs only (n = 10), anxiety disorders only (n = 21), or mixed MDEs/anxiety disorders (n = 28). Furthermore, having mixed SSDEs/anxiety disorders yielded a worse quality of life than having only SSDEs. Independent predictors of poor quality of life included having a psychiatric disorder and persistent epileptic seizures in the last 6 months.Although isolated mood and anxiety disorders, including SSDE, have a comparable negative impact on the quality of life of PWEs; the comorbid occurrence of mood and anxiety disorders yields a worse impact. In addition, seizure freedom in the previous 6 months predicts a better quality of life.

    View details for DOI 10.1111/j.1528-1167.2010.02582.x

    View details for Web of Science ID 000279441500007

    View details for PubMedID 20477847

  • Theta Oscillations Mediate Interaction between Prefrontal Cortex and Medial Temporal Lobe in Human Memory CEREBRAL CORTEX Anderson, K. L., Rajagovindan, R., Ghacibeh, G. A., Meador, K. J., Ding, M. 2010; 20 (7): 1604-1612

    Abstract

    The medial temporal lobe (MTL) and the prefrontal cortex (PFC) are known to be critical structures for human memory processes. Furthermore, it has been suggested that they are part of a memory network. Although memory-modulated interaction between PFC and MTL has been observed at the hemodynamic level, it remains unclear what the neuronal process is that mediates the communication between these 2 areas. Experiments in rodents suggest that field oscillations in the theta band (4-8 Hz) facilitate PFC-MTL interaction. No such evidence has been reported in humans. To address this problem, cortical electrical activity from MTL, PFC, and lateral temporal lobe was recorded from implanted electrode grids in 3 epilepsy patients performing a verbal free recall task. The data were analyzed using a parametric spectral method to obtain estimates of power, coherence, and Granger causality. A task-modulated increase in coherence values between PFC and MTL was seen during free recall as opposed to a baseline condition. Concurrently, the number of coherent PFC-MTL site pairs was significantly increased during recall. Granger causality analysis further revealed that the increased coherence is a consequence of higher bidirectional information flow between the 2 regions, with a generally greater driving from MTL to PFC, namely, (MTL-->PFC) > (PFC-->MTL).

    View details for DOI 10.1093/cercor/bhp223

    View details for Web of Science ID 000278690800009

    View details for PubMedID 19861635

  • Emotional Indifference in Alzheimer's Disease JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES Drago, V., Foster, P. S., Chanei, L., Rembisz, J., Meador, K., Finney, G., Heilman, K. M. 2010; 22 (2): 236-242

    Abstract

    One of the most common and disabling symptoms of Alzheimer's disease is apathy. Patients with Alzheimer's disease might appear apathetic for several reasons, including deficits in emotional communication, presence of depression, perceptual-semantic-cognitive deficits, and a degeneration of areas of the brain important in experiencing emotions. The purpose of this study was to learn if patients with Alzheimer's disease have a reduction in the depth of their emotional experiences. Participants with Alzheimer's disease and healthy comparison subjects were asked to view pleasant and unpleasant pictures and to rate these pictures by making a mark on pieces of paper that had a happy face on one end (proximal or distal) and a sad face at the other end. The more pleasant they found this picture, the closer their mark should be to the happy face and vice versa. Patients with Alzheimer's disease judged these pictures' emotional valence as less intense than did the comparison subjects and also made more valence-inconsistent responses. These results might have been induced by impaired picture comprehension or a reduction of emotional experiences induced by degeneration of the limbic-cortical-reticular networks.

    View details for Web of Science ID 000277654200012

    View details for PubMedID 20463118

  • Cognition across the lifespan: Antiepileptic drugs, epilepsy, or both? EPILEPSY & BEHAVIOR Hermann, B., Meador, K. J., Gaillard, W. D., Cramer, J. A. 2010; 17 (1): 1-5

    Abstract

    Cognitive problems in persons with epilepsy manifest over a lifetime; however, whether abnormal cognition in an individual with epilepsy is a result of comorbid brain substrate, the epilepsy itself or its underlying etiology, the antiepileptic agents used to control it, or a combination of these and other factors remains controversial. There is a continuing need for improved therapies to control seizures and reduce the incidence of adverse events, especially those involving the central nervous system that compromise attention, intelligence, language skills, verbal and nonverbal memory, executive function, and psychomotor speeds. Although cognitive decline typically occurs among patients with more severe epilepsy, physicians must judiciously select therapy with an eye toward not only controlling seizures but also ensuring that all patients retain as much function as possible throughout their lives.

