CAP Profiles

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 350 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; ranking in the top 10 experts in epilepsy worldwide by Expertscape; Distinguished Alumnus Award for Professional Achievement, Medical College of Georgia, Georgia Regents University 2015; American Epilepsy Society Clinical Research Award.

Clinical Focus

  • Neurology
  • epilepsy
  • epilepsy & pregnancy

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)

Contact

  • Robert (Bob) Pulliam Administrative Director Epilepsy Center
    • Tel: 650.721.5552
  • Stanford Neuroscience Health Center 213 Quarry Rd Rm 2851 MC 5957 Palo Alto, CA 94304
    • Tel: (650) 723-6463
    Fax: (650) 725-0390

Links

Research & Scholarship

Clinical Trials

  • Methylphenidate Treatment of Attention Deficits in Epilepsy Not Recruiting

    Methylphenidate (MPH) has long been used to improve attention and cognitive difficulties associated with ADHD, including in children with ADHD and epilepsy (Torres et al., 2008). Methylphenidate (MPH) is also helpful in treating attention and other cognitive difficulties in a variety of other neurological and medical conditions (Kajs-Wyllie, 2002; Prommer, 2012). We seek to evaluate the potential efficacy and safety of this medication in treating attention deficits, as well as other cognitive difficulties, experienced by adult patients with epilepsy. To our knowledge, there are currently very few studies which explicitly examine the impact of MPH on measureable attention deficits and other cognitive deficits in adult patients with epilepsy. We hope to quantify what impact, if any, methylphenidate has on attention, in addition to other specific measureable cognitive functions, in patients with cognitive complaints and epilepsy, and contribute to a growing body of evidence which supports the safety of methylphenidate's use for attention deficits in patients with epilepsy. As other effective treatments for attention and other cognitive difficulties in patients with epilepsy are not currently available, MPH could represent an important option in the treatment of such patients.

    Stanford is currently not accepting patients for this trial.

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  • Maternal and Neurodevelopmental Outcomes of in Utero Antiepileptic Drug (AED) Exposure Not Recruiting

    Epilepsy is one of the most common neurological disorders affecting women of childbearing age. Poor pregnancy outcomes are increased in these women and their children. The proposed studies will increase our knowledge on multiple levels to improve care and reduce adverse outcomes in these mothers and children. An overall goal of this study is to establish the relationship between antiepileptic drug exposure and outcomes in the mother and child as well as describe and explain the variability in antiepileptic drug exposure and response.

    Stanford is currently not accepting patients for this trial.

    View full details

Publications

All Publications

  • Laser interstitial thermal therapy (LITT): Seizure outcomes for refractory mesial temporal lobe epilepsy. Epilepsy & behavior : E&B Le, S., Ho, A. L., Fisher, R. S., Miller, K. J., Henderson, J. M., Grant, G. A., Meador, K. J., Halpern, C. H. 2018; 89: 37–41

    Abstract

    BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with less cognitive risks compared with traditional surgery for focal drug-resistant epilepsy.OBJECTIVE: We describe seizure outcomes and complications after LITT in our cohort with intractable mesial temporal lobe epilepsy (MTLE).MATERIAL AND METHODS: We prospectively tracked Stanford's MTLE cases treated with LITT from October 2014 to October 2017. Primary endpoints were seizure outcomes by (1) Engel classification and (2) reduction in baseline seizure frequency. Secondary outcomes were postablation complications.RESULTS: A total of 30 patients underwent selective amygdalohippocampotomy via LITT. Mesial temporal sclerosis (MTS) was present in 23/30 (77%) patients. Median follow-up was 18 ± 12 months (range: 6-44 months). Almost all 28/29 (97%) patients had >50% reduction, and 22/29 (76%) patients had >90% reduction in seizure frequency. Engel Class I outcome was achieved in 18/29 (62%) patients; with complete seizure freedom in 9/29 (31%) patients (Engel Class IA). Three (10%) patients have had only focal aware seizures (Engel Class 1B). Seizures only occurred with medication withdrawal in 6/29 (21%) patients (Engel Class ID). Class II was achieved by 6/29 (21%) and Class III by 5/29 (17%) patients. Complications included perioperative seizures in 10/29 (34%) and nonseizure complaints in 6/29 (21%) patients. Three (10%) patients had neurological deficits including one permanent superior quadrantanopsia, one transient trochlear, and one transient oculomotor nerve palsy.CONCLUSIONS: Overall, Engel Class I outcome was achieved in 62% of patients with MTLE, and 97% of patients achieved >50% seizure frequency reduction. Complications were largely temporary, though there was one persistent visual field deficit. Laser ablation is well-tolerated and offers marked seizure reduction for the majority of patients.

    View details for DOI 10.1016/j.yebeh.2018.09.040

    View details for PubMedID 30384097

  • Long-term effects of adjunctive perampanel on cognition in adolescents with partial seizures EPILEPSY & BEHAVIOR Pina-Garza, J. E., Lagae, L., Villanueva, V., Ben Renfroe, J., Laurenza, A., Williams, B., Kumar, D., Meador, K. J. 2018; 83: 50–58

    Abstract

    The aim of this study was to evaluate long-term effects of adjunctive perampanel on cognition, efficacy, growth, safety, and tolerability in adolescents with inadequately controlled partial seizures.Study 235, a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II study with an open-label extension phase (NCT01161524), was primarily designed to assess the effects of adjunctive perampanel on cognition. Patients (aged ≥12 to <18years) had a diagnosis of epilepsy with inadequately controlled partial seizures, with or without secondary generalization, despite receiving 1-3 antiepileptic drugs. During the double-blind phase, adjunctive perampanel or placebo was administered over a 6-week titration period and a 13-week maintenance period up to 12mg/day. During the extension phase, all patients received perampanel. Data from the extension phase are presented here. Study endpoints included change from baseline in Cognitive Drug Research (CDR) measures of cognition, seizure frequency, growth, development, the occurrence of treatment-emergent adverse events (TEAEs), and laboratory values.A total of 114 patients entered the extension phase (prior double-blind treatment: placebo, n=41; perampanel, n=73). Perampanel had no effect on the CDR system global cognition score, continuity of attention, quality of episodic memory, quality of working memory, or speed of memory but was associated with a significant decline in power of attention at end of treatment compared with baseline (p=0.03). There were no effects on language skills or manual dexterity from baseline to end of treatment. At Weeks 40-52, median reduction in seizure frequency was 74.1%, and 50% responder rate was 66.0%. There were no clinically relevant effects of perampanel on growth or development at end of treatment compared with baseline. Overall, 84.2% of patients experienced at least one TEAE and 70.2% experienced at least one treatment-related TEAE. The most common TEAEs were dizziness (29.8%) and somnolence (19.3%). The TEAEs resulted in the discontinuation of treatment in 6.1% of patients.In keeping with the 19-week double-blind phase, long-term adjunctive treatment with perampanel did not have any significant overall effects on the CDR system global cognition score in adolescent patients with inadequately controlled partial seizures. Similar trends were observed across the individual CDR system domains. Adjunctive perampanel showed sustained long-term seizure control and had a safety and tolerability profile similar to that observed in prior clinical studies.

    View details for DOI 10.1016/j.yebeh.2018.03.029

    View details for Web of Science ID 000434400600008

    View details for PubMedID 29653338

  • Cognitive safety of intracranial electrodes for epilepsy. Epilepsia Meador, K. J., Halpern, C. H., Hermann, B. P. 2018; 59 (6): 1132–37

    Abstract

    Two recent articles in Epilepsia have raised concerns about adverse cognitive effects associated with intracranial electrode implantation. However, both studies have important limitations, and their results contrast with studies that report no adverse cognitive effects of intracranial electrodes for diagnosis or neurostimulation in epilepsy. Furthermore, no data are provided on the relative safety of depth electrodes implanted along the longitudinal axis of the hippocampus vs other electrode locations or types of electrodes. Instituting changes in the use of depth electrodes based solely on these 2 studies is not clinically indicated. Further research is needed.

    View details for DOI 10.1111/epi.14197

    View details for PubMedID 29771452

  • Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy & behavior : E&B Meador, K. J., Pennell, P. B., May, R. C., Gerard, E., Kalayjian, L., Velez-Ruiz, N., Penovich, P., Cavitt, J., French, J., Hwang, S., Pack, A. M., Sam, M., Moore, E., Ippolito, D. M., MONEAD Investigator Group 2018; 84: 10–14

    Abstract

    OBJECTIVE: We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers.METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14-45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) <70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment.RESULTS: Three hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each <1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each <4%); only 5.2% of polytherapy subjects were on ≥3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy).CONCLUSIONS: The distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.

    View details for DOI 10.1016/j.yebeh.2018.04.009

    View details for PubMedID 29730500

  • Searching for the good and bad high-frequency oscillations NEUROLOGY Cendes, F., Meador, K. J. 2018; 90 (8): 347–48

    View details for DOI 10.1212/WNL.0000000000005008

    View details for Web of Science ID 000427814700014

    View details for PubMedID 29367442

  • Quantitative EEG Metrics Differ Between Outcome Groups and Change Over the First 72 h in Comatose Cardiac Arrest Patients NEUROCRITICAL CARE Wiley, S., Razavi, B., Krishnamohan, P., Mlynash, M., Eyngorn, I., Meador, K. J., Hirsch, K. G. 2018; 28 (1): 51–59

    Abstract

    Forty to sixty-six percent of patients resuscitated from cardiac arrest remain comatose, and historic outcome predictors are unreliable. Quantitative spectral analysis of continuous electroencephalography (cEEG) may differ between patients with good and poor outcomes.Consecutive patients with post-cardiac arrest hypoxic-ischemic coma undergoing cEEG were enrolled. Spectral analysis was conducted on artifact-free contiguous 5-min cEEG epochs from each hour. Whole band (1-30 Hz), delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (β, 13-30 Hz), α/δ power ratio, percent suppression, and variability were calculated and correlated with outcome. Graphical patterns of quantitative EEG (qEEG) were described and categorized as correlating with outcome. Clinical outcome was dichotomized, with good neurologic outcome being consciousness recovery.Ten subjects with a mean age = 50 yrs (range = 18-65) were analyzed. There were significant differences in total power (3.50 [3.30-4.06] vs. 0.68 [0.52-1.02], p = 0.01), alpha power (1.39 [0.66-1.79] vs 0.27 [0.17-0.48], p < 0.05), delta power (2.78 [2.21-3.01] vs 0.55 [0.38-0.83], p = 0.01), percent suppression (0.66 [0.02-2.42] vs 73.4 [48.0-97.5], p = 0.01), and multiple measures of variability between good and poor outcome patients (all values median [IQR], good vs. poor). qEEG patterns with high or increasing power or large power variability were associated with good outcome (n = 6). Patterns with consistently low or decreasing power or minimal power variability were associated with poor outcome (n = 4).These preliminary results suggest qEEG metrics correlate with outcome. In some patients, qEEG patterns change over the first three days post-arrest.

    View details for DOI 10.1007/s12028-017-0419-2

    View details for Web of Science ID 000425631100008

    View details for PubMedID 28646267

  • Periconceptional Folate Supplementation and the Risk of Autism Following Antiepileptic Drug Exposure ' JAMA NEUROLOGY Meador, K. J. 2018; 75 (2): 151–52

    View details for DOI 10.1001/jamaneurol.2017.3067

    View details for Web of Science ID 000424871100005

    View details for PubMedID 29279883

  • Pitfalls in developing precision medicine for genetic epilepsy NEUROLOGY Meador, K. J., Shin, C. 2018; 90 (1): 16–17

    View details for DOI 10.1212/WNL.0000000000004774

    View details for Web of Science ID 000427797500015

    View details for PubMedID 29196575

  • Methylphenidate, cognition, and epilepsy: A 1-month open-label trial EPILEPSIA Adams, J., Alipio-Jocson, V., Inoyama, K., Bartlett, V., Sandhu, S., Oso, J., Barry, J. J., Loring, D. W., Meador, K. J. 2017; 58 (12): 2124–32

    Abstract

    Cognitive difficulties are common in epilepsy. Beyond reducing seizures and adjusting antiepileptic medications, no well-validated treatment exists in adults. Methylphenidate is used effectively in children with epilepsy and attention-deficit/hyperactivity disorder, but its effects in adults have not been systematically evaluated. We hypothesized that methylphenidate can safely improve cognition in adults with epilepsy. We detail here the open-label follow-up to a double-blind, placebo-controlled, single-dose study.Thirty epilepsy patients entered a 1-month open-label methylphenidate trial after a double-blind phase. Doses were titrated according to clinical practice and patient tolerance, ranging 20-40 mg/day. Primary measures included: Conners' Continuous Performance Test (CPT), Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Memory Test (MCG). Secondary measures were: Beck Depression Inventory, 2nd Edition (BDI-II), Beck Anxiety Inventory, Apathy Evaluation Scale (AES), Stimulant Side-Effect Checklist, Adverse Events Profile, Quality of Life in Epilepsy-89 (QOLIE-89), and seizure frequency. Fourteen healthy, nonmedicated controls were tested concurrently.Twenty-eight participants with epilepsy (13 men/15 women) completed the trial. Withdrawals occurred due to anxiety (n = 1) and fatigue (n = 1). Mean age was 36.4 years (range = 20-60). Epilepsy types were: focal (n = 21), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.3 years. Mean baseline seizure frequency was 2.8/month. There were significant improvements on methylphenidate for SDMT, MCG, CPT (the ability to discriminate between targets and nontargets [d'] hits, hit reaction time standard deviation, omissions, and commissions), and QOLIE subscales (energy/fatigue, attention/concentration, memory, and language; paired t tests; p ≤ 0.002). BDI-II and additional subscales also improved, at a lower level of statistical significance. Effect sizes were moderate to large. Comparisons with untreated controls (n = 14) revealed greater improvement for epilepsy patients on omissions and commissions, with improvement trends on d' and hits. Seizure frequency did not increase with methylphenidate treatment (2.8/month vs. 2.4/month).Methylphenidate may be an effective and safe option for improving cognition and quality of life in epilepsy. Larger and longer double-blind, placebo-controlled clinical trials are needed.

    View details for DOI 10.1111/epi.13917

    View details for Web of Science ID 000419173300013

    View details for PubMedID 28990169

  • Is neurostimulation through the vagal nerve safe during pregnancy? EPILEPSY RESEARCH Voinescu, P., Meador, K. J. 2017; 137: 163–64

    View details for DOI 10.1016/j.eplepsyres.2017.07.008

    View details for Web of Science ID 000414825400027

    View details for PubMedID 29054514

  • Consciousness post corpus callosotomy. Brain Meador, K. J., Loring, D. W., Sathian, K. 2017

    View details for DOI 10.1093/brain/awx106

    View details for PubMedID 28460007

  • Methylphenidate, cognition, and epilepsy: A double-blind, placebo-controlled, single-dose study. Neurology Adams, J., Alipio-Jocson, V., Inoyama, K., Bartlett, V., Sandhu, S., Oso, J., Barry, J. J., Loring, D. W., Meador, K. 2017; 88 (5): 470-476

    Abstract

    To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy.This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere.Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20-62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive "fogginess" (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect.This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required.NCT02178995.This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints.

