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1.  Famous face identification in temporal lobe epilepsy: Support for a multimodal integration model of semantic memory 
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.
doi:10.1016/j.cortex.2012.08.009
PMCID: PMC3679345  PMID: 23040175
Famous face naming and recognition; Epilepsy surgery; Models of semantic memory
2.  Paying Attention to School Achievement in Childhood Absence Epilepsy 
Epilepsy Currents  2014;14(2):68-70.
doi:10.5698/1535-7597-14.2.68
PMCID: PMC4010878  PMID: 24872780
3.  Common Data Elements in Epilepsy Research: Development and Implementation of the NINDS Epilepsy CDE Project 
Epilepsia  2011;52(6):1186-1191.
Summary
The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection, decrease study start-up time, and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antepileptic Therapies (AETs), )2) Comorbidities, (3) Electrophysiology, (4) Imaging,(5) Neurological Exam, (6) Neuropsychology,(7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward “harmonization” of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during their further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.
doi:10.1111/j.1528-1167.2011.03018.x
PMCID: PMC3535455  PMID: 21426327
Research; Epilepsy; National Institute of Neurological Disorders and Stroke
4.  Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study 
Lancet neurology  2013;12(3):244-252.
Summary
Background
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.
Methods
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.
Findings
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).
Interpretation
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.
Funding
US National Institutes of Health, UK Epilepsy Research Foundation.
doi:10.1016/S1474-4422(12)70323-X
PMCID: PMC3684942  PMID: 23352199
5.  Risks of In Utero Exposure to Valproate 
doi:10.1001/jama.2013.4001
PMCID: PMC3685023  PMID: 23613078
6.  Testing the limits 
Neurology  2010;74(8):685-690.
The Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scale (WMS) are 2 of the most common psychological tests used in clinical care and research in neurology. Newly revised versions of both instruments (WAIS-IV and WMS-IV) have recently been published and are increasingly being adopted by the neuropsychology community. There have been significant changes in the structure and content of both scales, leading to the potential for inaccurate patient classification if algorithms developed using their predecessors are employed. There are presently insufficient clinical data in neurologic populations to insure their appropriate application to neuropsychological evaluations. We provide a perspective on these important new neuropsychological instruments, comment on the pressures to adopt these tests in the absence of an appropriate evidence base supporting their incremental validity, and describe the potential negative impact on both patient care and continuing research applications.
doi:10.1212/WNL.0b013e3181d0cd12
PMCID: PMC3462502  PMID: 20177123
7.  Fetal Antiepileptic Drug Exposure: Motor, Adaptive and Emotional/Behavioral Functioning at Age 3 Years 
Epilepsy & behavior : E&B  2011;22(2):240-246.
doi:10.1016/j.yebeh.2011.06.014
PMCID: PMC3185140  PMID: 21783425
antiepileptic drugs; child development; behavioral neurology; epilepsy; pregnancy
8.  Disparities in NIH funding for epilepsy research 
Neurology  2011;77(13):1305-1307.
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.
doi:10.1212/WNL.0b013e318230a18f
PMCID: PMC3265048  PMID: 21947534
9.  Relationship of Child IQ to Parental IQ and Education in Children with Fetal Antiepileptic Drug Exposure 
Epilepsy & behavior : E&B  2011;21(2):147-152.
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 NEAD Study is an ongoing prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs (AEDs). 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.
doi:10.1016/j.yebeh.2011.03.020
PMCID: PMC3114203  PMID: 21546316
antiepileptic drugs; IQ; neurodevelopment; epilepsy
10.  Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age 
Brain  2011;134(2):396-404.
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.
doi:10.1093/brain/awq352
PMCID: PMC3030767  PMID: 21224309
antiepileptic drugs; child development; cognitive neurology; epilepsy; pregnancy
11.  Different Structural Correlates for Verbal Memory Impairment in Temporal Lobe Epilepsy with and Without Mesial Temporal Lobe Sclerosis 
Human Brain Mapping  2011;33(2):489-499.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/hbm.21226
PMCID: PMC3259857  PMID: 21438080
TLE; CA1; CA3; dentate gyrus; MRI; recognition; recall; mesial temporal sclerosis; fusiform
12.  Mapping Anterior Temporal Lobe Language Areas with FMRI: A Multi-Center Normative Study 
NeuroImage  2010;54(2):1465-1475.
Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story-Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.
doi:10.1016/j.neuroimage.2010.09.048
PMCID: PMC2997157  PMID: 20884358
Language; semantics; anterior temporal lobe; fMRI; epilepsy
13.  History of Neuropsychology Through Epilepsy Eyes 
In the 19th century, Hughlings Jackson relied on clinical history, seizure semiology, and the neurologic examination as methods for seizure localization to inform the first epilepsy surgeries. In the 20th century, psychological and neuropsychological tests were first employed as both diagnostic and prognostic measures. The contemporary practice of epilepsy evaluation and management includes neuropsychology as a critical component of epilepsy care and research, and epilepsy and neuropsychology have enjoyed a very special and synergistic relationship. This paper reviews how epilepsy has shaped the practice of neuropsychology as a clinical service by asking critical questions that only neuropsychologists were in a position to answer, and how clinical care of epilepsy patients has been significantly improved based on neuropsychology's unique contributions.
doi:10.1093/arclin/acq024
PMCID: PMC2872650  PMID: 20395259
Epilepsy; Assessment
14.  Teaching the Teachers: Data to Benefit School Systems and Doctors about Children with Newly Diagnosed Epilepsy 
Epilepsy Currents  2010;10(2):38-39.
doi:10.1111/j.1535-7511.2009.01348.x
PMCID: PMC2836474  PMID: 20231920
15.  Antiepileptic drug use in women of childbearing age 
Epilepsy & behavior : E&B  2009;15(3):339-343.
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.
doi:10.1016/j.yebeh.2009.04.026
PMCID: PMC2741411  PMID: 19410654
Antiepileptic drugs; Epilepsy; Women; Pregnancy; Teratogenesis; Drug choice; Prescription practices
16.  Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs 
The New England journal of medicine  2009;360(16):1597-1605.
BACKGROUND
Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.
METHODS
Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age.
RESULTS
At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P = 0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P = 0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P = 0.04). The association between valproate use and IQ was dose dependent. Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.
CONCLUSIONS
In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.
doi:10.1056/NEJMoa0803531
PMCID: PMC2737185  PMID: 19369666
17.  Structured Cueing on a Semantic Fluency Task Differentiates Patients with Temporal Versus Frontal Lobe Seizure Onset 
Epilepsy & behavior : E&B  2006;9(2):339-344.
Patients with frontal lobe dysfunction (e.g., Huntington’s Disease) reportedly benefit more from cueing on measures of semantic fluency than do patients with damage to temporal lobe structures (e.g., Alzheimer’s disease). This differential benefit from cueing suggests that different neurocognitive functions are impaired in these two groups. Patients with frontal lobe dysfunction are presumed to have difficulty with the executive aspects of this generative fluency task while patients with temporal lobe impairment are limited by deficits in semantic memory. We studied the performance of patients with complex partial seizures of frontal or temporal lobe onset as determined by video-EEG monitoring on standard and cued measures of semantic fluency administered in a counterbalanced sequence across groups. These groups did not differ significantly in terms of age, education, gender, age of seizure onset, total number of antiepileptic drugs, or IQ, and all patients subsequently underwent surgery for intractable epilepsy. FL patients performed significantly worse than TL patients on the standard semantic fluency paradigm (TL M = 18.4, SD = 4.7; FL M = 11.1, SD = 5.3), t (27) = −3.75, p < .001. Nevertheless, results of an ANCOVA demonstrated that the FL patients showed significantly greater performance improvement than the TL patients when provided with a cued semantic fluency format even after controlling for baseline differences in ability on the standard semantic fluency task (TL M = 0.45, SD = 3.8; FL M = 9.4, SD = 5.1), F (1, 29) = 12.37, p = .002. These findings support previous research suggesting that frontal and temporal structures contribute uniquely to semantic generative fluency and suggest that using a combination of standard and cued semantic fluency tasks may help confirm localization of seizure onset in partial epilepsy by localizing the associated cognitive dysfunction
doi:10.1016/j.yebeh.2006.06.010
PMCID: PMC2727920  PMID: 16870509
semantic fluency; frontal and temporal lobe epilepsy; localization of seizures
18.  It's About Time: Long-term Memory Outcome Following Temporal Lobectomy 
Epilepsy Currents  2007;7(2):38-40.
doi:10.1111/j.1535-7511.2007.00162.x
PMCID: PMC1867081  PMID: 17505549

Results 1-18 (18)