    View details for DOI 10.1016/j.yebeh.2009.10.019

    View details for Web of Science ID 000273837700001

    View details for PubMedID 19931492

  • Auditory Responsive Naming versus Visual Confrontation Naming in Dementia CLINICAL NEUROPSYCHOLOGIST Miller, K. M., Finney, G. R., Meador, K. J., Loring, D. W. 2010; 24 (1): 103-118

    Abstract

    Dysnomia is typically assessed during neuropsychological evaluation through visual confrontation naming. Responsive naming to description, however, has been shown to have a more distributed representation in both fMRI and cortical stimulation studies. While naming deficits are common in dementia, the relative sensitivity of visual confrontation versus auditory responsive naming has not been directly investigated. The current study compared visual confrontation naming and auditory responsive naming in a dementia sample of mixed etiologies to examine patterns of performance across these naming tasks. A total of 50 patients with dementia of various etiologies were administered visual confrontation naming and auditory responsive naming tasks using stimuli that were matched in overall word frequency. Patients performed significantly worse on auditory responsive naming than visual confrontation naming. Additionally, patients with mixed Alzheimer's disease/vascular dementia performed more poorly on auditory responsive naming than did patients with probable Alzheimer's disease, although no group differences were seen on the visual confrontation naming task. Auditory responsive naming correlated with a larger number of neuropsychological tests of executive function than did visual confrontation naming. Auditory responsive naming appears to be more sensitive to effects of increased of lesion burden compared to visual confrontation naming. We believe that this reflects more widespread topographical distribution of auditory naming sites within the temporal lobe, but may also reflect the contributions of working memory and cognitive flexibility to performance.

    View details for DOI 10.1080/13854040903045074

    View details for Web of Science ID 000272972300009

    View details for PubMedID 19626564

  • BRAIN FUNCTION AND ANATOMY IN JUVENILE MYOCLONIC EPILEPSY EPILEPSY CURRENTS Meador, K. J. 2010; 10 (1): 13-14
  • A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy EPILEPSY & BEHAVIOR McVearry, K. M., Gaillard, W. D., VanMeter, J., Meador, K. J. 2009; 16 (4): 609-616

    Abstract

    To investigate the differential effects of fetal exposure to antiepileptic drugs (AEDs) on cognitive fluency and flexibility in a prospective sample of children.This substudy of the Neurodevelopmental Effects of Antiepileptic Drugs investigation enrolled pregnant women with epilepsy on AED monotherapy (carbamazepine, lamotrigine, and valproate). Blinded to drug exposure, 54 children were tested for ability to generate ideas in terms of quantity (fluency/flexibility) and quality (originality). Forty-two children met inclusion criteria (mean age=4.2 years, SD=0.5) for statistical analyses of drug exposure group differences.Fluency was lower in the valproate group (mean=76.3, SD=7.53) versus the lamotrigine (mean=93.76, SD=13.5, ANOVA P<0.0015) and carbamazepine (mean=95.5, SD=18.1, ANOVA P<0.003) groups. Originality was lower in the valproate group (mean=84.2, SD=3.23) versus the lamotrigine (mean=103.1, SD=14.8, ANOVA P<0.002) and carbamazepine (mean=99.4, SD=17.1, ANOVA P<0.01) groups. These results were not explained by factors other than AED exposure.Children prenatally exposed to valproate demonstrate impaired fluency and originality compared with children exposed to lamotrigine and carbamazepine.

    View details for DOI 10.1016/j.yebeh.2009.09.024

    View details for Web of Science ID 000272549200006

    View details for PubMedID 19892603

  • Diagnostic Utility of Wada Memory Asymmetries: Sensitivity, Specificity, and Likelihood Ratio Characterization NEUROPSYCHOLOGY Loring, D. W., Bowden, S. C., Lee, G. P., Meador, K. J. 2009; 23 (6): 687-693