    View details for DOI 10.1212/WNL.0000000000003564

    View details for PubMedID 28031390

    View details for PubMedCentralID PMC5278946

  • Neuroimaging somatosensory perception and masking NEUROPSYCHOLOGIA Meador, K. J., Revill, K. P., Epstein, C. M., Sathian, K., Loring, D. W., Rorden, C. 2017; 94: 44-51

    Abstract

    The specific cortical and subcortical regions involved in conscious perception and masking are uncertain. This study sought to identify brain areas involved in conscious perception of somatosensory stimuli during a masking task using functional magnetic resonance (fMRI) to contrast perceived vs. non-perceived targets. Electrical trains were delivered to the right index finger for targets and to the left index finger for masks. Target intensities were adjusted to compensate for threshold drift. Sham target trials were given in ~10% of the trials, and target stimuli without masks were delivered in one of the five runs (68 trials/run). When healthy dextral adult volunteers (n=15) perceived right hand targets, greater left- than right-cerebral activations were seen with similar patterns across the parietal cortex, thalamus, insula, claustrum, and midbrain. When targets were not perceived, left/right cerebral activations were similar overall. Directly comparing perceived vs. non-perceived stimuli with similar intensities in the masking task revealed predominate activations contralateral to masks. In contrast, activations were greater contralateral to perceived targets if no masks were given or if masks were given but target stimulus intensities were greater for perceived than non-perceived targets. The novel aspects of this study include: 1) imaging of cortical and subcortical activations in healthy humans related to somatosensory perception during a masking task, 2) activations in the human thalamus and midbrain related to perception of stimuli compared to matched non-perceived stimuli, and 3) similar left/right cerebral activation patterns across cortical, thalamic and midbrain structures suggesting interactions across all three levels during conscious perception in humans.

    View details for DOI 10.1016/j.neuropsychologia.2016.11.017

    View details for Web of Science ID 000392679300005

    View details for PubMedID 27894900

  • Combining adverse pregnancy and perinatal outcomes for women exposed to antiepileptic drugs during pregnancy, using a latent trait model BMC PREGNANCY AND CHILDBIRTH Wen, X., Hartzema, A., Delaney, J. A., Brumback, B., Liu, X., Egerman, R., Roth, J., Segal, R., Meador, K. J. 2017; 17

    Abstract

    Application of latent variable models in medical research are becoming increasingly popular. A latent trait model is developed to combine rare birth defect outcomes in an index of infant morbidity.This study employed four statewide, retrospective 10-year data sources (1999 to 2009). The study cohort consisted of all female Florida Medicaid enrollees who delivered a live singleton infant during study period. Drug exposure was defined as any exposure to Antiepileptic drugs (AEDs) during pregnancy. Mothers with no AED exposure served as the AED unexposed group for comparison. Four adverse outcomes, birth defect (BD), abnormal condition of new born (ACNB), low birth weight (LBW), and pregnancy and obstetrical complication (PCOC), were examined and combined using a latent trait model to generate an overall severity index. Unidimentionality, local independence, internal homogeneity, and construct validity were evaluated for the combined outcome.The study cohort consisted of 3183 mother-infant pairs in total AED group, 226 in the valproate only subgroup, and 43,956 in the AED unexposed group. Compared to AED unexposed group, the rate of BD was higher in both the total AED group (12.8% vs. 10.5%, P < .0001), and the valproate only subgroup (19.6% vs. 10.5%, P < .0001). The combined outcome was significantly correlated with the length of hospital stay during delivery in both the total AED group (Rho = 0.24, P < .0001) and the valproate only subgroup (Rho = 0.16, P = .01). The mean score for the combined outcome in the total AED group was significantly higher (2.04 ± 0.02 vs. 1.88 ± 0.01, P < .0001) than AED unexposed group, whereas the valproate only subgroup was not.Latent trait modeling can be an effective tool for combining adverse pregnancy and perinatal outcomes to assess prenatal exposure to AED, but evaluation of the selected components is essential to ensure the validity of the combined outcome.

    View details for DOI 10.1186/s12884-016-1190-7

    View details for Web of Science ID 000391772800003

    View details for PubMedID 28061833

    View details for PubMedCentralID PMC5219655

  • Randomized double-blind comparison of cognitive and EEG effects of lacosamide and carbamazepine EPILEPSY & BEHAVIOR Meador, K. J., Loring, D. W., Boyd, A., Echauz, J., LaRoche, S., Velez-Ruiz, N., Korb, P., Byrnes, W., Dilley, D., Borghs, S., De Backer, M., Story, T., Dedeken, P., Webster, E. 2016; 62: 267-275

    Abstract

    Differential effectiveness of antiepileptic drugs (AEDs) is more commonly determined by tolerability than efficacy. Cognitive effects of AEDs can adversely affect tolerability and quality of life. This study evaluated cognitive and EEG effects of lacosamide (LCM) compared with carbamazepine immediate-release (CBZ-IR). A randomized, double-blind, double-dummy, two-period crossover, fixed-dose study in healthy subjects compared neuropsychological and EEG effects of LCM (150mg, b.i.d.) and CBZ-IR (200mg, t.i.d.). Testing was conducted at screening, predrug baseline, the end of each treatment period (3-week titration; 3-week maintenance), and the end of each washout period (4weeks after treatment). A composite Z-score was derived for the primary outcome variable (computerized cognitive tests and traditional neuropsychological measures) and separately for the EEG measures. Other variables included individual computer, neuropsychological, and EEG scores and adverse events (AEs). Subjects included 60 healthy adults (57% female; mean age: 34.4years [SD: 10.5]); 44 completed both treatments; 41 were per protocol subjects. Carbamazepine immediate-release had worse scores compared with LCM for the primary composite neuropsychological outcome (mean difference=0.33 [SD: 1.36], p=0.011) and for the composite EEG score (mean difference=0.92 [SD: 1.77], p=0.003). Secondary analyses across the individual variables revealed that CBZ-IR was statistically worse than LCM on 36% (4/11) of the neuropsychological tests (computerized and noncomputerized) and 0% of the four EEG measures; none favored CBZ-IR. Drug-related AEs occurred more with CBZ-IR (49%) than LCM (22%). Lacosamide had fewer untoward neuropsychological and EEG effects and fewer AEs and AE-related discontinuations than CBZ-IR in healthy subjects. Lacosamide exhibits a favorable cognitive profile.

    View details for DOI 10.1016/j.yebeh.2016.07.007

    View details for Web of Science ID 000384392500046

    View details for PubMedID 27517350

  • Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: A randomized study evaluating behavior, efficacy, and safety EPILEPSIA Lagae, L., Villanueva, V., Meador, K. J., Bagul, M., Laurenza, A., Kumar, D., Yang, H. 2016; 57 (7): 1120-1129

    Abstract

    The noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel was shown in phase III trials to be an effective and well-tolerated adjunctive treatment for partial-onset seizures. In adolescents, it is necessary to characterize cognitive, neuropsychological, and behavioral side effects of antiepileptic drugs (AEDs). The current analysis focuses on behavioral outcomes, efficacy, and safety of perampanel in adolescents.Adolescents (12-17 years) on a stable regimen of 1-3 AEDs for partial-onset seizures were randomized (2:1 ratio) to receive up to 12 mg/day perampanel or placebo. Alongside efficacy, cognitive, and neuropsychological assessments, behavioral outcomes were measured with the Child Behavior Checklist (CBCL) before and after a 19-week titration and maintenance phase.Of the randomized patients, 85 received perampanel and 48 received placebo. Median reduction in seizure frequency from baseline was 58.0% for perampanel and 24.0% for placebo (p = 0.079). More patients had seizure frequency reduced by 50% after perampanel (n = 49 [59.0%]) than placebo (n = 17 [37.0%]; p = 0.0144). Changes in behavior were minimal, and there were no differences between groups on competency (p = 0.619) or problems (p = 0.174). A greater proportion of placebo patients were classified in the CBCL "clinical" range for competency at end of treatment, whereas the number in the perampanel group remained unchanged. The overall safety profile was similar to that reported previously for perampanel; most frequently reported adverse events (AEs) were dizziness (26 patients [30.6% vs. 14.6% placebo]), somnolence (13 patients [15.3% vs. 4.2%]), and headache (nine patients [10.6% vs. 14.6%]). Aggression was reported in seven patients receiving perampanel (8.2% vs. 2.1% placebo); two of these were serious AEs, with neither requiring treatment discontinuation.Adjunctive perampanel is efficacious and well tolerated in adolescents with partial-onset seizures, and appears to have no clinically important impact on behavior measured using the CBCL.

    View details for DOI 10.1111/epi.13417

    View details for Web of Science ID 000380151900018

    View details for PubMedID 27221398

  • Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial EPILEPSIA Meador, K. J., Yang, H., Pina-Garza, J. E., Laurenza, A., Kumar, D., Wesnes, K. A. 2016; 57 (2): 243-251

    Abstract

    Assess cognitive effects of adjunctive perampanel in adolescents.In this double-blind study (ClinicalTrials.gov identifier: NCT01161524), patients aged 12 to <18 years with partial-onset seizures despite receiving 1-3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2-mg increments to 8-12 mg/day (6-week titration; 13-week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), five CDR System domain T-scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT).One hundred thirty-three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) in CDR System Global Cognition Score (least squares mean change, -0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (-6.9 vs. -2.7; p = 0.219). There were small differences with perampanel vs. placebo in other CDR System domains: improvements in Quality of Episodic Memory (3.0 vs. -1.2; p = 0.012), and worsening in Continuity of Attention (-3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, and LGPT were not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%).Perampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain.

    View details for DOI 10.1111/epi.13279

    View details for Web of Science ID 000370048100010

    View details for PubMedID 26724782

    View details for PubMedCentralID PMC4785606

  • Developmental effects of antiepileptic drugs and the need for improved regulations NEUROLOGY Meador, K. J., Loring, D. W. 2016; 86 (3): 297-306

    View details for DOI 10.1212/WNL.0000000000002119

    View details for Web of Science ID 000368542300009

  • Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy EPILEPSIA Loring, D. W., Kapur, R., Meador, K. J., Morrell, M. J. 2015; 56 (11): 1836-1844

    View details for DOI 10.1111/epi.13191

    View details for Web of Science ID 000363884100030

    View details for PubMedID 26385758

  • Cessation of gamma activity in the dorsomedial nucleus associated with loss of consciousness during focal seizures EPILEPSY & BEHAVIOR Leeman-Markowski, B. A., Smart, O. L., Faught, R. E., Gross, R. E., Meador, K. J. 2015; 51: 215-220

    View details for DOI 10.1016/j.yebeh.2015.07.027

    View details for Web of Science ID 000362290200033

    View details for PubMedID 26295448

  • Decline of clinical research in academic medical centers NEUROLOGY Meador, K. J. 2015; 85 (13): 1171-1176

    View details for DOI 10.1212/WNL.0000000000001818

    View details for Web of Science ID 000365645100004

    View details for PubMedID 26156509

  • Improving clinical cognitive testing Report of the AAN Behavioral Neurology Section Workgroup NEUROLOGY Daffner, K. R., Gale, S. A., Barrett, A. M., Boeve, B. F., Chatterjee, A., Coslett, H. B., D'Esposito, M., Finney, G. R., Gitelman, D. R., Hart, J. J., Lerner, A. J., Meador, K. J., Pietras, A. C., Voeller, K. S., Kaufer, D. I. 2015; 85 (10): 910-918

    Abstract

    To evaluate the evidence basis of single-domain cognitive tests frequently used by behavioral neurologists in an effort to improve the quality of clinical cognitive assessment.Behavioral Neurology Section members of the American Academy of Neurology were surveyed about how they conduct clinical cognitive testing, with a particular focus on the Neurobehavioral Status Exam (NBSE). In contrast to general screening cognitive tests, an NBSE consists of tests of individual cognitive domains (e.g., memory or language) that provide a more comprehensive diagnostic assessment. Workgroups for each of 5 cognitive domains (attention, executive function, memory, language, and spatial cognition) conducted evidence-based reviews of frequently used tests. Reviews focused on suitability for office-based clinical practice, including test administration time, accessibility of normative data, disease populations studied, and availability in the public domain.Demographic and clinical practice data were obtained from 200 respondents who reported using a wide range of cognitive tests. Based on survey data and ancillary information, between 5 and 15 tests in each cognitive domain were reviewed. Within each domain, several tests are highlighted as being well-suited for an NBSE.We identified frequently used single-domain cognitive tests that are suitable for an NBSE to help make informed choices about clinical cognitive assessment. Some frequently used tests have limited normative data or have not been well-studied in common neurologic disorders. Utilizing standardized cognitive tests, particularly those with normative data based on the individual's age and educational level, can enhance the rigor and utility of clinical cognitive assessment.

    View details for Web of Science ID 000370509100015

    View details for PubMedID 26163433

  • Cognitive outcomes of prenatal antiepileptic drug exposure EPILEPSY RESEARCH Inoyama, K., Meador, K. J. 2015; 114: 89-97

    Abstract

    Antiepileptic drugs (AEDs) have been known to have teratogenic effects for a little over 50 years. While early reports focused on fetal malformations, there has been an increasing amount of data over the last few decades exploring the cognitive outcomes of offspring exposed to AEDs in utero. Although the challenges of confounding factors and varied methodologies have led to inconsistent results, the negative impact of some of the agents, such as valproate, have become clear. Further studies are needed to evaluate the cognitive effects of prenatal exposure to many AEDs which have not been tested, to clarify the effects of existing AEDs which have yielded mixed results, and to better understand the effects of polytherapy. Research in animal models is warranted to screen AEDs for their effects on cognition in exposed offspring and to further our understanding of the underlying mechanisms by which AEDs exert their harmful effects on the developing brain. And finally, new AEDs without these harmful effects and agents which can prevent or reverse the negative consequences imparted by AED therapy on cognition should be sought.

    View details for DOI 10.1016/j.eplepsyres.2015.04.016

    View details for Web of Science ID 000357438400013

    View details for PubMedID 26088891

  • Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation EPILEPSY & BEHAVIOR Meador, K. J., Kapur, R., Loring, D. W., Kanner, A. M., Morrell, M. J. 2015; 45: 242-247

    Abstract

    The primary efficacy and safety measures from a trial of responsive neurostimulation for focal epilepsy were previously published. In this report, the findings from the same study are presented for quality of life, which was a supportive analysis, and for mood, which was assessed as a secondary safety endpoint.The study was a multicenter randomized controlled double-blinded trial of responsive neurostimulation in 191 patients with medically resistant focal epilepsy. During a 4-month postimplant blinded period, patients were randomized to receive responsive stimulation or sham stimulation, after which all patients received responsive neurostimulation in open label to complete 2years. Quality of life (QOL) and mood surveys were administered during the baseline period, at the end of the blinded period, and at year 1 and year 2 of the open label period.The treatment and sham groups did not differ at baseline. Compared with baseline, QOL improved in both groups at the end of the blinded period and also at 1year and 2years, when all patients were treated. At 2years, 44% of patients reported meaningful improvements in QOL, and 16% reported declines. There were no overall adverse changes in mood or in suicidality across the study. Findings were not related to changes in seizures and antiepileptic drugs, and patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL.Treatment with targeted responsive neurostimulation does not adversely affect QOL or mood and may be associated with improvements in QOL in patients, including those with seizures of either mesial temporal origin or neocortical origin.