    Abstract

    The authors used logistic regression, dichotomous and multiple level likelihood ratios, and receiver operating characteristic (ROC) analyses to examine Wada Memory Asymmetries (WMAs) in 324 patients who subsequently underwent temporal lobe (TL) surgery (left TL surgery = 172; right TL surgery = 152) using the Medical College of Georgia Wada protocol. Logistic regression correctly classified 84% of left TL patients and 77% of right TL patients using WMA. Corresponding dichotomous likelihood ratios (LRs) were: LR+ = 3.64; LR- = 0.21. The area under the curve using ROC was similarly highly significant (.886, standard error = .018, p < .001). When classifying patients using multiple level LRs, 40 left TL patients (23.3%) obtained asymmetry scores greater than +4, whereas no right TL patients obtained asymmetry scores in this range. No left TL patients obtained a WMA of -8 or less, although 12 right TL patients (7.9%) obtained a difference score of -8. Multiple level LRs indicate impressive diagnostic sensitivity for certain WMA ranges, greatly increasing the probability of undergoing either left or right TL surgery depending on WMA magnitude.

    View details for DOI 10.1037/a0016528

    View details for Web of Science ID 000271689300001

    View details for PubMedID 19899827

  • Loss of Somatosensory-evoked Potentials and the Timing of Perception COGNITIVE AND BEHAVIORAL NEUROLOGY Kluger, B. M., Garvan, C. W., Loring, D. W., Juras, D. M., Townsend, D. T., Heilman, K. M., Meador, K. J. 2009; 22 (3): 173-179

    Abstract

    To determine if patients with brain lesions who have a unilateral loss of their primary somatosensory-evoked potential (SSEP) have altered temporal perception.Benjamin Libet postulated that the neural processing of stimuli to reach the conscious awareness takes 300 to 500 milliseconds and that accurate temporal perception of stimulus onset requires a retroactive computation. Although Libet proposed that the primary SSEP acts as a timing marker for this backward referral of perceived stimulus onset time, there has not been a systematic study of the necessity of the primary SSEP for perceptual timing.Participants were 10 healthy older adults and 10 stroke patients with hemisensory deficits. SSEPs were recorded from each hemisphere using median nerve stimulation. The participants' temporal perception of sensory stimuli was determined by asking them the temporal order of bilateral hand stimuli over varying interstimulus intervals.Patients with unilateral loss of SSEPs had a significantly greater mean delay in perception of stimuli from their contralesional arm than participants with intact bilateral SSEPs [mean delay (+/-standard deviation): 134 (+/-142) msec vs. 2.5 (+/-13) msec; P=0.03].These results demonstrate that loss of SSEP is associated with a delay in perceptual awareness. This observation is consistent with the hypotheses that the SSEP acts as a marker for cortical events important for perceptual timing.

    View details for Web of Science ID 000270061500004

    View details for PubMedID 19741327

  • No kidding High risk of cognitive difficulty in new-onset pediatric epilepsy NEUROLOGY Loring, D. W., Meador, K. J. 2009; 73 (7): 496-497

    View details for DOI 10.1212/WNL.0b013e3181b2358a

    View details for Web of Science ID 000269038300002

    View details for PubMedID 19675308

  • Practice Parameter update: Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society NEUROLOGY Harden, C. L., Hopp, J., Ting, T. Y., Pennell, P. B., French, J. A., Hauser, W. A., Wiebe, S., Gronseth, G. S., Thurman, D., Meador, K. J., Koppel, B. S., Kaplan, P. W., Robinson, J. N., Gidal, B., Hovinga, C. A., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., le Guen, C. 2009; 73 (2): 126-132

    Abstract

    To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy.A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008.For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%-92%) of remaining seizure-free during pregnancy.Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%-92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).

    View details for DOI 10.1212/WNL.0b013e3181a6b2f8

    View details for Web of Science ID 000267936400009

    View details for PubMedID 19398682

  • Practice Parameter update: Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society NEUROLOGY Harden, C. L., Pennell, P. B., Koppel, B. S., Hovinga, C. A., Gidal, B., Meador, K. J., Hopp, J., Ting, T. Y., Hauser, W. A., Thurman, D., Kaplan, P. W., Robinson, J. N., French, J. A., Wiebe, S., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., Shafer, P. O., le Guen, C. 2009; 73 (2): 142-149

    Abstract

    To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy.A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007.Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

    View details for DOI 10.1212/WNL.0b013e3181a6b325

    View details for Web of Science ID 000267936400011

    View details for PubMedID 19398680

  • 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 NEUROLOGY Harden, C. L., Meador, K. J., Pennell, P. B., Hauser, W. A., Gronseth, G. S., French, J. A., Wiebe, S., Thurman, D., Koppel, B. S., Kaplan, P. W., Robinson, J. N., Hopp, J., Ting, T. Y., Gidal, B., Hovinga, C. A., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., Hirtz, D., le Guen, C. 2009; 73 (2): 133-141

    Abstract

    To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy.Systematic review of relevant articles published between January 1985 and June 2007.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.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).