    View details for DOI 10.1016/j.yebeh.2015.01.012

    View details for Web of Science ID 000353830700047

    View details for PubMedID 25819949

  • Antiepileptic drug use by pregnant women enrolled in Florida Medicaid NEUROLOGY Wen, X., Meador, K. J., Hartzema, A. 2015; 84 (9): 944-950

    Abstract

    The study aims were to investigate secular trends in antiepileptic drug (AED) use in women during pregnancy, and to compare the use of first- and second-generation AEDs.Study participants consisted of female Florida Medicaid beneficiaries, older than 15 years, and pregnant within the time period 1999 to 2009. Fifteen AEDs were categorized into first and second generation of AEDs. Continuous use of AEDs was defined as at least 2 consecutive AED prescriptions totaling more than a 30-day supply. Polytherapy was defined as 2 or more AEDs continuously used for at least 30 overlapping days. Annual prevalence was estimated and compared.We included 2,099 pregnant women who were enrolled in Florida Medicaid from 1999 to 2009 and exposed to AEDs during pregnancy. Although there were fluctuations, overall AED use in the study cohort did not increase from 2000 to 2009 (β ± standard error [SE]: -0.07 ± 0.06, p = 0.31). The use of first-generation AEDs decreased (β ± SE: -6.21 ± 0.47, p < 0.0001), whereas the use of second-generation AEDs increased (β ± SE: 6.27 ± 0.52, p < 0.0001) from 2000 to 2009. AED use in polytherapy did not change through the study period. Valproate use reduced from 23% to 8% in the study population (β ± SE: -1.61 ± 0.36, p = 0.0019), but this decrease was only for women receiving an AED for epilepsy and was not present for other indications.The second-generation AEDs are replacing first-generation AEDs in both monotherapy and polytherapy. Valproate use has declined for epilepsy but not other indications. Additional changes in AED use are expected in future years.

    View details for DOI 10.1212/WNL.0000000000001304

    View details for Web of Science ID 000350576700018

    View details for PubMedID 25653296

  • Neurodevelopmental Effects of Fetal Antiepileptic Drug Exposure DRUG SAFETY Velez-Ruiz, N. J., Meador, K. J. 2015; 38 (3): 271-278

    Abstract

    Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents.

    View details for DOI 10.1007/s40264-015-0269-9

    View details for Web of Science ID 000351698400005

    View details for PubMedID 25693658

  • IQ at 6 years after in utero exposure to antiepileptic drugs A controlled cohort study NEUROLOGY Baker, G. A., Bromley, R. L., Briggs, M., Cheyne, C. P., Cohen, M. J., Garcia-Finana, M., Gummery, A., Kneen, R., Loring, D. W., Mawer, G., Meador, K. J., Shallcross, R., Clayton-Smith, J. 2015; 84 (4): 382-390

    Abstract

    To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85.Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

    View details for DOI 10.1212/WNL.0000000000001182

    View details for Web of Science ID 000348905800015

    View details for PubMedID 25540307

  • Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy EPILEPSIA Drane, D. L., Loring, D. W., Voets, N. L., Price, M., Ojemann, J. G., Willie, J. T., Saindane, A. M., Phatak, V., Ivanisevic, M., Millis, S., Helmers, S. L., Miller, J. W., Meador, K. J., Gross, R. E. 2015; 56 (1): 101-113

    Abstract

    Patients with temporal lobe epilepsy (TLE) experience significant deficits in category-related object recognition and naming following standard surgical approaches. These deficits may result from a decoupling of core processing modules (e.g., language, visual processing, and semantic memory), due to "collateral damage" to temporal regions outside the hippocampus following open surgical approaches. We predicted that stereotactic laser amygdalohippocampotomy (SLAH) would minimize such deficits because it preserves white matter pathways and neocortical regions that are critical for these cognitive processes.Tests of naming and recognition of common nouns (Boston Naming Test) and famous persons were compared with nonparametric analyses using exact tests between a group of 19 patients with medically intractable mesial TLE undergoing SLAH (10 dominant, 9 nondominant), and a comparable series of TLE patients undergoing standard surgical approaches (n=39) using a prospective, nonrandomized, nonblinded, parallel-group design.Performance declines were significantly greater for the patients with dominant TLE who were undergoing open resection versus SLAH for naming famous faces and common nouns (F=24.3, p<0.0001, η2=0.57, and F=11.2, p<0.001, η2=0.39, respectively), and for the patients with nondominant TLE undergoing open resection versus SLAH for recognizing famous faces (F=3.9, p<0.02, η2=0.19). When examined on an individual subject basis, no SLAH patients experienced any performance declines on these measures. In contrast, 32 of the 39 patients undergoing standard surgical approaches declined on one or more measures for both object types (p<0.001, Fisher's exact test). Twenty-one of 22 left (dominant) TLE patients declined on one or both naming tasks after open resection, while 11 of 17 right (nondominant) TLE patients declined on face recognition.Preliminary results suggest (1) naming and recognition functions can be spared in TLE patients undergoing SLAH, and (2) the hippocampus does not appear to be an essential component of neural networks underlying name retrieval or recognition of common objects or famous faces.

    View details for DOI 10.1111/epi.12860

    View details for Web of Science ID 000348534000016

    View details for PubMedID 25489630

  • Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia Herzog, A. G., Fowler, K. M., Sperling, M. R., Massaro, J. M., Progesterone Trial Study Group 2015; 56: e58-62

    View details for DOI 10.1111/epi.12969

  • Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia Herzog, A. G., Fowler, K. M., Sperling, M. R., Massaro, J. M. 2015; 56 (5): e58–62

    Abstract

    The purpose of this study was to determine whether seizure frequency and cycle days with seizure occurrence vary across the menstrual cycle. The subjects were the first 100 women with intractable focal onset seizures, 13-45 years old, who completed the baseline phase of the National Institutes of Health (NIH) Progesterone Trial. Each subject recorded seizures and menses during a 3-month baseline phase. Data consisted of (1) seizure numbers for each cycle day and (2) cycle days with seizure occurrence. Statistical comparisons of seizure frequency and days with seizures were performed using generalized estimating equation one-way analysis of variance (ANOVA) and logistic regression followed by pairwise multiple comparisons of days based on the least square means. Seizure numbers and cycle days with seizure occurrence varied across the menstrual cycle. There was an approximately twofold difference between the highest (day 1) and lowest (day -8) values for both seizure frequency and days with occurrence. The demonstration of variation in seizure frequency and cycle days with seizure occurrence across the menstrual cycle, as well as identification of specific days that have substantially higher or lower frequencies than other days, supports the existence of catamenial epilepsy.

    View details for DOI 10.1111/epi.12969

    View details for PubMedID 25823700

  • Low vitamin D levels are common in patients with epilepsy EPILEPSY RESEARCH Teagarden, D. L., Meador, K. J., Loring, D. W. 2014; 108 (8): 1352-1356

    Abstract

    Vitamin D is important for bone health, and vitamin D deficiency may contribute to other disorders (e.g., autoimmune, infections, cancer, degenerative, diabetic, and vascular). Enzyme-inducing antiepileptic drugs have been particularly implicated for osteoporosis risk given their effects on vitamin D. We examined the prevalence of vitamin D deficiency in adult epilepsy patients.We conducted an observational study of consecutive epilepsy patients treated by two clinicians at the Emory University Epilepsy Center from 2008 to 2011 in order to determine the frequency of low vitamin D levels and possible differential antiepileptic drug risks. Vitamin D 25-OH levels were categorized as low (<20 ng/ml), borderline (20-29 ng/ml), or normal (≥30 ng/ml). Antiepileptic drugs were categorized based on their enzyme inducing properties. Descriptive and inferential statistics were employed.Vitamin D levels were obtained on 596 patients with epilepsy. Mean age was 41 years (SD=14; range=18-81); 56% were women. Race/ethnicity was 55% Caucasian, 34% Black, 2% Asian, and 7% Unknown. The mean vitamin D level was 22.5 (SD=11.9; range = <4 to 98), and 45% had level <20 ng/ml. Mean vitamin D levels (F=6.48, p=.002) and frequencies of vitamin D categories (p=.002, Chi square test) differed across the antiepileptic drug groups. Vitamin D deficiency was present in 54% of enzyme-inducing and 37% of non-enzyme-inducing antiepileptic drugs groups.Vitamin D deficiency is common in patients with epilepsy on antiepileptic drugs. Monitoring of vitamin D should be considered as part of the routine management of patients with epilepsy.

    View details for DOI 10.1016/j.eplepsyres.2014.06.008

    View details for Web of Science ID 000342269000011

    View details for PubMedID 25060996

  • 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

    View details for PubMedCentralID PMC4122685

  • 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

  • Seizure Reduction with Fluoxetine in Dravet Syndrome. Epilepsy & behavior case reports Meador, K. J. 2014; 2: 54–56

    Abstract

    An adult woman with Dravet syndrome (documented SCN1A mutation) experienced a marked reduction in seizures when treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. The seizure reduction may be partly to reductions associated with aging in Dravet patients, but it appears to be due at least in part to the fluoxetine. A prior preliminary study reported that fenfluramine reduces seizures in patients with Dravet syndrome. Fenfluramine may produce this effect by increasing serotonin brain levels, and SSRIs have been found to possess antiepileptic properties in animal models of epilepsy. Given the known cardiac risks of fenfluramine, consideration of randomized clinical trials with SSRIs should be considered in Dravet syndrome and other epilepsies.

    View details for DOI 10.1016/j.ebcr.2014.03.001

    View details for PubMedID 24955329

    View details for PubMedCentralID PMC4062308

  • 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

  • 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

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

    View details for DOI 10.1016/j.eplepsyres.2013.08.006

    View details for Web of Science ID 000328524800021

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 Web of Science ID 000302032600071

    View details for PubMedID 23105174

  • 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

  • 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

  • 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

  • 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

  • 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

    View details for PubMedCentralID PMC3019365

  • 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

    View details for DOI 10.1111/j.1535-7511.2009.01340.x

    View details for Web of Science ID 000282020200005

    View details for PubMedID 20126333

  • 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): 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

  • 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

  • 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

  • Teratogenicity of antiepileptic medications SEMINARS IN NEUROLOGY Kluger, B. M., Meador, K. J. 2008; 28 (3): 328-335

    Abstract

    Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control.

    View details for DOI 10.1055/s-2008-1079337

    View details for Web of Science ID 000258374400007

    View details for PubMedID 18777479

  • Applicability of NINDS-sponsored studies to community-based physician involvement NEUROLOGY Lindblad, A. S., Clemons, T., Lindblad, R. W., Sykes, R., Meador, K. J., ODENKIRCHEN, J. C., Hart, R. G. 2008; 70 (19): 1688-1690

    Abstract

    The National Institute of Neurological Disorders and Stroke (NINDS) Clinical Trials Group established the Clinical Research Collaboration (CRC) Project in 2005 to increase community-based physician involvement in NINDS-sponsored research.We assessed a random sample of 112 of the more than 1,000 current NINDS-sponsored clinical research studies to determine which could involve community physicians in enrollment or follow-up. Scoring factors were based on the premise that participation is feasible for noninvasive studies with simple screening, and follow-up criteria and visit frequency consistent with usual care. Scored studies included 26 Phase III, 31 Phase I/II, and 55 nonclinical trials.Overall, 41% of the sampled research studies were considered conducive to community physician participation that exceeds referral only; 21% with participation in all study activities and 20% with ability to provide some follow-up. Specialized neuropsychological or neurologic scale testing was judged to exclude community physician participation in 16% of studies.Many National Institute of Neurological Disorders and Stroke studies are available in which community-based physicians could participate. Involving community physicians may increase efficiency of completing clinical research and encourage application of research findings in community practices.

    View details for Web of Science ID 000256707100008

    View details for PubMedID 18057316

  • Ethical and regulatory issues related to pregnancy registries and their outcomes EPILEPSY & BEHAVIOR French, J. A., Meador, K., Cnaan, A., Gilliam, F., Conway, J., Araojo, R., Feibus, K. 2008; 12 (4): 587-591

    Abstract

    Pregnancy registries should be devised so that the interests of science, society, and the individual are all considered. For example, there may be ethical issues that relate to how women are chosen to participate in the registry and how informed consent is obtained. In most cases, consent is required for both the mother and the infant. Some institutional review boards will require that consent be obtained by someone other than the woman's physician. Once data are obtained, there may be an issue as to when results should be released. Options are to release data when there is the first indication of a concerning finding, thereby potentially preventing exposure in the largest number of women, versus waiting until the finding is absolutely confirmed. In a related issue, there are questions of when and how regulatory agencies should change labeling based on findings.

    View details for DOI 10.1016/j.yebeh.2007.11.005

    View details for Web of Science ID 000254703800006

    View details for PubMedID 18158272

  • Differential neuropsychological test sensitivity to left temporal lobe epilepsy JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Loring, D. W., Strauss, E., Hermann, B. P., Barr, W. B., Perrine, K., Trenerry, M. R., Chelune, G., Westerveld, M., Lee, G. P., Meador, K. J., Bowden, S. C. 2008; 14 (3): 394-400

    Abstract

    We examined the sensitivity of the Rey Auditory Verbal Learning Test (AVLT), California Verbal Learning Test (CVLT), Boston Naming Test (BNT), and Multilingual Aphasia Examination Visual Naming subtest (MAE VN) to lateralized temporal lobe epilepsy (TLE) in patients who subsequently underwent anterior temporal lobectomy. For the AVLT (n = 189), left TLE patients performed more poorly than their right TLE counterparts [left TLE = 42.9 (10.6), right TLE = 47.7 (9.9); p < .002 (Cohen's d = .47)]. Although statistically significant, the CVLT group difference (n = 212) was of a smaller magnitude [left LTE = 40.7 (11.1), right TLE = 43.8 (9.9); (p < .03, Cohen's d = .29)] than the AVLT. Group differences were also present for both measures of confrontation naming ability [BNT: left LTE = 43.1 (8.9), right TLE = 48.1 (8.9); p < .001 (Cohen's d = .56); MAE VN: left TLE = 42.2, right TLE = 45.6, p = .02 (Cohen's d = .36)]. When these data were modeled in independent logistic regression analyses, the AVLT and BNT both significantly predicted side of seizure focus, although the positive likelihood ratios were modest. In the subset of 108 patients receiving both BNT and AVLT, the AVLT was the only significant predictor of seizure laterality, suggesting individual patient variability regarding whether naming or memory testing may be more sensitive to lateralized TLE.

    View details for DOI 10.1017/S1355617708080582

    View details for Web of Science ID 000258537300005

    View details for PubMedID 18419838

  • A test of the mechanisms of sensory extinction to simultaneous stimulation NEUROLOGY Kluger, B. M., Meador, K. J., Garvan, C. W., Loring, D. W., Townsend, D. T., Heilman, K. M. 2008; 70 (18): 1644-1645

    View details for DOI 10.1212/01.wnl.0000310988.11575.fa

    View details for Web of Science ID 000256706900014

    View details for PubMedID 18443317

  • Neuropsychological and behavioral effects of antiepilepsy drugs NEUROPSYCHOLOGY REVIEW Loring, D. W., Marino, S., Meador, K. J. 2007; 17 (4): 413-425

    Abstract

    Antiepilepsy drugs work by decreasing neuronal irritability, which may also result in the non-desired side effect of decreased neuropsychological function. In addition to cognitive side effects, antiepilepsy drugs (AEDs) may be associated with behavioral effects which may range from irritability and hyperactivity to positive psychotropic effects on mood. There have been many new medications released since the 1990s, and although they tend to have more favorable side effect profiles compared to their older counterparts, there continues to be a risk of decreased cognitive function with the majority of these agents. The effects of in utero antiepilepsy drug exposure are increasingly being investigated, and differential drug risk is beginning to be described for both anatomic and cognitive outcomes. Patients with epilepsy undergoing neuropsychological evaluations are commonly on AEDs, and it is important for the clinician to recognize the potential contribution of AED therapy to neuropsychological profiles. The present article serves to provide an overview of our current understanding regarding the risks of antiepilepsy drug use for both cognitive and behavioral side effects.