    View details for DOI 10.1212/WNL.0b013e3181a6b312

    View details for Web of Science ID 000267936400010

    View details for PubMedID 19398681

  • Antiepileptic drug use in women of childbearing age. Epilepsy & behavior Meador, K. J., Penovich, P., Baker, G. A., Pennell, P. B., Bromfield, E., Pack, A., Liporace, J. D., Sam, M., Kalayjian, L. A., Thurman, D. J., Moore, E., Loring, D. W. 2009; 15 (3): 339-343

    Abstract

    Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice.

    View details for DOI 10.1016/j.yebeh.2009.04.026

    View details for PubMedID 19410654

  • Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding EPILEPSIA Harden, C. L., Pennell, P. B., Koppel, B. S., Hovinga, C. A., Gidal, B., Meador, K. J., Hopp, J., Ting, T. Y., Hauser, W. A., Thurman, D., Kaplan, P. W., Robinson, J. N., French, J. A., Wiebe, S., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., Shafer, P. O., Le Guen, C. L. 2009; 50 (5): 1247-1255

    Abstract

    A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

    View details for DOI 10.1111/j.1528-1167.2009.02130.x

    View details for Web of Science ID 000265770000035

    View details for PubMedID 19507305

  • Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes EPILEPSIA Harden, C. L., Meador, K. J., Pennell, P. B., Hauser, W. A., Gronseth, G. S., French, J. A., Wiebe, S., Thurman, D., Koppel, B. S., Kaplan, P., Robinson, J. N., Hopp, J., Ting, T. Y., Gidal, B., Hovinga, C. A., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., Hirtz, D., Le Guen, C. 2009; 50 (5): 1237-1246

    Abstract

    A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) 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. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.

    View details for DOI 10.1111/j.1528-1167.2009.02129.x

    View details for Web of Science ID 000265770000034

    View details for PubMedID 19507301

  • Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency EPILEPSIA Harden, C. L., Hopp, J., Ting, T. Y., Pennell, P. B., French, J. A., Hauser, W. A., Wiebe, S., Gronseth, G. S., Thurman, D., Meador, K. J., Koppel, B. S., Kaplan, P. W., Robinson, J. N., Gidal, B., Hovinga, C. A., Wilner, A. N., Vazquez, B., Holmes, L., Krumholz, A., Finnell, R., Le Guen, C. 2009; 50 (5): 1229-1236

    Abstract

    A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

    View details for DOI 10.1111/j.1528-1167.2009.02128.x

    View details for Web of Science ID 000265770000033

    View details for PubMedID 19496807

  • Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs NEW ENGLAND JOURNAL OF MEDICINE Meador, K. J., Baker, G. A., Browning, N., Clayton-Smith, J., Combs-Cantrell, D. T., Cohen, M., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W. 2009; 360 (16): 1597-1605

    Abstract

    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.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.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. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.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.

    View details for Web of Science ID 000265178000004

    View details for PubMedID 19369666

  • Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero CURRENT OPINION IN NEUROLOGY Bromley, R. L., Baker, G. A., Meador, K. J. 2009; 22 (2): 162-166

    Abstract

    The last two decades have witnessed a growing concern over the treatment of epilepsy in women of childbearing age, with an increased risk of major congenital malformations and possible cognitive difficulties associated with certain antiepileptic drugs. The aim here is to review the literature regarding the possible cognitive and behavioural impact of exposure to antiepileptic drugs in utero.Recent evidence from large prospective cohorts indicates that there is a longer term risk to the cognitive and behavioural development of the child exposed in utero to sodium valproate. Information on other antiepileptic agents is conflicting or nonexistent and more research in this area is urgently required.Despite the methodological shortfalls of some of the research in this area, there is an accumulation of evidence highlighting an increased risk for cognitive and behavioural difficulties in children exposed to sodium valproate in utero. Although less certain, there may also be risks associated with phenobarbital and phenytoin exposure. Information regarding these risks should be communicated to the potential mother who has epilepsy.

    View details for DOI 10.1097/WCO.0b013e3283292401

    View details for Web of Science ID 000265172000008

    View details for PubMedID 19532040

  • Subjective perception of cognition is related to mood and not performance EPILEPSY & BEHAVIOR Marino, S. E., Meador, K. J., Loring, D. W., Okun, M. S., Fernandez, H. H., Fessler, A. J., Kustra, R. P., MILLER, J. M., Ray, P. G., Roy, A., Schoenberg, M. R., Vahle, V. J., Werz, M. A. 2009; 14 (3): 459-464

    Abstract

    Clinicians monitor cognitive effects of drugs primarily by asking patients to describe their side effects. We examined the relationship of subjective perception of cognition to mood and objective cognitive performance in healthy volunteers and neurological patients.Three separate experiments used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease. Correlations were calculated for change scores on and off drugs in the first two experiments and for the single assessment in Experiment 3.Across all three experiments, significant correlations were more frequent (chi(2)=259, P < or = 0.000) for mood versus subjective cognitive perception (59%) compared with subjective versus objective cognition (2%) and mood versus objective cognitive performance (2%).Subjective perception of cognitive effects is related more to mood than objective performance. Clinicians should be aware of this relationship when assessing patients' cognitive complaints.

    View details for DOI 10.1016/j.yebeh.2008.12.007

    View details for Web of Science ID 000265040200008

    View details for PubMedID 19130899

  • A brief computerized self-screen for dementia JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Kluger, B. M., Saunders, L. V., Hou, W., Garvan, C. W., Kirli, S., Efros, D. B., Chau, Q. N., Crucian, G. P., Finney, G. R., Meador, K. J., Heilman, K. M. 2009; 31 (2): 234-244

    Abstract

    Among his many contributions to the field of neuropsychology, Arthur Benton recognized the broad public health significance and unique ability of focused neuropsychological tests to screen for dementia. The need for validated screening tests for the presence of dementia will continue to grow as the cumulative prevalence of dementia grows and as our ability to treat or slow the progression of these diseases improves. We have developed a brief, self-administered computerized screening test for dementia, which is user friendly to the majority of elderly participants, including those with dementia. This test demonstrates comparable discriminant validity to the Mini Mental State Examination (MMSE), and its subscales correlate well with the traditional neuropsychological tests upon which it is based. We discuss its relative merits and limitations in comparison to other current instruments as well as suggesting future directions for this field.

    View details for DOI 10.1080/13803390802317559

    View details for Web of Science ID 000262647600009

    View details for PubMedID 19051092

  • Effects of in utero antiepileptic drug exposure. Epilepsy currents Meador, K. J. 2008; 8 (6): 143-147

    Abstract

    Recent studies demonstrate an increased teratogenic risk for valproate and a probable increased risk for phenobarbital. Carbamazepine and lamotrigine appear relatively safe; however, results are inconclusive concerning a specific risk for cleft lip/palate for both drugs as well as a dose-dependent effect for malformations associated with lamotrigine. Data regarding teratogenic risks for other antiepileptic drugs are inadequate. Additional studies are needed to delineate further the risks for all antiepileptic drugs and determine the underlying mechanisms.

    View details for DOI 10.1111/j.1535-7511.2008.00273.x

    View details for PubMedID 19127305

  • Pregnancy registries in epilepsy - A consensus statement on health outcomes NEUROLOGY Meador, K. J., Pennell, P. B., Harden, C. L., Gordon, J. C., Tomson, T., Kaplan, P. W., Holmes, G. L., French, J. A., Hauser, W. A., Wells, P. G., CRAMER, J. A. 2008; 71 (14): 1109-1117

    Abstract

    Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

    View details for Web of Science ID 000259649100013

    View details for PubMedID 18703463

  • Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts EPILEPSY RESEARCH Meador, K., Reynolds, M. W., Crean, S., Fahrbach, K., Probst, C. 2008; 81 (1): 1-13

    Abstract

    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.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.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.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.