    View details for DOI 10.1007/s11065-007-9043-9

    View details for Web of Science ID 000251426300004

    View details for PubMedID 17943448

  • Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam NEUROLOGY Meador, K. J., Gevins, A., Loring, D. W., McEvoy, L. K., Ray, P. G., Smith, M. E., Motamedi, G. K., Evans, B. M., Baum, C. 2007; 69 (22): 2076-2084

    Abstract

    The relative effects of levetiracetam (LEV) and carbamazepine (CBZ) on cognitive and neurophysiologic measures are uncertain.The effects of LEV and CBZ were compared in healthy adults using a randomized, double-blind, two-period crossover design. Outcome measures included 11 standard neuropsychological tests and the score from a cognitive-neurophysiologic test of attention and memory. Evaluations were conducted at screening, baseline pre-drug treatment, end of each maintenance phase (4 weeks), and end of each washout period after drug treatment.A total of 28 adults (17 women) with mean age of 33 years (range 18 to 51) completed the study. Mean maintenance doses (+/-SD) were CBZ = 564 mg/day (110) and LEV = 2,000 mg/day (0). CBZ was adjusted to mid-range therapeutic level. Mean serum levels (+/-SD) were CBZ = 7.5 mcg/mL (1.5) and LEV = 32.2 mcg/mL (11.2). An overall composite score including all measures revealed worse effects for CBZ compared to LEV (p

    View details for Web of Science ID 000251243700008

    View details for PubMedID 18040014

  • What constitutes high quality of care for adults with epilepsy? NEUROLOGY Pugh, M. J., Berlowitz, D. R., Montouris, G., Bokhour, B., CRAMER, J. A., Bohm, V., Bollinger, M., Helmers, S., Ettinger, A., Meador, K. J., Fountain, N., Boggs, J., Tatum, W. O., Knoefel, J., Harden, C., Mattson, R. H., Kazis, L. 2007; 69 (21): 2020-2027

    Abstract

    Providers are increasingly being held accountable for the quality of care provided. While quality indicators have been used to benchmark the quality of care for a number of other disease states, no such measures are available for evaluating the quality of care provided to adults with epilepsy. In order to assess and improve quality of care, it is critical to develop valid quality indicators. Our objective is to describe the development of quality indicators for evaluating care of adults with epilepsy. As most care is provided in primary and general neurology care, we focused our assessment of quality on care within primary care and general neurology clinics.We reviewed existing national clinical guidelines and systematic reviews of the literature to develop an initial list of quality indicators; supplemented the list with indicators derived from patient focus groups; and convened a 10-member expert panel to rate the appropriateness, reliability, and necessity of each quality indicator.From the original 37 evidence-based and 10 patient-based quality indicators, the panel identified 24 evidence-based and 5 patient-based indicators as appropriate indicators of quality. Of these, the panel identified 9 that were not necessary for high quality care.There is, at best, a poor understanding of the quality of care provided for adults with epilepsy. These indicators, developed based on published evidence, expert opinion, and patient perceptions, provide a basis to assess and improve the quality of care for this population.

    View details for Web of Science ID 000251054500009

    View details for PubMedID 17928576

  • Cognitive/behavioral teratogenetic effects of antlepileptic drugs EPILEPSY & BEHAVIOR Meador, K. J., Baker, G., Cohen, M. J., Gaily, E., Westerveld, M. 2007; 11 (3): 292-302

    Abstract

    The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain.

    View details for DOI 10.1016/j.yebeh.2007.08.009

    View details for Web of Science ID 000251067800008

    View details for PubMedID 17996637

  • Afterdischarges during cortical stimulation at different frequencies and intensities EPILEPSY RESEARCH Motamedi, G. K., Okunola, O., Kalhorn, C. G., Mostofi, N., Mizuno-Matsumoto, Y., Cho, Y., Meador, K. J. 2007; 77 (1): 65-69

    Abstract

    The occurrence of unwanted afterdischarges (ADs) impedes cortical stimulation for mapping purposes. We investigated the safety of several stimulation paradigms.We compared the incidence of ADs and behavioral responses of two stimulation frequencies (50 and 100 Hz), at two intensities (1 and 0.2 ms pulse widths).Stimulation with 100 Hz was more likely to cause ADs than 50 Hz, and stimulation using 1 ms pulse width was more likely to cause ADs than 0.2 ms.Stimulation using 50 Hz frequency with a pulse width of 0.2 ms might be safer during cortical mapping.

    View details for DOI 10.1016/j.eplepsyres.2007.08.001

    View details for Web of Science ID 000251118900009

    View details for PubMedID 17869064

  • Victoria symptom validity test performance in a heterogenous clinical sample CLINICAL NEUROPSYCHOLOGIST Loring, D. W., Larrabee, G. J., Lee, G. P., Meador, K. J. 2007; 21 (3): 522-531

    Abstract

    We retrospectively reviewed Victoria Symptom Validity Test (VSVT) in 374 patients who underwent neuropsychological assessment in an academic hospital-based practice. Patients were classified as either non-TBI clinically referred (generally patients referred from neurology, neurosurgery, or medicine), clinically referred TBI (no known external financial incentive), and non-clinical referrals (e.g., attorney-referred, Worker's Compensation). Three patients were not classified into any group and considered separately. Intentional response distortion, defined as statistically less than chance performance on hard VST items, was present in only 1/306 (0.3%) clinically referred non-TBI patients, and no clinically referred TBI patient obtained scores significantly less than chance on this measure. One additional clinically referred patient with a non-neurologic diagnosis who was subsequently found to be pursuing a disability claim also performed worse than chance. In contrast, 5/25 patients (20%) referred by attorneys or otherwise deemed a priori to be at-risk for deficit exaggeration performed less than chance. These data suggest that intentional response distortion in patients referred for non-forensic neuropsychological evaluation is rare. Performances by specific diagnosis using different classification criteria are also presented.

    View details for DOI 10.1080/13854040600611384

    View details for Web of Science ID 000245781200089

    View details for PubMedID 17455035

  • Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy NEUROLOGY Blum, D., Meador, K., Biton, V., Fakhoury, T., Shneker, B., Chung, S., Mills, K., Hammer, A., Isojaervi, J. 2006; 67 (3): 400-406

    Abstract

    To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy.A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test).For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013).Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.

    View details for Web of Science ID 000239603500009

    View details for PubMedID 16894098

  • 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

  • Antiepileptic drugs and neurodevelopment CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Motamedi, G. K., Meador, K. J. 2006; 6 (4): 341-346

    Abstract

    Clinical studies have documented the teratogenic potential of antiepileptic drugs (AEDs). More recent cohort studies have been trying to sort out which AEDs impose the highest risk of teratogenicity. Currently, there is evidence demonstrating an increased risk of major congenital malformations (MCMs) for valproate, phenobarbital, and polytherapy during pregnancy. Based on the current data from multiple studies, the risk for valproate is the highest. Additional studies are needed to fully delineate if differences exist for other AEDs, especially the newer AEDs. However, although MCMs are easy to recognize and have been shown to be more common after in utero exposure to AEDs, there are insufficient data regarding their long-term effects on cognition and behavior in exposed children. Although most children born to women with epilepsy are healthy, in recent years there has been increasing awareness of the long-term effects of in utero exposure to AEDs. Recent discovery of neuronal apoptosis following in utero AED exposure in animals during a period that corresponds to the third trimester and early infancy in humans raises further concerns. Prospective clinical studies seem necessary in order to better understand the long-term neurodevelopmental effects of in utero exposure to AEDs.

    View details for Web of Science ID 000245203100010

    View details for PubMedID 16822356

  • 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

  • Distinct cognitive neurophysiologic profiles for lamotrigine and topiramate EPILEPSIA Smith, M. E., Gevins, A., McEvoy, L. K., Meador, K. J., Ray, P. G., Gilliam, F. 2006; 47 (4): 695-703

    Abstract

    To contrast the effects of lamotrigine (LTG) and topiramate (TPM) on cognitive task-related and resting-state EEG and evoked potential (EP) measures.We used a double-blind, randomized, crossover design. Healthy adults (N = 29) had two 8-week periods of dose escalation, 4 weeks of drug maintenance (300 mg daily), and 4 weeks of washout. EEG was recorded during working memory (WM) tasks and resting conditions at baseline, at the end of each maintenance phase, and after final washout. RESULTS. LTG did not affect overt performance on the tasks, although it reduced EEG power in both resting and WM task conditions, most prominently in the 6- to 12-Hz frequency range, and attenuated P300 evoked-potential amplitude equally in both WM task loads. TPM slowed responses and increased errors. It also increased EEG power below 6 Hz in all conditions, and reduced the amplitude of a slow wave observed in a difficult version of the WM task.The drugs produced both task-independent and task-related alterations in neurophysiologic measures. The EEG and EP changes produced by TPM are consistent with an impairment of WM, as evidenced by overt performance deficits on the behavioral tasks. By contrast, the reduction in synchronous cortical activity produced by LTG was not accompanied by cognitive impairment. It is unknown whether such effects would also be observed at lower doses, such as those that often are used in monotherapy for newly diagnosed patients.

    View details for Web of Science ID 000236549800005

    View details for PubMedID 16650135

  • Subjective preference for lamotrigine or topiramate in healthy volunteers: Relationship to cognitive and behavioral functioning EPILEPSY & BEHAVIOR Werz, M. A., Schoenberg, M. R., Meador, K. J., Loring, D. W., Ray, P. G., Kaul-Gupta, R., Ogrocki, P. 2006; 8 (1): 181-191

    Abstract

    Outcomes research emphasizes patient self-assessment and preferences in optimizing treatment. We previously showed that lamotrigine produces significantly less cognitive and behavioral impairment compared with topiramate. In the current study we extend these observations to subject self-report of preference for lamotrigine or topiramate independent of potentially confounding effects of seizures or seizure control. Additionally, drug preference was related to effects of lamotrigine and topiramate on objective neuropsychological tests as well as self-perception on behavioral instruments.Thirty-seven healthy volunteers completed a double-blind, randomized crossover design incorporating two 12-week treatment periods of lamotrigine and topiramate each titrated to a dose of 300 mg/day. Evaluation of 23 objective neuropsychological and 15 subjective behavioral measures occurred at four times: pretreatment baseline, first treatment, second treatment, and posttreatment baseline. Preference for lamotrigine or topiramate was assessed, while blinding was maintained, at the final study visit when each subject was asked which drug he or she would prefer to take.A large majority (70%) preferred lamotrigine, 16% stated preference for topiramate, and 14% had no preference (drugs equivalent). Consistent with preference, those preferring lamotrigine performed better on 19 of 23 objective and 13 of 15 subjective behavioral measurements while on lamotrigine. Inconsistent with preference, subjects preferring topiramate performed better on 19 of 23 objective and 9 of 15 subjective behavioral measures while on lamotrigine. Topiramate preference also did not correlate with IQ, serum concentration, body mass index, age, or gender. Topiramate preference did relate to responses on the Profile of Mood States.Lamotrigine was preferred by the majority of subjects, congruent with objective neuropsychological and subjective behavioral measures. In contrast, for those stating a preference for topiramate the results on objective neuropsychological measures were impaired while fewer complaints were noted on the Profile of Mood States. This suggests that preference for topiramate may be determined by an effect on mood.

    View details for DOI 10.1016/j.yebeh.2005.09.003

    View details for Web of Science ID 000235225900019

    View details for PubMedID 16377253

  • The Wada test for language and memory lateralization. Neurology Meador, K. J., Loring, D. W. 2005; 65 (5): 659-?

    View details for PubMedID 16163792

  • Victoria symptom validity test performance in non-litigating epilepsy surgery candidates JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Loring, D. W., Lee, G. P., Meador, K. J. 2005; 27 (5): 610-617

    Abstract

    We report Victoria Symptom Validity Test (VSVT) performance in 120 epilepsy patients undergoing neuropsychological assessment as part of their evaluation as epilepsy surgery candidates. Patients were grouped according to their performance on hard VSVT stimuli. Scores of at least 21/24 on the hard VSVT items were classified as valid (n=86), scores of 18/24-20/24 were considered questionably valid (n=20), and scores of 17/24 and below were designated as invalid (n=14). Significant group effects were observed for WAIS-III Full Scale IQ, Verbal IQ, Performance IQ, Digit Span, Rey 3x5 Memory, Selective Reminding Recognition, and Complex Figure Immediate Recall; poorer cognitive scores were associated with lower VSVT scores. Age was also related to VSVT performance, with patients older that 40 years of age (16/42) more likely to fail the VSVT (i.e., hard scores < or = 20/24) than their younger counterparts (8/78) (p=.0006, Fisher's Exact Test). These results indicate that VSVT may identify cases of incomplete effort in patients being evaluated for strictly clinical purposes in which no external incentive to perform poorly has been identified, although the potential confound of low IQ on VSVT cannot be determined from this sample. Older patients also appear to be at increased risk for suboptimal performance, and may need additional encouragement or education regarding the need to perform to the best of their ability, and thereby maximize the likelihood of obtaining valid neuropsychological test results.

    View details for DOI 10.1080/13803390490918471

    View details for Web of Science ID 000229885000008

    View details for PubMedID 16019637

  • 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

  • Antiepileptic drugs and memory EPILEPSY & BEHAVIOR Motamedi, G. K., Meador, K. J. 2004; 5 (4): 435-439

    Abstract

    Impaired memory is among the most common complaints of patients with epilepsy. Multiple factors contribute to memory impairment in patients with epilepsy. Thus, delineation of the effects of antiepileptic drugs (AEDs) on memory in clinical populations faces methodological difficulties. Further, subjective perception of memory problems by patients is influenced by mood. However, there is evidence from animal and healthy volunteer studies supporting an independent potential for AEDs to impair memory. Differential AED effects on memory have been observed, and AED effects may interact with focal brain lesions. Memory impairment from AEDs is a greater concern at the age extremes, although the effects of AEDs, especially the newer agents, have not been thoroughly studied in these populations. Well-controlled studies are needed to understand the underlying mechanisms and to further delineate the magnitude and relative effects of AEDs on memory.

    View details for DOI 10.1016/j.yebeh.2004.03.006

    View details for Web of Science ID 000222890800002

    View details for PubMedID 15256178

  • Role of cerebral lateralization in control of immune processes in humans ANNALS OF NEUROLOGY Meador, K. J., Loring, D. W., Ray, P. G., Helman, S. W., Vazquez, B. R., Neveu, P. J. 2004; 55 (6): 840-844

    Abstract

    Cerebral lateralization may be important in neural control of immune function. Animal studies have demonstrated differential effects of left and right brain lesions on immune function, but human studies are inconclusive. Here, we show that resections in the language dominant hemisphere of patients with epilepsy reduce lymphocytes, total T cells, and helper T cells. In contrast, resections in the language nondominant hemisphere increased the same cellular elements. T-cell responses to mitogens and microbial antigens were not differentially affected. Left/right arm histamine skin response ratios were altered in patients with left cerebral epileptic focus, and flare skin responses were reduced by left cerebral resections in contrast with an increase after right cerebral resections. The findings demonstrate a differential role of the left and right cerebral hemispheres on immune functions in humans.

    View details for DOI 10.1002/ana.20105

    View details for Web of Science ID 000221716300010

    View details for PubMedID 15174018

  • Structural versus functional prediction of memory change following anterior temporal lobectomy EPILEPSY & BEHAVIOR Loring, D. W., Meador, K. J., Lee, G. P., Smith, J. R. 2004; 5 (2): 264-268

    Abstract

    Decline in recent memory function is a significant risk for patients undergoing anterior temporal lobectomy. We report a patient with a febrile seizure history, complex partial seizures arising from the left anterior temporal lobe, and MRI evidence suggesting left hippocampal sclerosis, all of which indicate a low likelihood of significant postoperative memory decline. However, high normal verbal memory on neuropsychological testing and bilaterally normal Wada memory scores indicated increased risk for postoperative memory decline. Following left anterior temporal lobectomy, the patient displayed a significant decline in verbal recent memory that affected school performance. Despite the worsening in memory, the patient reported a significant improvement in his self-reported quality-of-life perception, demonstrating that factors other than change in cognitive performance are related to whether a patient considers epilepsy surgery worthwhile. In the present case, behavioral measures were superior to structural measures in predicting cognitive change following surgery.

    View details for DOI 10.1016/j.yebeh.2004.01.001

    View details for Web of Science ID 000220531700021

    View details for PubMedID 15123031

  • Cognitive side effects of antiepileptic drugs in children NEUROLOGY Loring, D. W., Meador, K. J. 2004; 62 (6): 872-877

    Abstract

    Cognitive impairment associated with antiepileptic drug (AED) therapy in children is an important concern given the potential negative effects of treatment on school learning and performance. Unfortunately, there have been few studies examining the cognitive effects of AEDs in this population and no adequate studies of newer AEDs. This article will discuss the effects of the traditional and newer AEDs on neuropsychological function in children. Because of various limitations in the designs of these studies, however, many of the studies report inconclusive findings. Although it will be necessary to overcome many programmatic and procedural hurdles, well-designed randomized prospective studies that are of adequate length to determine how AEDs ultimately relate to school performance and social adjustment are needed to firmly establish the cognitive and behavioral effects of AEDs in children.

    View details for Web of Science ID 000220365300007

    View details for PubMedID 15037684

  • Neural substrates of emotion as revealed by functional magnetic resonance imaging. Cognitive and behavioral neurology Lee, G. P., Meador, K. J., Loring, D. W., Allison, J. D., Brown, W. S., Paul, L. K., Pillai, J. J., Lavin, T. B. 2004; 17 (1): 9-17

    Abstract

    To examine the brain circuitry involved in emotional experience and determine whether the cerebral hemispheres are specialized for positive and negative emotional experience.Recent research has provided a preliminary sketch of the neurologic underpinnings of emotional processing involving specialized contributions of limbic and cortical brain regions. Electrophysiologic, functional imaging, and Wada test data have suggested positive, approach-related emotions are associated with left cerebral hemisphere regions, whereas negative, withdrawal-related emotions appear to be more aligned with right hemisphere mechanisms.These emotional-neural associations were investigated using functional magnetic resonance imaging in 10 healthy controls with 20 positively and 20 negatively valenced pictures from the International Affective Picture System in a counterbalanced order. Pictures were viewed within a 1.5 Telsa scanner through computerized video goggles.Emotional pictures resulted in significantly increased blood flow bilaterally in the mesial frontal lobe/anterior cingulate gyrus, dorsolateral frontal lobe, amygdala/anterior temporal regions, and cerebellum. Negative emotional pictures resulted in greater activation of the right hemisphere, and positive pictures caused greater activation of the left hemisphere.Results are consistent with theories emphasizing the importance of circuitry linking subcortical structures with mesial temporal, anterior cingulate, and frontal lobe regions in emotion and with the valence model of emotion that posits lateralized cerebral specialization for positive and negative emotional experience.

    View details for PubMedID 15209221

  • Epilepsy in cortical dysplasia: Factors affecting surgical outcome STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Fountas, K. N., King, D. W., Meador, K. J., Lee, G. P., Smith, J. R. 2004; 82 (1): 26-30

    Abstract

    To determine the factors influencing the outcome of cortical dysplasia resection for medically refractory epilepsy.13 patients underwent craniotomy for resection of epileptogenic foci using electrographic and MRI guidance. All patients had had seizures for more than 2 years and were on 3 or more antiepileptic medications. Their preoperative evaluation included MRI, neuropsychological evaluation including the WADA test, video EEG monitoring and intraoperative electrocorticography. Invasive preoperative monitoring was employed in 8 cases. The Engel outcome classification system was used. The mean follow-up time was 60.1 months with a minimum follow-up of 24 months.Postoperatively, all 6 patients younger than 18 years were seizure free. Among 7 patients older than 18 years, 6 were class II and 1 was class III. Based on their preoperative MRI studies, among the patients with abnormal studies, 2 were class I, 5 were class II and 1 was class III. Among patients with normal studies, 4 were class I and 1 class II. Regarding the ictal EEG findings, among patients with localizing findings, 4 were class I and 5 were class II. Among patients with no localization in their ictal EEG, 2 were class I, 1 class II and 1 class III. Regarding the invasive preoperative monitoring of the 7 patients with localizing findings, 5 were class I and 2 were class II. The only patient with nonlocalizing findings was class II. Finally, among the patients with no invasive preoperative monitoring, 3 were class I, 1 was class II and 1 was class III.Cortical resection is an effective treatment modality in patients with medically refractory epilepsy. In our series, the outcome was better in patients less than 18 years old and patients with normal preoperative MRI studies.

    View details for DOI 10.1159/000076657

    View details for Web of Science ID 000220083400004

    View details for PubMedID 15007216

  • A pilot study of feasibility and efficacy of telemedicine-delivered psychophysiological treatment for vascular headache TELEMEDICINE JOURNAL AND E-HEALTH Arena, J., Dennis, N., Devineni, T., Maclean, R., Meador, K. 2004; 10 (4): 449-454

    Abstract

    Headache is a common complaint. Psychological treatment has been effective in managing the symptoms of vascular (migraine and combined migraine-tension) headache. Traditional office-based treatment may be inconvenient for many patients in terms of time and travel constraints, thereby limiting access. Telemedicine has emerged as a promising delivery medium to address these barriers to access. However, the efficacy of remotely delivered treatment for vascular headache remains untested. This case series is a preliminary evaluation of effectiveness and feasibility of an analogue telemedicine system for delivery of psychophysiological treatment for vascular headache. Three of four subjects showed improvement. These findings are encouraging for follow-up study of the clinical utility and broader viability of headache treatment via distance technology.

    View details for Web of Science ID 000226849700006

    View details for PubMedID 15689649

  • 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

  • Epilepsy and cognition EPILEPSY & BEHAVIOR Motamedi, G., Meador, K. 2003; 4: S25-S38

    Abstract

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

    View details for DOI 10.1016/j.yebeh.2003.07.004

    View details for Web of Science ID 000186064700004

    View details for PubMedID 14527481

  • Now you see it, now you don't: statistical and methodological considerations in fMRI EPILEPSY & BEHAVIOR Loring, D. W., Meador, K. J., Allison, J. D., Pillai, J. J., Lavin, T., Lee, G. P., Balan, A., Dave, V. 2002; 3 (6): 539-547

    View details for Web of Science ID 000184199700013

  • Cognitive and behavioral effects of antiepileptic drugs EPILEPSY & BEHAVIOR Drane, D. L., Meador, K. J. 2002; 3 (5): S49-S53

    View details for Web of Science ID 000179698000011

  • Cognitive and behavioral effects of antiepileptic drugs. Epilepsy & behavior Drane, D. L., Meador, K. J. 2002; 3 (5S): 49-53

    Abstract

    Multiple factors contribute to the increased risk of cognitive and emotional deficits experienced by patients with epilepsy, including both the underlying disease state from which they suffer and the psychosocial disruption in their lifestyles that their seizures can produce. While antiepileptic drugs (AEDs) have the potential to reduce such risks by reducing seizure activity, they can also compound problems by dampening neuronal excitability throughout the brain and altering underlying neurochemical systems that impact thinking and mood. Therefore, for optimal treatment of epilepsy, one must achieve a balance between adequate seizure control and minimizing the potential side effects of the employed AEDs. This requires knowledge of the specific cognitive and behavioral effects of both established newer AEDs and an understanding of the general principles governing their delivery.

    View details for PubMedID 12609322

  • Task-related EEG and ERP changes without performance impairment following a single dose of phenytoin CLINICAL NEUROPHYSIOLOGY Chung, S. S., McEvoy, L. K., Smith, M. E., Gevins, A., Meador, K., Laxer, K. D. 2002; 113 (6): 806-814

    Abstract

    The acute effects of a single, low dose of phenytoin on behavioral and neurophysiological measures of cognitive function were examined in healthy adults.Electroencephalograms (EEGs) were recorded from 7 healthy volunteers while they performed spatial working memory tasks and while they rested quietly. Behavioral measures, EEG power spectra, and event-related potentials (ERPs) were compared between separate sessions in which subjects ingested either 10mg/kg of phenytoin or placebo.Peak serum levels of phenytoin were in the low therapeutic range. Although participants reported subjective effects of the drug, task accuracy and response time were not affected. In the resting EEG, phenytoin decreased power in the alpha band. In the task-related EEG, the frontal midline theta signal was enhanced in response to increased task difficulty following placebo but not following phenytoin. An attention-related augmentation of the N160 ERP to matching stimuli was also reduced by phenytoin.Neurophysiological measures displayed sensitivity to subtle alterations in attentional processing even in response to a dose of phenytoin too low to produce behavioral impairment. Such results indicate that EEG and ERP measures can provide information about the neurocognitive side effects of medications that cannot be inferred from cognitive task performance measures alone.

    View details for Web of Science ID 000176503000004

    View details for PubMedID 12048040

  • Lateralized changes in autonomic arousal during emotional processing in patients with unilateral temporal lobe seizure onset INTERNATIONAL JOURNAL OF NEUROSCIENCE Lee, G. P., Meador, K. J., Loring, D. W., Bradley, K. P. 2002; 112 (6): 743-757

    Abstract

    The valence model of emotion, which posits cerebral lateralization for positive and negative emotional processing, was investigated in patients with unilateral mesial temporal lobe epilepsy (TLE) and controls by measuring skin conductance levels (SCLs) and heart rate (HR) while positive and negative emotional photographs were viewed. Left TLEs exhibited selective SCL hyperarousal when viewing negative emotional slides relative to controls and right TLEs. In contrast, right TLEs showed no significant differences compared with the other groups. Results are consistent with left hemispheric specialization for positive emotional expression. Dysfunction of left mesial temporal lobe structures may result in autonomic hyperarousal and a release of the unrestrained negative emotional tendencies of the right hemisphere.

    View details for DOI 10.1080/00207450290025743

    View details for Web of Science ID 000175943900007

    View details for PubMedID 12325313

  • 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

  • Cognitive and Behavioral Effects of Antiepileptic Drugs EPILEPSY & BEHAVIOR Meador, K. J., Gilliam, F. G., Kanner, A. M., Pellock, J. M. 2001; 2 (4): SS1-SS17

    View details for DOI 10.1006/ebeh.2001.0235

    View details for Web of Science ID 000208208600001

  • Cognitive and behavioral effects of antiepileptic drugs. Epilepsy & behavior Meador, K. J., Gilliam, F. G., Kanner, A. M., Pellock, J. M. 2001; 2 (4): SS1-SS17

    View details for PubMedID 12609218

  • Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults EPILEPSIA Martin, R., Meador, K., Turrentine, L., Faught, E., Sinclair, K., Kuzniecky, R., Gilliam, F. 2001; 42 (6): 764-771

    Abstract

    This study compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in healthy senior adults by using a randomized, double-blind crossover design.Thirty-four senior adults were randomized to receive one of the two drugs followed by a 5-week treatment period. A 4-week washout phase preceded initiation of the second drug. Antiepileptic drugs (AEDs) were titrated to target doses of either CBZ (800 mg/day) or GBP (2,400 mg/day). Primary outcome measures were standardized neuropsychological tests of attention/vigilance, psychomotor speed, motor speed, verbal and visual memory, and the Profile of Mood State (POMS), yielding a total of 17 variables. Each subject received cognitive testing at predrug baseline, end of first drug phase, end of second drug phase, and 4 weeks after completion of the second drug phase.Fifteen senior adults (mean age, 66.5 years; range, 59-76 years) completed the study. Seniors completing the study did not differ significantly from noncompleting seniors in terms of demographic features or baseline cognitive performances. Fifteen of the 19 seniors not completing the study dropped out while receiving CBZ. Adverse events were frequently reported for both AEDs, although they were more common for CBZ. Mean serum levels for the completers were within midrange clinical doses (CBZ, 6.8 microg/ml; GBP, 7.1 microg/ml). Significant differences between CBZ and GBP were found for only one of 11 cognitive variables, with better attention/vigilance for GBP, although the effect was modest. Performances on the nondrug average were significantly better on 45% of cognitive variables compared with CBZ and 36% compared with GBP. The overall pattern of means favored GBP over CBZ on 15 of 17 (p < 0.001), nondrug over CBZ on 17 of 17 (p < 0.0000), and nondrug over GBP on eight of 17 (NS).Mild cognitive effects were found for both AEDs compared with the nondrug average condition. The magnitude of difference between the two AEDs across the cognitive variables was modest. Self-reported mood was not significantly affected by either AED. However, overall tolerability and side-effect profile of CBZ were poorer than those of GBP in senior adults at doses and titration rates reported in this study.

    View details for Web of Science ID 000169449500011

    View details for PubMedID 11422333

  • 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

  • Cognitive and behavioral effects of epilepsy treatment EPILEPSIA Loring, D. W., Meador, K. J. 2001; 42: 24-32

    View details for Web of Science ID 000172832800005

    View details for PubMedID 11902326

  • Arrhythmias in neurofibromatosis CARDIOLOGY Verma, S., Ahmed, S., Gudapati, S. B., King, D. W., Meador, K. J., Ahmed, R. 2001; 95 (3): 167-169

    Abstract

    Patients with neurofibromatosis have a higher incidence of anatomic cardiac abnormalities. However, there is little data regarding incidence of arrhythmias in this population. It is known that these patients have a higher mortality than the normal population, and it is possible that some deaths may be due to preventable causes such as cardiac arrhythmias. We report a patient with neurofibromatosis who was treated for a refractory seizure disorder for 8 years. However, video/EEG monitoring demonstrated that the patient had recurrent syncopal seizures secondary to sinus node dysfunction. Complete resolution of symptoms occurred after a permanent pacemaker implantation. We believe this is the first reported case of sinus node dysfunction associated with neurofibromatosis.