    View details for DOI 10.1016/j.eplepsyres.2008.04.022

    View details for Web of Science ID 000260330000001

    View details for PubMedID 18565732

  • In utero antiepileptic drug exposure - Fetal death and malformations NEUROLOGY Meador, K. J., Baker, G. A., Finnell, R. H., Kalayjian, L. A., Liporace, J. D., Loring, D. W., Mawer, G., Pennell, P. B., Smith, J. C., Wolff, M. C. 2006; 67 (3): 407-412

    Abstract

    Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach.To determine if fetal outcomes vary as a function of different in utero AED exposures.This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69).Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect.More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

    View details for Web of Science ID 000239603500010

    View details for PubMedID 16894099

  • Rapid detection of major depression in epilepsy: a multicentre study LANCET NEUROLOGY Gilliam, F. G., Barry, J. J., Hermann, B. P., Meador, K. J., Vahle, V., Kanner, A. M. 2006; 5 (5): 399-405

    Abstract

    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.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.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.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.

    View details for DOI 10.1016/S1474-4422(06)70415-X

    View details for Web of Science ID 000237147600021

    View details for PubMedID 16632310

  • Screening for major depression in epilepsy with common self-report depression inventories EPILEPSIA Jones, J. E., Hermann, B. P., Woodard, J. L., Barry, J. J., Gilliam, F., Kanner, A. M., Meador, K. J., Sheehan, D. V., Lecrubier, Y. 2005; 46 (5): 731-735

    Abstract

    Major depression is a common psychiatric comorbidity in chronic epilepsy that is frequently unrecognized and untreated. A variety of self-report mood inventories are available, but their validity as well as ability to detect major depression in epilepsy remains uncertain. The purpose of this study was to determine the ability of two common depressive symptom inventories to identify major depression in people with epilepsy.In total, 174 adult patients with epilepsy underwent standardized psychiatric interview techniques [Mini International Neuropsychiatric Interview (MINI) and Mood Disorders module of the Structured Clinical Interview for DSM-IV Axis I Disorders-Research Version (SCID-I)] to determine the presence of current major depression. Subjects completed two self-report depression inventories [Beck Depression Inventory-II (BDI-II), Center for Epidemiological Study of Depression (CES-D)]. The ability of these self-report measures to identify major depression as identified by the gold standard structured interviews was examined by using diagnostic efficiency statistics.Both the BDI-II and the CES-D exhibited significant ability to identify major depression in epilepsy. All ROC analyses were highly significant (mean area under the curve, 0.92). Mean sensitivity (0.93) and specificity (0.81) were strong, with excellent negative predictive value (0.98) but lower positive predictive value (0.47).Common self-report depression measures can be used to screen for major depression in clinical settings. Use of these measures will assist in the clinical identification of patients with major depression so that treatment can be initiated.

    View details for Web of Science ID 000228560000017

    View details for PubMedID 15857440

  • Clinical assessment of axis I psychiatric morbidity in chronic epilepsy: A multicenter investigation JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES Jones, J. E., Hermann, B. P., Barry, J. J., Gilliam, F., Kanner, A. M., Meador, K. J. 2005; 17 (2): 172-179

    Abstract

    This study characterizes the rate of current Axis I DSM-IV disorders using a brief standardized psychiatric interview procedure, the Mini International Neuropsychiatric Interview (v5.0) (MINI), and determined the validity of MINI diagnoses of current depressive episodes to the research standard (Structured Clinical Interview for DSM-IV Disorders [SCID]). One hundred seventy-four patients with chronic epilepsy from five tertiary medical centers were interviewed using the MINI and the mood disorders module of the SCID. Current Axis I disorders were evident in one-half the sample (49%), with prevalent anxiety (30.4%) and mood (21.8%) disorders. Major depressive episode was the most common individual diagnosis (17.2%). Concordance was high between the MINI and SCID for diagnoses of current depression, especially for major depression. Of those with current major depression, less than one-half were treated with antidepressant medications. Current Axis I DSM-IV diagnoses can be effectively and accurately identified in clinical settings using shorter standardized psychiatric interview techniques. Issues regarding recognition and treatment of psychiatric morbidity in epilepsy are discussed.

    View details for Web of Science ID 000229541000006

    View details for PubMedID 15939970

  • Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy EPILEPSY & BEHAVIOR Jones, J. E., Hermann, B. P., Barry, J. J., Gilliam, F. G., Kanner, A. M., Meador, K. J. 2003; 4: S31-S38

    Abstract

    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.