    View details for Web of Science ID 000170270600010

    View details for PubMedID 11474165

  • The Wada test in the evaluation for epilepsy surgery. Neurosciences Loring, D. W., Meador, K. J., Westerveld, M. 2000; 5 (4): 203-208

    Abstract

    The Wada test is the standard part of the pre-operative evaluation for epilepsy surgery. The procedure involves the slow injection of sodium amobarbital (typically 100-500mg) into the internal carotid artery following a transfermoral approach. The amobarbital anesthetizes the anterior two-thirds of the ipsilateral cerebral hemisphere for approximately 5-10 minutes. During this period of hemispheric anesthesia, assessment of expressive and receptive language can establish cerebral language representation. In addition, the procedure provides a reversible model to assess the risk of significant memory change following surgery. This is important because patients undergoing surgery involving the temporal lobe may experience significant memory decline following surgical resection of a temporal lobe seizure focus. This paper will represent information about the use of Wada testing, and discuss issues involved in establishing cerebral language representation, lateralization of temporal lobe dysfunction, seizure and memory outcome prediction, and future directions of this technique.

    View details for PubMedID 24276596

  • Anosognosia and asomatognosia during intracarotid amobarbital inactivation NEUROLOGY Meador, K. J., Loring, D. W., FEINBERG, T. E., Lee, G. P., Nichols, M. E. 2000; 55 (6): 816-820

    Abstract

    Anosognosia (i.e., denial of hemiparesis) and asomatognosia (i.e., inability to recognize the affected limb as one's own) occur more frequently with right cerebral lesions. However, the incidence, relative recovery, and underlying mechanisms remain unclear.Anosognosia and asomatognosia were examined in 62 patients undergoing the intracarotid amobarbital procedure as part of their preoperative evaluation for epilepsy surgery. Additional questions were asked in the last 32 patients studied.During inactivation of the non-language-dominant cerebral hemisphere, 88% of the 62 patients were unaware of their paralysis, and 82% could not recognize their own hand at some point. Only 3% did not exhibit anosognosia or asomatognosia. In general, asomatognosia resolved earlier than anosognosia. When patients could not recognize their hand, they uniformly thought that it was someone else's hand. Dissociations in awareness were seen in the second series of 32 patients. Although 23 patients (72%) thought that both arms were in the air, 31% pointed to the correct position of the paralyzed arm on the table. Despite the inability of 24 of 32 patients (75%) to recognize their own hand, 21% of these patients were aware that their arm was weak, and 38% had correctly located their paralyzed arm on the angiography table.Anosognosia and asomatognosia are both common during acute dysfunction of the non-language-dominant cerebral hemisphere. Dissociations of perception of location, weakness, and ownership of the affected limb are frequent, as are misperceptions of location and body part identity. The dissociations suggest that multiple mechanisms are involved.

    View details for Web of Science ID 000089484800014

    View details for PubMedID 10994002

  • Hemispheric asymmetries of limb-kinetic apraxia - A loss of deftness NEUROLOGY Heilman, K. M., Meador, K. J., Loring, D. W. 2000; 55 (4): 523-526

    Abstract

    Unlike patients with ideomotor apraxia who make temporal and spatial errors and patients with ideational or conceptual apraxia who make content errors, patients with limb-kinetic apraxia have loss of deftness, including fine and precise movements, independent finger movements, and difficulty coordinating simultaneous movements. This study was conducted to learn the relationship between limb-kinetic apraxia and hemisphere dysfunction by using selective hemisphere anesthesia, the Wada test.Subjects were 90 patients undergoing Wada testing for intractable epilepsy. They were divided into typical (right-handed with left hemisphere language dominance) and atypical (nonright-handed, or without left hemisphere language dominance). Before and during Wada testing, subjects were shown line drawings of tools, four for each hand tested. After being shown each picture, subjects pantomimed the use of this tool. A behavioral neurologist and neuropsychologist scored the pantomimes for the presence of limb-kinetic errors.For the typical group, during left hemisphere anesthesia, the limb-kinetic errors made by the right and left hands did not differ, but during right hemisphere anesthesia the left hand made more errors than the right. Unlike the typical subjects, when the left hemisphere was anesthetized, the atypical subjects made more errors with their right hands than left. However, similar to the typical subjects with right hemisphere anesthesia, the atypical subjects made more left- than right-hand limb-kinetic errors.For people with typical brain organization, the left hemisphere mediates motor deftness for both hands, but the right hemisphere primarily controls deftness for the left hand. For people with atypical brain organization, each hemisphere primarily controls deftness for the contralateral hand.

    View details for Web of Science ID 000088855000012

    View details for PubMedID 10953184

  • Pre-surgical evaluation for epilepsy surgery. Neurosciences Loring, D. W., Meador, K. J. 2000; 5 (3): 143-150

    Abstract

    Neuropsychological testing may reflect subtle structural changes that may not be readily apparent with neuroimaging studies, and physiologic disruption of normal neural function secondary to epileptic activity. Neuropsychological testing is used during the pre-operative evaluation for epilepsy surgery to assess functional brain status, which, in turn, provides important information on the risks for post-operative neruopsychological deficits and also provides confirmatory evidence of seizure onset laterality in patients whose seizures originate in temporal lobes. This review will focus primarily on the pre-operative neuropsychological of candidates for temporal lobectomy surgery since they represent the majority of individuals undergoing ablative epilepsy surgery, and also because the literature and knowledge for the neuropsychology of temporal lobectomy far exceeds that of any other epilepsy surgical group.

    View details for PubMedID 24276801

  • 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

  • Limb and hemispatial hypometria JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Meador, K. J., Moore, E. E., Martin, R. C., Loring, D. W., Hess, D. C., Heilman, K. M. 2000; 6 (1): 71-75

    Abstract

    In a previous study, we demonstrated that unilateral cerebral lesions produce hypometric limb movements of the contralateral arm and hemispatial (i.e., directional) hypometria for movements towards contralateral hemispace. In the present study, we investigated 10 patients with right cerebral lesions and 25 healthy controls using a task to uncouple deficits in sensory perceptual systems and motor-action output systems on directional hypometria. This task required participants, with their eyes closed, to reproduce lateral and medial horizontal displacements (15-27 cm) with each arm. Each participant was seated at a waist high table and had their hand placed at an origin point aligned with the axillary fold on the same side. Their hand was moved by the investigator from the origin point to a target point and brought back to the point of origin (input displacement). The participant was then asked to return their hand to either the same target point or to an equidistant target point in the opposite direction. Healthy dextral participants were significantly more hypometric with their right arm, but patients with right cerebral lesions exhibited an opposite pattern with overall left arm hypometria. In addition, patients were significantly more hypometric for movements when output displacements were toward left hemispace. No effect was found for direction of sensory input. The results suggest that the directional hypometria is predominantly produced by hemispatial output deficits.

    View details for Web of Science ID 000084876200008

    View details for PubMedID 10761369

  • Cerebral lateralization - Relationship of language and ideomotor praxis NEUROLOGY Meador, K. J., Loring, D. W., Lee, K., Hughes, M., Lee, G., Nichols, M., Heilman, K. M. 1999; 53 (9): 2028-2031

    Abstract

    To determine the relationship of language lateralization and hand preference to praxis performance following left and right hemispheric amobarbital-induced inactivations.Patients who are aphasic from left cerebral dysfunction also frequently exhibit ideomotor apraxia in which they make temporal, spatial, and postural errors of learned skilled movements. However, hemispheric lateralization of the systems mediating ideomotor praxis in patients with atypical cerebral language dominance (i.e., bilateral or right hemispheric language function) remains uncertain.Subjects included 90 patients with intractable seizures who were undergoing the intracarotid amobarbital procedure (IAP) as part of their preoperative evaluation for epilepsy surgery. Hand preference was determined by the Benton Handedness Questionnaire. Praxis was assessed by the subject's performance when pantomiming the use of four pictured tools.During left IAP, patients with typical language dominance made more ideomotor apraxic errors than did patients with atypical language dominance. During right IAP, patients with atypical language dominance made more ideomotor apraxic errors than did patients with typical language dominance. Overall, patients with atypical language dominance made fewer ideomotor apraxic errors than did patients with typical language dominance. These relationships were present irrespective of hand preference.Language dominance is more closely associated with the laterality of temporal and spatial movement representations (i.e., ideomotor praxis dominance) than is hand preference. Patients with atypical language dominance exhibit more bilateral cerebral distribution of both language and praxis function.

    View details for Web of Science ID 000084255300022

    View details for PubMedID 10599776

  • Patient-oriented outcome assessment after temporal lobectomy for refractory epilepsy NEUROLOGY Gilliam, F., Kuzniecky, R., Meador, K., Martin, R., Sawrie, S., Viikinsalo, M., Morawetz, R., Faught, E. 1999; 53 (4): 687-694

    Abstract

    To determine patient-oriented outcome after anterior temporal lobectomy (ATL) for refractory epilepsy.Health-related quality of life (HRQOL) is an important component of the assessment of outcome from epilepsy surgery, but prior controlled studies of the effect of surgery on HRQOL are inconclusive. Direct assessment of the effect of surgery on patient concerns of living with epilepsy has not been reported.We used reliable and valid instruments to compare HRQOL and patient concerns of 125 patients who had received an ATL more than than one year previously to a clinically similar group of 71 patients who were awaiting ATL. All patients were selected for surgery based on similar criteria. We also used bivariate correlation analysis and multivariate regression modeling to determine the association of traditional outcome variables with HRQOL.Patients who had undergone ATL reported significantly less concern of living with epilepsy in 16 of 20 items of the EFA Concerns Index and better HRQOL in 8 of 11 scales of the Epilepsy Surgery Inventory-55. Regression analysis in the postoperative group demonstrated that mood status, employment, driving, and antiepileptic drug (AED) cessation, but not seizure-free status or IQ, were associated with better HRQOL.Our findings support a positive affect of ATL on patient concerns and HRQOL in refractory temporal lobe epilepsy, although longitudinal studies are needed to corroborate these results. Mood, employment, driving ability, and AED use are important postoperative predictors of HRQOL.

    View details for Web of Science ID 000082518300007

    View details for PubMedID 10489027

  • Differential cognitive effects of carbamazepine and gabapentin EPILEPSIA Meador, K. J., Loring, D. W., Ray, P. G., Murro, A. M., King, D. W., Nichols, M. E., Deer, E. M., Goff, W. T. 1999; 40 (9): 1279-1285

    Abstract

    The cognitive effects of the newer antiepileptic drugs (AEDs) compared with the older standard AEDs are uncertain.We directly compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in 35 healthy subjects by using a double-blind, randomized crossover design with two 5-week treatment periods. During each treatment condition, subjects received either GBP, 2,400 mg/day, or CBZ (mean, 731 mg/day) adjusted to a dose to achieve midrange standard therapeutic blood levels (mean, 8.3 microg/ml). Subjects were tested at the end of each AED treatment period and in four drug-free conditions [two pretreatment baselines and two post-treatment washout periods (1 month after each AED)]. The neuropsychological test battery included 17 measures yielding 31 total variables.Direct comparison of the two AEDs revealed significantly better performance on eight variables for GBP, but none for CBZ. Comparison of CBZ and GBP to the nondrug average revealed significant statistical differences for 15 (48%) of 31 the variables. Pairwise follow-up analyses of the 15 variables revealed significantly better performance for nondrug average on 13 variables compared with CBZ, and on four compared with GBP. GBP was better than nondrug average on one variable.Although both CBZ and GBP produced some effects, GBP produced significantly fewer untoward cognitive effects compared with CBZ at the dosages used in this study.

    View details for Web of Science ID 000082367300014

    View details for PubMedID 10487192

  • Effects of anomalous language representation on neuropsychological performance in temporal lobe epilepsy NEUROLOGY Loring, D. W., Strauss, E., Hermann, B. P., Perrine, K., Trenerry, M. R., Barr, W. B., Westerveld, M., Chelune, G. J., Lee, G. P., Meador, K. J. 1999; 53 (2): 260-264

    Abstract

    To examine the effects of anomalous language representation (i.e., mixed- and right-cerebral dominant) on neuropsychological performance.Right cerebral language dominance resulting from early cerebral injury is associated with relatively preserved language function with decreased visuospatial ability. However, previous reports of this phenomenon have examined patients with relatively large cerebral injuries (e.g., infantile hemiplegia) or limited sample sizes.A total of 561 patients with complex partial seizures of left temporal lobe origin were studied. Patients were classified into left (n = 455), bilateral (n = 58), and right (n = 48) language dominant groups based on Wada testing.Right language dominant patients performed more poorly on multiple tests of visuospatial function, including Performance IQ (PIQ), than did left language patients. No significant group differences were detected for measures of language or general verbal function. The effects of bilateral language on PIQ differed according to handedness. Lowered PIQ was present in the bilateral nondextral group but not for bilateral dextral patients, and this pattern was observed with other visuospatial measures.In patients with relatively small lesions restricted to the left mesial temporal lobe, a shift in language dominance to the right hemisphere is associated with decreased visuospatial functions but preserved verbal abilities. Nondextral patients with bilateral language representation also displayed decreased visuospatial performance, although dextral patients with bilateral language did not.

    View details for Web of Science ID 000081587300004

    View details for PubMedID 10430411

  • A comparison of magnetoencephalography, MRI, and V-EEG in patients evaluated for epilepsy surgery EPILEPSIA Wheless, J. W., Willmore, L. J., Breier, J. I., Kataki, M., Smith, J. R., King, D. W., Meador, K. J., Park, Y. D., Loring, D. W., Clifton, G. L., Baumgartner, J., Thomas, A. B., Constantinou, J. E., Papanicolaou, A. C. 1999; 40 (7): 931-941

    Abstract

    To determine the efficacy and relative contribution of several diagnostic methods [ictal and interictal scalp and intracranial EEG, magnetic resonance imaging (MRI), and magnetoencephalography (MEG)] in identifying the epileptogenic zone for resection.This was a prospective study using a masked comparison-to-criterion standard. Fifty-eight consecutive patients with refractory partial epilepsy from two university comprehensive epilepsy programs were studied. Patients who were evaluated for and underwent epilepsy surgery were recruited. The main outcome measure was the efficacy of each diagnostic method to identify the resected epileptogenic zone, when referenced to surgical outcome.MEG (52%) was second only to ictal intracranial V-EEG in predicting the epileptogenic zone for the entire group of patients who had an excellent surgical outcome (seizure free or rare seizure). In a subanalysis, for patients who had temporal lobe surgery, this same relation was seen (MEG, 57%, ictal intracranial V-EEG, 62%). With extratemporal resection, ictal (81%) and interictal (75%) intracranial EEG were superior to MEG (44%) in predicting the surgery site in those patients with an excellent outcome. Finally, for all patients who had a good surgical outcome, MEG (52%) was better than ictal (33%) or interictal (45%) scalp VEEG in predicting the site of surgery.These results indicate that MEG is a very promising diagnostic method and raise the possibility that it may obviate the need for invasive EEG in some cases or reduce the length of scalp EEG evaluation in others.

    View details for Web of Science ID 000081247200015

    View details for PubMedID 10403217

  • Time perception following unilateral amobarbital injection in patients with temporal lobe epilepsy JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Drane, D. L., Lee, G. P., Loring, D. W., Meador, K. J. 1999; 21 (3): 385-396

    Abstract

    Estimates of elapsed time were obtained from 53 patients with unilateral temporal lobe epilepsy (Left TLE = 27; Right TLE = 26) following Wada (intracarotid amobarbital) assessment. After resolution of drug effects, patients were asked to estimate how much time had passed since amobarbital administration. Estimates were also obtained from 24 healthy control subjects using the same cognitive tasks over a similar time frame. Elapsed time was significantly underestimated by both left and right TLE groups following right hemisphere injection. In addition, there was an interaction effect involving patient group, side of injection, and sequence of injection. Left TLE patients, consistent with normal controls, made more accurate time estimates when they could anticipate the estimation task following the second amobarbital administration. More accurate time estimates, however, occurred only when left hemisphere injection was second in sequence. In contrast, right TLE patients did not improve regardless of the order of injection. These results suggest that right hemisphere function plays a critical role in the accuracy of time estimations of intermediate temporal duration and that interhemispheric interaction may be required to make accurate retrospective temporal judgments. These findings are discussed in the context of the growing evidence for a right-hemispheric attentional network.

    View details for Web of Science ID 000082474700010

    View details for PubMedID 10474177

  • Localization and characterization of speech arrest during transcranial magnetic stimulation CLINICAL NEUROPHYSIOLOGY Epstein, C. M., Meador, K. J., Loring, D. W., Wright, R. J., Weissman, J. D., Sheppard, S., Lah, J. J., Puhalovich, F., Gaitan, L., Davey, K. R. 1999; 110 (6): 1073-1079

    Abstract

    To determine the anatomic and physiologic localization of speech arrest induced by repetitive transcranial magnetic stimulation (rTMS), and to examine the relationship of speech arrest to language function.Ten normal, right-handed volunteers were tested in a battery of language tasks during rTMS. Four underwent mapping of speech arrest on a 1 cm grid over the left frontal region. Compound motor action potentials from the right face and hand were mapped onto the same grid. Mean positions for speech arrest and muscle activation were identified in two subjects on 3-dimensional MRI.All subjects had lateralized arrest of spontaneous speech and reading aloud during rTMS over the left posterior-inferior frontal region. Writing, comprehension, repetition, naming, oral praxis, and singing were relatively spared (P < .05). Stimulation on the right during singing abolished melody in two subjects, but minimally affected speech production. The area of speech arrest overlay the caudal portion of the left precentral gyrus, congruous with the region where stimulation produced movement of the right face.The site of magnetic speech arrest appears to be the facial motor cortex. Its characteristics differ from those of classic aphasias, and include a prominent dissociation among different types of speech output.

    View details for Web of Science ID 000081024900008

    View details for PubMedID 10402094

  • Physiology of perception - Cortical stimulation and recording in humans NEUROLOGY Ray, P. G., Meador, K. J., Smith, J. R., Wheless, J. W., Sittenfeld, M., Clifton, G. L. 1999; 52 (5): 1044-1049

    Abstract

    1) To determine the effect of stimulus train duration (TD) on sensory perception using direct stimulation of somatosensory and visual cortices. 2) To investigate the occurrence of evoked potentials in response to stimulation that is subthreshold for perception.Studies of the mechanisms of conscious perception using direct cortical stimulation and recording techniques are rare. The clinical necessity to implant subdural electrode grids in epilepsy patients undergoing evaluation for surgery offers an opportunity to examine the role of stimulus parameters and evoked potentials in conscious perception.Subjects included epilepsy patients with grids over somatosensory or occipital cortex. Single pulses (100 microseconds) and stimulus trains were applied to electrodes, and thresholds for perception were found. Evoked potentials were recorded in response to peripheral stimulation at intensities at, above, and below sensory threshold.During cortical stimulation, sensory threshold changed little for stimulus trains of 250 milliseconds and longer, but increased sharply as TD decreased below this level. Primary evoked activity was recorded in response to peripheral stimulations that were subthreshold for conscious perception.The results confirm a previous report of the effects of stimulus TD on sensory threshold. However, no motor responses occurred following somatosensory stimulation with short trains, as previously reported. The TD threshold pattern was similar in visual cortex. In agreement with the previous report, early components of the primary evoked response were not correlated with conscious sensory awareness.

    View details for Web of Science ID 000079516900025

    View details for PubMedID 10102426

  • Physiology of somatosensory perception - Cerebral lateralization and extinction NEUROLOGY Meador, K. J., Ray, P. G., Day, L., Ghelani, H., Loring, D. W. 1998; 51 (3): 721-727

    Abstract

    To demonstrate the effects of cerebral lateralization and temporal dynamics on somatosensory perception.We postulated that perceptual thresholds for simple somatosensory stimuli would be less in the left than the right hand, and that a left/right asymmetry in extinction would exist in healthy right-handed subjects (but not in left-handed subjects). During the course of these experiments we also examined the controversy concerning the temporal dynamics of somatosensory perception.A total of 126 healthy subjects (age range, 6 to 73 years) participated in the study. Effects of handedness, age, vigilance, gaze, and temporal interval on somatosensory perception were examined in a series of experiments. Brief electric pulses were applied to the index finger of one or both hands.Perceptual thresholds are lower in the left than the right hand of healthy right-handed subjects in a large cohort across a wide age range. Left-handed subjects have no overall asymmetry. Even after compensation for baseline threshold differences, single stimuli in right-handed subjects are perceived more readily in the left than the right hand, and left-hand targets are more difficult to mask. Leftward eye/head gaze lowers thresholds in both hands of right-handed subjects (compared with right or straight gaze). Extinction was consistently maximal when the mask followed the target by 50 to 100 msec.The findings demonstrate clearly that left/right perceptual thresholds for simple somatosensory stimuli are asymmetric in healthy right-handed subjects. Both central and peripheral asymmetries exist. The central asymmetry and gaze effects are consistent with right cerebral dominance for externally directed attention. Access of somatosensory stimuli to conscious awareness is delayed and particularly vulnerable to disruption at 50 to 100 msec after onset of the stimulus.

    View details for Web of Science ID 000075898300016

    View details for PubMedID 9748016

  • Magnetic stimulation of visual cortex: Factors influencing the perception of phosphenes JOURNAL OF CLINICAL NEUROPHYSIOLOGY Ray, P. G., Meador, K. J., Epstein, C. M., Loring, D. W., Day, L. J. 1998; 15 (4): 351-357

    Abstract

    Using transcranial magnetic stimulation of occipital cortex, the authors studied the stimulus parameters that generate phosphenes in healthy volunteers. Single pulses or trains of stimuli readily elicited phosphenes in all subjects. The threshold current needed to elicit perception of phosphenes was essentially the same for stimulus trains from 250 msec to 2000 msec in length, but increased dramatically for trains of shorter duration. The effect of stimulus frequency was variable, with each subject having a distinctive "frequency tuning curve," but overall, the threshold current necessary to produce phosphenes decreased as frequency of stimulation increased. Using paired pulses, the perceptual threshold was flat for interstimulus intervals between 2 msec and 100 msec, but increased rapidly as the interstimulus interval was increased above 100 msec. Stimulation of sites lateral to the midline elicited phosphenes in the contralateral visual field. Phosphenes were dominant in the lower and peripheral aspects of the visual fields. The findings are discussed in relation to similar studies of electrical stimulation of somatosensory cortex.

    View details for Web of Science ID 000079168300007

    View details for PubMedID 9736469

  • Verapamil for severe hyperkinetic movement disorders MOVEMENT DISORDERS Ovsiew, F., Meador, K. J., Sethi, K. 1998; 13 (2): 341-344

    Abstract

    The use of verapamil in three cases of severe hyperkinetic movement disorders resulted in dramatic improvement in patients who had been refractory to many other treatments over a prolonged period. A videotape illustration of one of the patients is provided. The mechanism of action and evidence of efficacy of calcium-channel blockers for abnormal movements are discussed.

    View details for Web of Science ID 000072468100023

    View details for PubMedID 9539352

  • Trial-length sensitivity of the verbal selective reminding test to lateralized temporal lobe impairment CLINICAL NEUROPSYCHOLOGIST Drane, D. L., Loring, D. W., Lee, G. P., Meador, K. J. 1998; 12 (1): 68-73

    View details for Web of Science ID 000072810000007

  • Behavioral and cognitive effects of lamotrigine JOURNAL OF CHILD NEUROLOGY Meador, K. J., Baker, G. A. 1997; 12: S44-S47

    Abstract

    Lamotrigine is a new antiepileptic drug that may possess unique cognitive and behavioral characteristics. Although lamotrigine can produce neurobehavioral toxicity, it is generally well tolerated. In one study directly comparing lamotrigine to placebo as add-on therapy in patients with intractable epilepsy, no objective cognitive effects were observed in a limited neuropsychological battery. Several studies have demonstrated favorable effects of lamotrigine on psychological well-being that were not explained by simple effects on seizure frequency and severity. In direct comparisons with carbamazepine and phenytoin, lamotrigine has been reported to produce positive effects on quality of life scales of patient perception. In addition, positive behavioral effects have also been observed in two blinded studies and several open trials for patients with severe mental disability and refractory epilepsy. Future studies with more extensive neuropsychological assessments are needed to delineate the differential cognitive and behavioral effects of lamotrigine in epilepsy and psychiatric disorders.

    View details for Web of Science ID 000071202800009

    View details for PubMedID 9429130

  • A comparison of tension headache sufferers and nonpain controls on the state-trait anger expression inventory: An exploratory study with implications for applied psychophysiologists APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK ARENA, J. G., BRUNO, G. M., Rozantine, G. S., Meador, K. J. 1997; 22 (3): 209-214

    Abstract

    Studies that have examined the relationship between personality characteristics and tension headache have arrived at conflicting and, for the most part, negative results. In recent years, a number of investigators have begun examining the relationship between anger and psychophysiological disorders, focusing mostly on anger which is suppressed or held in rather than expressed behaviorally. The present study explored the relationship between anger in 59 tension headache subjects and compared their results to 33 nonpain controls. Materials consisted of the revised research edition of the Spielberger State-Trait Anger Expression Inventory. As predicted, tension headache sufferers were found to have significantly more anger held inward than nonpain controls. Implications for applied psychophysiology treatment and future research directions are discussed.

    View details for Web of Science ID 000071000800005

    View details for PubMedID 9428970

  • Wada memory and timing of stimulus presentation EPILEPSY RESEARCH Loring, D. W., Meador, K. J., Lee, G. P., Nichols, M. E., King, D. W., Murro, A. M., Park, Y. D., Smith, J. R. 1997; 26 (3): 461-464

    Abstract

    We compared Wada memory performance for stimuli presented at two timing intervals following amobarbital injection in 47 non-lesional patients with complex partial seizures (L = 26; R = 21). A significant interaction between seizure focus and timing of presentation was present (P < 0.03). Memory performance for objects whose presentation began approximately 50-55 s following amobarbital administration differed as a function of ipsilateral vs. contralateral injection at a very high level of statistical significance (P < 0.00001). Items presented approximately 4 min, 30 s post injection were also related to seizure onset literality, but at a lower statistical level (P < 0.01). Presentation of Wada memory stimuli earlier during hemispheric anaesthesia yields results that are more sensitive to lateralized temporal lobe seizure onset than does presentation of items later during the procedure.

    View details for Web of Science ID A1997WU54100008

    View details for PubMedID 9127727

  • Level of consciousness and memory during the intracarotid sodium amobarbital procedure BRAIN AND COGNITION Meador, K. J., Loring, D. W., Lee, G. P., Nichols, M. E., Moore, E. E., Figueroa, R. E. 1997; 33 (2): 178-188

    Abstract

    Controversy exists regarding differential effects on consciousness of left/right cerebral inactivation via intracarotid amobarbital. Further, the effects of level of consciousness (LOC) on memory during the intracarotid sodium amobarbital procedure (IAP) are unclear. A modified version of the Glasgow Coma Scale altered to avoid the confounding effects of aphasia was employed to assess LOC in 97 patients during the IAP. A greater impairment in LOC occurred with left cerebral inactivation. Memory was more impaired following left hemisphere injections as well as from injections contralateral to seizure focus. Memory was correlated with LOC, and this effect was more prominent for right hemisphere injections and for injections ipsilateral to seizure focus. These findings support differential cerebral roles in consciousness and demonstrate that IAP memory performance may be affected by the patient's LOC.

    View details for Web of Science ID A1997WN65400004

    View details for PubMedID 9073372

  • Effect of Wada memory stimulus type in discriminating lateralized temporal lobe impairment EPILEPSIA Loring, D. W., Hermann, B. P., Perrine, K., PLENGER, P. M., Lee, G. P., Meador, K. J. 1997; 38 (2): 219-224

    Abstract

    To examine the effects of memory stimulus type on Wada memory performance.Ninety-six patients (left, 47; right, 49) from four epilepsy centers who were candidates for anterior temporal lobectomy (ATL) and who have subsequently undergone surgery were studied. Patients with atypical cerebral language lateralization or with evidence on magnetic resonance imaging (MRI) to suggest a lesion other than hippocampal sclerosis were excluded. Wada memory performance was obtained by using both real objects and line drawings as memory stimuli.Wada memory laterality scores with either real objects or line drawings as memory stimuli discriminated left from right-ATL groups. However, objects were superior to line drawings in making this differentiation. Further, objects were superior to line drawings in individual patient classification of candidates for left ATL, with no difference in the classification rates using either objects or line drawings in candidates for right ATL.Type of memory stimuli is an important factor affecting memory results during the Wada test.

    View details for Web of Science ID A1997WJ30800011

    View details for PubMedID 9048675

  • Epilepsy, anticonvulsant drugs and cognition BAILLIERES CLINICAL NEUROLOGY Drane, D. L., Meador, K. J. 1996; 5 (4): 877-885

    Abstract

    The use of AEDs in the management of epilepsy requires an ongoing risk-benefit analysis that attempts to maximize seizure control while minimizing adverse cognitive side-effects. Although the effects of other factors on cognition are generally greater than AED effects in patients with epilepsy, the cognitive effects of AEDs are of special concern because they are iatrogenically induced. Baseline evaluation of mental functioning is essential and should be repeated whenever a change in cognitive performance is suspected. The cognitive effects of the major AEDs, including phenytoin, carbamazepine and valproate, appear modest when dosages are kept within standard therapeutic ranges and polypharmacy is avoided. Violation of these guidelines increases the risk of alterations in arousal, attention, memory and psychomotor functioning. In turn, dysfunction in these areas can contribute to deficits in higher cognitive processes. Evidence suggests that these primary and secondary deficits are relatively greater for benzodiazepines, bromide and phenobarbital. Initial studies involving the newer AEDs suggest that the cognitive profile of these drugs is favourable, but further research is required to determine their relative effects to each other and to the older AEDs. For some patients, optimal seizure management may require the use of polypharmacy or AED dosages that exceed the standard therapeutic range. In such cases, the physician should remain sensitive to the increased risk of cognitive side-effects. The impact of such effects will be greatest for those whose daily functioning requires sustained attention or psychomotor speed. Although the cognitive risks of AEDs appear rather modest for most adults, questions remain regarding the impact of AEDs on patients at extremes of age. Initial studies with children and older adults suggest that the effects of the major AEDs are comparable across the developmental lifespan. However, during the formative years of a child's intellectual development, close scrutiny should be paid to the possibility that subtle attentional or arousal deficits could contribute to cumulative deficits in learning or memory. Preliminary studies involving both animals and humans suggest that the impact of AEDs might be greatest during in utero exposure; however, additional research is required to fully delineate the long-term effects of AED exposure in this earliest period of neurodevelopment.