    View details for DOI 10.1016/j.yebeh.2003.08.019

    View details for Web of Science ID 000186466800005

    View details for PubMedID 14592638

  • Gamma coherence and conscious perception NEUROLOGY Meador, K. J., Ray, P. G., Echauz, J. R., Loring, D. W., Vachtsevanos, G. J. 2002; 59 (6): 847-854

    Abstract

    High-frequency (e.g., gamma 30 to 50 Hz) coherent neural activity has been postulated to underlie binding of independent neural assemblies and thus integrate processing across distributed neuronal networks to achieve a unified conscious experience. Prior studies suggest that gamma activity may play a role in perceptual mechanisms, but design limitations raise concerns. Thus, controversy exists as to the hypothesis that gamma activity is necessary for perceptual awareness. In addition, controversy exists as to whether the primary sensory cortices are involved directly in the mechanisms of conscious perception or just in processes prior to conscious awareness.To investigate the relation of gamma coherence and perception.Digital intracranial electrocorticographic recordings from implanted electrodes were obtained in six patients with intractable epilepsy during a simple somatosensory detection task for near-threshold stimuli applied to the contralateral hand. Signal analyses were then conducted using a quantitative approach that employed two-way Hanning digital bandpass filters to compute running correlations across pairs of channels at various time epochs for each patient and each perception state across multiple bandwidths.Gamma coherence occurs in the primary somatosensory cortex approximately 150 to 300 milliseconds after contralateral hand stimuli that are perceived, but not for nonperceived stimuli, which did not differ in character/intensity or early somatosensory evoked potentials.The results are consistent with the possible direct involvement of primary sensory cortex in elemental awareness and with a role for gamma coherence in conscious perception.

    View details for Web of Science ID 000178161100010

    View details for PubMedID 12297565

  • Pathophysiology of altered consciousness during seizures - Subtraction SPECT study NEUROLOGY Lee, K. H., Meador, K. J., Park, Y. D., King, D. W., Murro, A. M., Pillai, J. J., Kaminski, R. J. 2002; 59 (6): 841-846

    Abstract

    The mechanisms underlying altered consciousness during seizures are poorly understood. Previous clinicopathologic studies suggest a role for the thalamus and upper brainstem in consciousness mechanisms.To examine blood flow changes associated with altered consciousness during seizures.Seventy-one patients with epilepsy who underwent video-EEG monitoring and ictal/interictal SPECT were studied. Patients were divided into three groups depending on their conscious state during seizures: 1) complete impairment of consciousness (CI), 2) no impairment of consciousness (NI), or 3) uncertain impairment of consciousness (UI). The distribution of blood flow changes during these seizures was assessed by subtraction (ictal - interictal) SPECT co-registered to MRI. Conscious state was assessed in relation to secondary ictal hyperperfusion in subcortical regions (i.e., thalamus and upper brainstem).Impairment of consciousness showed a strong association with secondary hyperperfusion in the thalamic/upper brainstem region (p = 0.01), occurring in 92% (45/49) of CI, 69% (9/13) of UI, and 11% (1/9) of NI.These findings are consistent with a role for the thalamus and upper brainstem in consciousness mechanisms. The authors suggest that the spread of epileptic discharges or a trans-synaptic activation (diaschisis) of these structures is an important mechanism in the alteration of consciousness during seizures. Variance in the results may be due to differences in timing of radioisotope injection, sensitivity of the subtraction SPECT technique, and the ability to clinically assess the conscious state.

    View details for Web of Science ID 000178161100008

    View details for PubMedID 12297563

  • Topography of somatosensory processing: Cerebral lateralization and focused attention JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Meador, K. J., Allison, J. D., Loring, D. W., Lavin, T. B., Pillai, J. J. 2002; 8 (3): 349-359

    Abstract

    Healthy dextrals underwent fMRI during a task of graphesthesia requiring detection of any number written consecutively from an otherwise random number sequence. Test conditions included (1) focus on unilateral right hand stimuli, (2) focus on unilateral left hand stimuli, (3) focus on right hand only during bilateral hand stimulation, (4) focus on left hand only during bilateral hand stimulation, and (5) rest. Attention to unilateral hand stimulation produced bihemispheric activation with minimal or no activation of ipsilateral primary sensorimotor region. Attention to unilateral left hand stimuli resulted in more activation than attention to unilateral right hand stimuli. Stimulation of the nonattended hand activated the contralateral somatosensory area, but to a lesser spatial extent than attended stimuli. Comparing focused attention to the left versus right side during identical sensory inputs (i.e., bilateral hand stimulation), focused attention to the right hand increased activation in the left somatosensory region, but focused attention to the left hand increased activation in both cerebral hemispheres. Thus, focused attention to unilateral somatosensory stimuli produces bilateral cerebral activation, but the increase in blood flow is greater in the contralateral hemisphere. Unattended stimuli activate the contralateral primary somatosensory area. Left/right asymmetries were demonstrated consistent with cerebral lateralization.

    View details for DOI 10.1017/S1355617702813169

    View details for Web of Science ID 000174602600002

    View details for PubMedID 11939694

  • Relationship of extinction to perceptual thresholds for single stimuli NEUROLOGY Meader, K. J., Ray, P. G., Day, L. J., Loring, D. W. 2001; 56 (8): 1044-1047

    Abstract

    To demonstrate the effects of target stimulus intensity on extinction to double simultaneous stimuli.Attentional deficits contribute to extinction in patients with brain lesions, but extinction (i.e., masking) can also be produced in healthy subjects. The relationship of extinction to perceptual thresholds for single stimuli remains uncertain.Brief electrical pulses were applied simultaneously to the left and right index fingers of 16 healthy volunteers (8 young and 8 elderly adults) and 4 patients with right brain stroke (RBS). The stimulus to be perceived (i.e., target stimulus) was given at the lowest perceptual threshold to perceive any single stimulus (i.e., Minimal) and at the threshold to perceive 100% of single stimuli. The mask stimulus (i.e., stimulus given to block the target) was applied to the contralateral hand at intensities just below discomfort.Extinction was less for target stimuli at 100% than Minimal threshold for healthy subjects. Extinction of left targets was greater in patients with RBS than elderly control subjects. Left targets were extinguished less than right in healthy subjects. In contrast, the majority of left targets were extinguished in patients with RBS even when right mask intensity was reduced below right 100% threshold for single stimuli. RBS patients had less extinction for right targets despite having greater left mask - threshold difference than control subjects. In patients with RBS, right "targets" at 100% threshold extinguished left "masks" (20%) almost as frequently as left masks extinguished right targets (32%).Subtle changes in target intensity affect extinction in healthy adults. Asymmetries in mask and target intensities (relative to single-stimulus perceptual thresholds) affect extinction in RBS patients less for left targets but more for right targets as compared with control subjects.

    View details for Web of Science ID 000168264000012

    View details for PubMedID 11320176

  • Train duration effects on perception: Sensory deficit, neglect, and cerebral lateralization JOURNAL OF CLINICAL NEUROPHYSIOLOGY Meader, K. J., Ray, P. G., Day, L. J., Loring, D. W. 2000; 17 (4): 406-413

    Abstract

    The mechanisms of conscious perception are uncertain. In a preliminary study, dramatic effects of train duration on perception in a patient with right brain stroke were noted. In this study, the mechanisms of train duration on perception of peripheral somatosensory stimuli are examined. Subjects included healthy adults and patients with right brain infarctions. Train duration effects on perception were examined in relation to cerebral infarction, handedness, age, elevated peripheral threshold via bupivacaine, and impaired attention via diazepam or scopolamine. Perceptual thresholds to electrical pulses on the hand decreased as train duration increased, but only over the first several hundred milliseconds. Compared to controls, right brain stroke patients showed much greater lowering of threshold in the affected hand as train duration was extended. Age and bupivacaine elevated thresholds, but had little or no influence on train duration effects. Diazepam and scopolamine had no effect on thresholds. Thresholds were lower in the left than right hand of healthy dextral subjects, irrespective of age. Sinistral subjects had less left/right asymmetry. Increased train duration effect in patients is not explained by a primary elevation in threshold or by impaired vigilance. Lower perceptual thresholds in the left hand of healthy dextral subjects is consistent with right cerebral dominance for externally directed attention.

    View details for Web of Science ID 000089386600006

    View details for PubMedID 11012043

  • Functional MRI cerebral activation and deactivation during finger movement NEUROLOGY Allison, J. D., Meader, K. J., Loring, D. W., Figueroa, R. E., Wright, J. C. 2000; 54 (1): 135-142

    Abstract

    To examine interhemispheric interactions of motor processes by using functional MRI (fMRI).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.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.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.Unilateral hand movements are associated with contralateral cerebral activation and ipsilateral cerebral deactivation, which we hypothesize result from transcallosal inhibition.

    View details for Web of Science ID 000084727900025

    View details for PubMedID 10636139

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