    View details for Web of Science ID A1996WL15500012

    View details for PubMedID 9068886

  • Optimum stimulus parameters for lateralized suppression of speech with magnetic brain stimulation NEUROLOGY Epstein, C. M., Lah, J. J., Meador, K., Weissman, J. D., Gaitan, L. E., Dihenia, B. 1996; 47 (6): 1590-1593

    Abstract

    Rapid-rate transcranial magnetic brain stimulation produces lateralized suppression of speech output over the frontal lobe, consistent with cerebral dominance for language. But the sensitivity of magnetic speech localization has been limited, and reports are imprecise concerning the amount of discomfort involved. Using a focal magnetic coil, we evaluated the effectiveness and pain of stimulation at different intensities, orientations, and repetition rates (2 to 32 Hz) in six normal volunteers. We obtained complete and clearly lateralized speech arrest in all subjects. The best ratio of efficacy to pain occurred using slower repetition rates of 4 to 8 Hz with a horizontal alignment of the induced electric field. Lower stimulation frequency also allowed clearer distinction between speech arrest and dysarthria from tonic contraction of cranial muscles. The relative comfort and safety of stimulation at 4 Hz should allow more widespread use of magnetic speech localization in clinical and research applications.

    View details for Web of Science ID A1996VX50700047

    View details for PubMedID 8960755

  • A brief questionnaire to screen for quality of life in epilepsy: The QOLIE-10 EPILEPSIA CRAMER, J. A., Perrine, K., Devinsky, O., Meador, K. 1996; 37 (6): 577-582

    Abstract

    To evaluate a brief questionnaire to screen aspects of health-related quality of life for persons with epilepsy.A study of 304 adults with epilepsy was undertaken at 25 seizure clinics in the United States. It was used for derivation of a brief screening tool from a longer instrument (QOLIE-89).The 10-item questionnaire (QOLIE-10) covers general and epilepsy-specific domains, grouped into three factors: Epilepsy Effects (memory, physical effects, and mental effects of medication), Mental Health (energy, depression, overall quality of life), and Role Functioning (seizure worry, work, driving, social limits). Scale scores were significantly different among seizure groups (p = 0.003).The QOLIE-10 can be completed by a patient in several minutes and reviewed rapidly by the physician. This screening tool could provide potentially useful information for initial assessment or follow-up of problem areas that are not commonly evaluated during routine clinical visits with patients with epilepsy.

    View details for Web of Science ID A1996UN42000012

    View details for PubMedID 8641236

  • Amobarbital evaluation of neurobehavioral function prior to therapeutic occlusion of brain arteriovenous malformations: a new neuropsychological procedure. Applied neuropsychology Lee, G. P., Meador, K. J., Murro, A. M., Bauzá-Armstrong, J. A., Loring, D. W., Gover, C. B., Drane, D. L. 1996; 3 (1): 1-7

    Abstract

    Because untreated arteriovenous malformations (AVMs) frequently result in some form of permanent neurological complication, treatment of AVMs is aggressively pursued A relatively new treatment consists of sending micropellets into blood vessels supplying the AVM core to block blood flow and "shrink" the AVM When vessels supplying the AVM are thought to also irrigate vital portions of brain, evaluations of neurobehavioral function after injection of amobarbital into intracranial vessels (Wada testing) may be performed to prevent significant complications folIowing embolization This study details our preliminary experience with Wada testing and electroencephalography (EEG) prior to AVM embolization in seven patients Neurobehavioral functions were continuously monitored after injection of 50-75 mg of amobarbital into target cerebral vessels No change in sensorimotor, cognitive, or EEG functions were detected in any of the superselective Wada examinations Embolization was performed following all negative Wada evaluations The only irreversible complication after embolization was a superior quadrantanopia No other permanent neurobehavioral sequelae resulted from embolization These preliminary findings suggest that simultaneous Wada/EEG monitoring may be useful in predicting neurobehavioral complications prior to AVM embolization.

    View details for PubMedID 16318539

  • DEVELOPMENT OF THE QUALITY-OF-LIFE IN EPILEPSY INVENTORY EPILEPSIA Devinsky, O., Vickrey, B. G., Cramer, J., Perrine, K., Hermann, B., Meador, K., Hays, R. D. 1995; 36 (11): 1089-1104

    Abstract

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

    View details for Web of Science ID A1995TC20300005

    View details for PubMedID 7588453

  • THE RELATIONSHIP OF NEUROPSYCHOLOGICAL FUNCTIONING TO QUALITY-OF-LIFE IN EPILEPSY ARCHIVES OF NEUROLOGY Perrine, K., Hermann, B. P., Meador, K. J., Vickrey, B. G., CRAMER, J. A., Hays, R. D., Devinsky, O. 1995; 52 (10): 997-1003

    Abstract

    To examine the relationship of objectively assessed cognitive functioning to self-reported quality of life.Correlational, multiple regression, and factor analytic comparisons of a new self-report quality of life inventory with neuropsychological tests of cognition and mood.Two hundred fifty-seven patients with epilepsy.Twenty-five epilepsy centers and neurology clinics across the United States.A recently developed self-report (ie, Quality of Life in Epilepsy-89 inventory) and objective tests of memory, verbal abilities, spatial functions, psychomotor and cognitive processing speed, cognitive flexibility, and mood.Factors that assessed mood, psychomotor speed, verbal memory, and language correlated significantly with selected scales of the Quality of Life in Epilepsy-89 inventory (P < .0001) and were predictive of overall quality of life (P < .002 to P < .0001). The mood factor showed the highest correlations (r = -.20 to r = -.73) and was the strongest predictor of quality of life in regression analyses (46.7% explained variance, P < .0001).Mood may be adversely affected by diminished quality of life, or perceived quality of life may be affected by mood disturbance. Quantitative quality of life assessments can be used in conjunction with formal neuropsychological testing of mood and cognition when evaluating patients with epilepsy.

    View details for Web of Science ID A1995RY60900010

    View details for PubMedID 7575228

  • COMPARATIVE COGNITIVE EFFECTS OF PHENOBARBITAL, PHENYTOIN, AND VALPROATE IN HEALTHY-ADULTS NEUROLOGY Meador, K. J., Loring, D. W., Moore, E. E., Thompson, W. O., Nichols, M. E., OBERZAN, R. E., DURKIN, M. W., GALLAGHER, B. B., King, D. W. 1995; 45 (8): 1494-1499

    Abstract

    The relative effects of antiepileptic drugs (AEDs) on cognition are controversial. We compared the cognitive effects of phenobarbital, phenytoin, and valproate in 59 healthy adults using a randomized, double-blind, incomplete-block, crossover design. Cognitive assessments were conducted at baseline, after 1 month on each drug (two AEDs per subject), and at two repeat baselines 11 weeks after each AED treatment. The neuropsychological battery included 12 tests, yielding 22 variables: Choice Reaction Time, P3 Event-Related Potential, Finger Tapping, Lafayette Grooved Pegboard, Selective Reminding Test, Paragraph Memory, Complex Figures, Symbol Digit Modalities Test, Stroop Test, Visual Serial Addition Test, Hopkins Symptom Checklist, and Profile of Mood States. More than one-half of the variables exhibited AED effects when compared with nondrug baselines, and all three AEDs produced some untoward effects. Differential AED effects on cognition were present for approximately one-third of the variables. Phenobarbital produced the worst performance; there was no clinically significant difference between phenytoin and valproate.

    View details for Web of Science ID A1995RP30400012

    View details for PubMedID 7644047

  • SYNERGISTIC ANTICHOLINERGIC AND ANTISEROTONERGIC EFFECTS IN HUMANS JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Meador, K. J., Loring, D. W., Hendrix, N., Nichols, M. E., OBERZAN, R., Moore, E. E. 1995; 17 (4): 611-621

    Abstract

    Animal research suggests an important interactive role for ascending cholinergic and serotonergic systems in modulation of cerebral function. Employing a randomized, double-blind, crossover design, 11 healthy young adults were tested in each of four conditions: (1) placebo, (2) fenfluramine (a serotonin depleting agent), (3) scopolamine (a muscarinic antagonist), and (4) fenfluramine and scopolamine. P3 latency was slowed by the dual drug treatment to an extent greater than the sum of individual drug effects. EEG mean frequency was decreased by behavioral activation, and this decrease was reversed by the combined drug treatment but not by single drugs. In contrast, verbal memory, EEG alpha power, and P3 amplitude were significantly affected only by scopolamine. No drug effects were found for the N1 and P2 potentials. The results provide the first demonstration of combined anticholinergic and antiserotonergic effects in humans, and offer partial support to the concept of an interactive role of cholinergic and serotonergic systems in cerebral mechanisms.

    View details for Web of Science ID A1995RQ80300010

    View details for PubMedID 7593479

  • A COMPARISON OF FRONTAL ELECTROMYOGRAPHIC BIOFEEDBACK TRAINING, TRAPEZIUS ELECTROMYOGRAPHIC BIOFEEDBACK TRAINING, AND PROGRESSIVE MUSCLE-RELAXATION THERAPY IN THE TREATMENT OF TENSION HEADACHE HEADACHE ARENA, J. G., BRUNO, G. M., Hannah, S. L., Meador, K. J. 1995; 35 (7): 411-419

    Abstract

    This study is the first systematic examination of a trapezius EMG biofeedback training regimen with tension headache sufferers. It evaluated the differential effects of three psychophysiological treatments for tension headache: (1) a standard 12-session frontal EMG biofeedback training regimen (n = 8), (2) a 12-session upper trapezius EMG biofeedback training regimen (n = 10), and (3) a standard seven-session progressive muscle relaxation therapy regimen (n = 8). Posttreatment assessment at 3 months following cessation of treatment revealed clinically significant decreases in overall headache activity (50% or greater) in 50% of subjects in the frontal biofeedback group, 100% in the trapezius biofeedback group, and 37.5% in the relaxation therapy group. Chi-squared analyses indicated that the trapezius biofeedback group was more effective in obtaining significant clinical improvement than the frontal biofeedback and relaxation therapy groups (which did not differ from each other). The three treatments did not differ on secondary measures of headache improvement (number of headache-free days, peak headache activity, and medication index). Implications for the psychophysiological treatment of tension headache, as well as future research directions, are discussed.

    View details for Web of Science ID A1995RM33500007

    View details for PubMedID 7672959

  • RELIABILITY OF AN AMBULATORY ELECTROMYOGRAPHIC ACTIVITY DEVICE FOR MUSCULOSKELETAL PAIN DISORDERS INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY ARENA, J. G., BRUNO, G. M., BRUCKS, A. G., Searle, J. R., Sherman, R. A., Meador, K. J. 1994; 17 (2): 153-157

    Abstract

    A number of investigators in recent years have called for the development of devices that can monitor surface EMG levels in individuals' normal environments for use with patients who suffer from disorders in which the etiology or maintenance of the pathology is presumed to be due at least in part to musculoskeletal dysfunction, such as low back pain, phantom limb pain and tension headache. This study examined the test-retest reliability of just such a device. Twenty-six healthy controls wore a lightweight (24 ounce) device which measured bilateral upper trapezius EMG, as well as peak and integral motion, for 5 consecutive days for up to 18 h each day. ANOVAs on the four measures revealed no difference between any of the four measures over the 5 days. Intra-class correlation coefficients for the two EMG variables across 5 days were both significant with alpha levels set at 0.01. The two EMG measures were highly correlated (r = 0.77); the two motion measures were also highly correlated (r = 0.60), but at a lower magnitude than EMG values; the relationship between EMG and motion was significant, but the magnitude of the between EMG motion correlations (0.26 and 0.35) were lower than the within EMG or motion ones. It was concluded that the test-retest reliability of the ambulatory monitoring device is within acceptable limits. Implications for the use of the device with musculoskeletal pain disorders--particularly headache--are discussed.

    View details for Web of Science ID A1994PC05900004

    View details for PubMedID 7995777

  • ELECTROMYOGRAPHIC BIOFEEDBACK TRAINING FOR TENSION HEADACHE IN THE ELDERLY - A PROSPECTIVE-STUDY BIOFEEDBACK AND SELF-REGULATION ARENA, J. G., Hannah, S. L., BRUNO, G. M., Meador, K. J. 1991; 16 (4): 379-390

    Abstract

    This study evaluated the effects of a 12-session frontal electromyographic biofeedback training regimen on the headache activity of eight tension headache sufferers aged 62 and older. The biofeedback sessions were slightly modified for a geriatric population, essentially to increase comprehension and retention of rationale and instructions. Post-treatment assessment at three months revealed significant decreases in overall headache activity (50% or greater) in 50% of the subjects, and moderate improvement (35%-45%) in three of the remaining four subjects. Significant clinical and/or statistical pre-post differences were also found for the number of headache-free days, peak headache activity, and medication index. This is the first prospective study of biofeedback training for tension headache in an elderly population and, unlike previous retrospective studies, suggests that such therapy may be an effective intervention in the treatment of tension headaches in the elderly.

    View details for Web of Science ID A1991GT54200005

    View details for PubMedID 1760459

  • Neuropsychological Performance in Hallervorden-Spatz Syndrome: A Report of Two Cases NEUROPSYCHOLOGY Loring, D. W., Sethi, K. D., Lee, G. P., Meador, K. J. 1990; 4 (3): 191-199

    View details for Web of Science ID 000209746600006

  • Revising the Rey-Osterrieth: rating right hemisphere recall. Archives of clinical neuropsychology Loring, D. W., Lee, G. P., Meador, K. J. 1988; 3 (3): 239-247

    Abstract

    Recall performance of the Rey-Osterrieth Complex Figure was examined in patients with partial complex seizures originating from either the right or left temporal lobe and who underwent subsequent unilateral temporal lobectomy. A scoring system was developed to assess the types of errors frequently observed in the recall of patients with right temporal lobe epilepsy (TLE), but absent in left TLE patients. The scoring system was initially developed on a single group of patients, and then "cross-validated" on an independent sample. Performance analysis of the cross-validation group revealed a significant difference in the frequency of right hemisphere errors. In contrast, no significant difference using standard quantitative scoring was present. By applying the new scoring criteria alone, a rater blind to seizure onset correctly predicted seizure laterality in 15/18 of the cross-validation patients. These results suggest that evaluation of qualitative errors may be a valuable adjunct to standard scoring criteria, thereby extending the range of applications for this test.

    View details for PubMedID 14589695

  • GRADED NEUROLOGIC SCALE FOR USE IN ACUTE HEMISPHERIC STROKE TREATMENT PROTOCOLS STROKE Adams, R. J., Meador, K. J., Sethi, K. D., Grotta, J. C., Thomson, D. S. 1987; 18 (3): 665-669

    Abstract

    A standardized neurologic assessment scoring instrument was developed and tested for use in a multicenter trial of hypervolemic hemodilution in acute hemispheric stroke. Components of the neurologic examination pertinent to hemispheric stroke syndromes were emphasized. The scale was evaluated using 16 acute stroke patients for concurrent validity (Pearson coefficient r = 0.89 compared with global assessments by neurologists or neurosurgeons) and interobserver reliability (r = 0.95 interobserver reliability estimate). Such a scale should prove useful in quantifying neurologic deficits in hemispheric stroke and in following changes in neurologic status during multicenter acute treatment protocols.

    View details for Web of Science ID A1987H714200023

    View details for PubMedID 3109080